192-IgG-SAP References

192-IgG-SAP (Cat. #IT-01)

805 entries found for : it-01

Long-term nucleus basalis cholinergic depletion induces attentional deficits and impacts cortical neurons and BDNF levels without affecting the NGF synthesis

Orciani C, Hall H, Pentz R, Foret MK, Do Carmo S, Cuello AC (2022) Long-term nucleus basalis cholinergic depletion induces attentional deficits and impacts cortical neurons and BDNF levels without affecting the NGF synthesis. J Neurochem doi: 10.1111/jnc.15683

Objective: To determine whether reciprocal interaction of basal forebrain cholinergic neurons (BFCN) impact neurotrophin availability and affect cortical neuronal markers.

Summary: There is a neuroprotective role of cholinergic neurotransmission in the adult, fully-differentiated cortex.

Usage: Immunolesioned BFCN projecting mainly to the cortex with 192-IgG-SAP (bilateral 0.5 ug/ul; 1.0 ul/hemisphere) in 2.5 month-old Wistar rats.

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Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer’s disease

Liu W, Li J, Yang M, Ke X, Dai Y, Lin H, Wang S, Chen L, Tao J (2022) Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer's disease. Alzheimers Res Ther 14(1):53. doi: 10.1186/s13195-022-00994-w

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Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats

Barros JFF, Sant'Ana AMS, Dias LC, Murashima AAB, Silva LECMD, Fantucci MZ, Rocha EM (2022) Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats. Arq Bras Oftalmol 85(1):59-67. doi: 10.5935/0004-2749.20220008

Summary: This study compared the changes in the lacrimal functional unit in the following two models of neurogenic dry eye syndrome: sensory denervation of the cornea versus autonomic denervation of the lacrimal gland.

Usage: Rats received 2.5 μg of 192-IgG-SAP (Cat. #IT-01) directly into the left extraorbital lacrimal gland.

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Perspective: Estrogen and the risk of cognitive decline: a missing choline(rgic) link?

Bortz J, Klatt KC, Wallace TC (2021) Perspective: Estrogen and the risk of cognitive decline: a missing choline(rgic) link?. Adv Nutr 13(2):376-387. doi: 10.1093/advances/nmab145

Objective: Explore the relationship between cognitive aging and sex hormones, the cholinergic system, and choline as an essential nutrient.

Summary: This perspective identifies numerous areas for future preclinical and clinical research, highlighting the need for randomized controlled trials in postmenopausal women to assess the impact of choline supplementation on cognitive decline, with appropriate consideration of the estrogen availability, critical windows, dose, and PEMT genotype.

Usage: The authors reference a publication about the effects of estrogen on cognitive improvements where 192-IgG-SAP was used as a specific cholinergic system lesioning tool.

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Intrahippocampal adeno-associated virus-mediated overexpression of nerve growth factor reverses 192IgG-saporin-induced impairments of hippocampal plasticity and behavior

Dobryakova YV, Spivak YS, Zaichenko MI, Koryagina AA, Markevich VA, Stepanichev MY, Bolshakov AP (2021) Intrahippocampal adeno-associated virus-mediated overexpression of nerve growth factor reverses 192IgG-saporin-induced impairments of hippocampal plasticity and behavior. Front Neurosci 15:745050. doi: 10.3389/fnins.2021.745050

Objective: Determine any beneficial effects of adeno-associated virus (AAV)-mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic loss.

Summary: 192-IgG-SAP was used to induce a rat animal model of cholinergic deficit. The authors concluded that NGF overexpression in the hippocampus after cholinergic loss induces beneficiall effects which are not related to maintenance of cholinergic function.

Usage: 1.5 mg of 192-IgG-SAP was injected into the medial septum area.

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Effects of age on sexually dimorphic food protection behavior associated with hippocampal cholinergic deafferentation.

Osterlund Oltmanns JR, Schaeffer EA, Blackwell AA, Pietrucha SA, Yang H, Tasi S, Kartje GL, Wallace D (2021) Effects of age on sexually dimorphic food protection behavior associated with hippocampal cholinergic deafferentation. Neuroscience 2021 Abstracts P210.07. Society for Neuroscience, Virtual.

Summary: Loss of hippocampal cholinergic projection originating from basal forebrain structures has been associated with the progression of Dementia of the Alzheimer’s Type. The role of these fibers in information processing deficits has been debated; however, spontaneous behaviors such as food protection have been observed to dissociate the contributions of hippocampal and cortical cholinergic function. Sexual dimorphism and age are critical factors in the progression of neurodegenerative disorders, yet these factors have not been evaluated in food protection behavior. The current study infused the immunotoxin 192-IgG-Saporin bilaterally into the medial septum to produce selective cholinergic deafferentation of the hippocampal formation. Female and male rats received infusion of the immunotoxin at either three or 18 months of age. Testing in the in the food protection paradigm began six weeks after the surgery. During the five days of testing, rats received two food protection sessions. Each of these sessions involved the rat (dodger) being placed in a transparent cylinder with a same sex conspecific (robber). The dodger was given a one-gram food item to consume, while the robber made multiple attempts to obtain the food item. The number, success rate, and type of food protection behaviors were recorded across all food protection sessions. Rats also received a third session each day in which the latency to consume the food item was recorded in the absence of the conspecific. Preliminary results indicate that sex and age interact with cholinergic hippocampal deafferentation to influence the organization of food protection behaviors. These observations establish a foundation for future work investigating novel therapeutic interventions that target neuroplasticity within spared cholinergic systems.

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Toxic substance-induced hippocampal neurodegeneration in rodents as model of Alzheimer’s dementia

Nurmasitoh T, Sari DCR, Susilowati R (2021) Toxic substance-induced hippocampal neurodegeneration in rodents as model of Alzheimer’s dementia. Open Access Maced J Med Sci [Internet] 9(F):523.

Summary: In this review, the authors discussed hippocampal neurodegeneration rodent animal models of Alzheimer’s Dementia and their induction via a toxic substance. Between 2016-2021, 80 studies were reported with 17 different modeling techniques mentioned.

Usage: 192-IgG-Saporin was referenced using intracerebroventricular injection (ICV) as the route of administration where the parameters studied included, neurotrophic factors, cholinergic activity and neuro-degeneration markers.

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Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders

Sałaciak K, Pytka K (2022) Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders. Neurosci Biobehav Rev 132:1114-1136. doi: 10.1016/j.neubiorev.2021.10.037

Objective: This review focuses on the sigma-1 receptor as a target for treatment of depression and cognitive disorders.

Summary: Sigma-1 receptor ligands, and predominantly agonists, might be the next generation of psychotherapeutic agents.

Usage: 192-IgG-SAP is listed as a neurotoxin that induced a memory impairment in rats based on the Morris water maze.

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Evaluation of the activity of choline acetyltransferase from different synaptosomal fractions at the distinct stages of spatial learning in the morris water maze

Storozheva ZI, Zakharova EI, Proshin AT (2021) Evaluation of the activity of choline acetyltransferase from different synaptosomal fractions at the distinct stages of spatial learning in the morris water maze. Front Behav Neurosci 15:755373. doi: 10.3389/fnbeh.2021.755373

Objective: To examine the role of hippocampal and cortical ACh in the acquisition, consolidation, storage, retention and adaptive flexibility of new, recent and remote memory traces in spatial learning models.

Summary: The application of functional ablation or stimulation techniques is necessary. The approach used can be regarded as one of the possible ways of delineating temporal stages of spatial learning and could be applied in the studies of other signalling pathways.

Usage: Selective loss of septohippocampal and/or corticopetal cholinergic projections has been shown to cause attention deficit.

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Heart failure impairs mood and memory in male rats and down-regulates the expression of numerous genes important for synaptic plasticity in related brain regions

Parent MB, Ferreira-Neto HC, Kruemmel AR, Althammer F, Patel AA, Keo S, Whitley KE, Cox DN, Stern JE (2021) Heart failure impairs mood and memory in male rats and down-regulates the expression of numerous genes important for synaptic plasticity in related brain regions. Behav Brain Res 414:113452. doi: 10.1016/j.bbr.2021.113452

Objective: To assess the effects of heart failure (HF) on genetic markers of synaptic plasticity in brain areas critical for memory and mood, and to assess the effects of severely reduced ejection fraction (≤40 %) on cognition regulation.

Summary: Collectively, the present findings provide support for the growing consensus that HF is not only a neurohumoral cardiovascular problem but is also a disorder of mood and memory.

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Overexpression of nerve growth factor in the hippocampus induces behavioral changes in rats with 192IgG-saporin-induced cholinergic deficit

Dobryakova YV, Zaichenko MI, Spivak YS, Stepanichev MY, Markevich VA, Bolshakov AP (2021) Overexpression of nerve growth factor in the hippocampus induces behavioral changes in rats with 192IgG-saporin-induced cholinergic deficit. Neurochem J 15:273-281. doi: 10.1134/S1819712421030028

Summary: Degeneration of septal cholinergic neurons caused by the immunotoxin 192-IgG-SAP produces a model of the pathological state that occurs in Alzheimer’s Disease. This study investigated whether overexpression of NGF in the hippocampus, where septal neurons send their projections, may reduce the consequences of this damage. Data suggest that NGF overexpression in the hippocampus of rats may partly compensate some 192 IgG-SAP-induced impairments related to cholinergic deficit.

Usage: 192-IgG-SAP or an equivalent volume of PBS (4 µg/site) was administered bilaterally into the ventricles.

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Neural circuitry underlying REM sleep: A review of the literature and current concepts

Wang YQ, Liu WY, Li L, Qu WM, Huang ZL (2021) Neural circuitry underlying REM sleep: A review of the literature and current concepts. Prog Neurobiol 204:102106. doi: 10.1016/j.pneurobio.2021.102106

Summary: To investigate the role of the LC in sleep the authors injected 0.3 µl of 192-Saporin (Cat. IT-01) or anti-DBH-SAP (Cat. #IT-03) at 1 µg/µl. They also used 0.3 µl of orexin-SAP (Cat. #IT-20) at either 90 ng/µl or 60 ng/µl in a separate group of animals. The results indicate that orexin innervation to the pons plays a role in arousal from sleep.

Related Products: Orexin-B-SAP (Cat. #IT-20), 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03)

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Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory

Soma S, Suematsu N, Sato AY, Tsunoda K, Bramian A, Reddy A, Takabatake K, Karube F, Fujiyama F, Shimegi S (2021) Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory. Neurobiol Learn Mem 183:107484. doi: 10.1016/j.nlm.2021.107484

Summary: The authors tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. The results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.

Usage: Cholinergic neurons of the nucleus basalis magnocellularis (NBM) were lesioned with 192-IgG-SAP. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. Saline with or without 192-IgG-SAP (0.3 μg in 1 μL, per site) was bilaterally injected into 2 sites of the NBM.

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Chemogenetic inhibition of prefrontal projection neurons constrains top-down control of attention in young but not aged rats

Duggan MR, Joshi S, Strupp J, Parikh V (2021) Chemogenetic inhibition of prefrontal projection neurons constrains top-down control of attention in young but not aged rats. Brain Struct Funct 226(7):2357-2373. doi: 10.1007/s00429-021-02336-2

Objective: To test the hypothesis that reduced PFC output would exert differential effects on attentional capacities in young and aged rats, with the latter exhibiting a more robust decline in performance.

Summary: There is a reduced efficiency of PFC-mediated top–down control of attention and cholinergic system in aging, and that activity of PFC output neurons does not reflect compensation in aged rats, at least in the attention domain.

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Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease

Barrett MJ, Murphy JM, Zhang J, Blair JC, Flanigan JL, Nawaz H, Dalrymple WA, Sperling SA, Patrie J, Druzgal TJ (2021) Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease. Parkinsonism Relat Disord 90:27-32. doi: 10.1016/j.parkreldis.2021.07.024

Summary: This study examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early Parkinson’s Disease.

See: Linster C et al. Selective Loss of Cholinergic Neurons Projecting to the Olfactory System Increases Perceptual Generalization Between Similar, but Not Dissimilar, Odorants. Behav Neurosci 115(4):826-833, 2001.

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Therapeutic agent delivery across the blood-brain barrier using focused ultrasound

McMahon D, O'Reilly MA, Hynynen K (2021) Therapeutic agent delivery across the blood-brain barrier using focused ultrasound. Annu Rev Biomed Eng 23:89-113. doi: 10.1146/annurev-bioeng-062117-121238

Summary: Review of the use of focused ultrasound, in combination with circulating microbubbles, can be used to transiently and noninvasively increase cerebrovascular permeability with a high level of spatial precision. For minutes to hours following sonication, drugs can be administered systemically to extravasate in the targeted brain regions and exert a therapeutic effect, after which permeability returns to baseline levels.

Usage: Shin et al. reported improved spatial memory following FUS+MB exposure in a rat model of cholinergic neuron degeneration. 192-IgG-SAP was injected bilaterally into the lateral ventricle (4  μl at a concentration of 0.63  μg/μl at a rate of 1 μl/min).

See: Shin J et al. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res Ther 11(1):110, 2019.

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The medial septum as a potential target for treating brain disorders associated with oscillopathies

Takeuchi Y, Nagy AJ, Barcsai L, Li Q, Ohsawa M, Mizuseki K, Berényi A (2021) The medial septum as a potential target for treating brain disorders associated with oscillopathies. Front Neural Circuits 15:701080. doi: 10.3389/fncir.2021.701080

Summary: The medial septum (MS) may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders.

Usage: 192-IgG-SAP. The MS cholinergic neurons along with theta oscillations are known to be essential for memory because selective lesion of the cholinergic neurons resulted in spatial memory impairments (150 ng; Easton et al., 2011) (5.04 μg icv; Jeong et al., 2014). Orexin-SAP. The enhanced gamma oscillations and altered PPI and auditory gating created by psychoactive drugs in rats were mediated by GABAergic neurons in the MS because they were abolished by ablation of these neurons by Orexin-SAP (140 ng total bilateral; Ma et al., 2012). mu p75-SAP. Anxious environment-induced type 2 theta oscillation and associated anxiety were shown to be dependent on the MS cholinergic neurons because lesion of MS cholinergic neurons reduced them (0.65 or 1.3 µg, bilateral; Nag et al., 2009).

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16), Orexin-B-SAP (Cat. #IT-20)

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Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071

Kucinski A, Sarter M (2021) Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071. Psychopharmacology (Berl) 238(7):1953-1964. doi: 10.1007/s00213-021-05822-x

Summary: In addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. The muscarinic M1-positive allosteric modulator (PAM) TAK-071 improves the attentional performance of rats with BF cholinergic losses. The authors previously developed a rodent model of PD falls by demonstrating that rats with dual basal forebrain cholinergic and mediodorsal striatal dopamine losses (“DL rats”) exhibit a heightened fall rate when required to traverse dynamic surfaces. This study tested the hypothesis that TAK-071 reduces fall rates in DL rats.

Usage: Rats received bilateral infusions of 192-IgG-SAP (200 ng/μL; 0.8 μL/hemisphere) or an equal volume of artificial cerebral spinal fluid into the nucleus basalis and substantia innominata of the basal forebrain.

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Neurotoxic effects, mechanisms, and outcome of 192 IgG-Saporin lesions.

Petrosini L, De Bartolo P, Cutuli D (2021) Neurotoxic effects, mechanisms, and outcome of 192 IgG-Saporin lesions. RM Kostrzewa (Ed.): Handbook of Neurotoxicity . Springer, Cham doi: 10.1007/978-3-030-71519-9_79-1

Summary: 192-IgG-saporin selectively destroys basal forebrain cholinergic neurons that provide cholinergic input to the hippocampus, entire cortical mantle, amygdala, and olfactory bulb. Immunotoxic lesions by 192-IgG-saporin represent a valid animal model of Alzheimer’s disease, given the degeneration of basal cholinergic system present in this pathology. The selective lesioning of cholinergic innervation by means of 192-IgG-saporin (injected i.p. or i.c.v.) is able to interfere with experience-dependent plasticity.

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Specific phospholipid modulation by muscarinic signaling in a rat lesion model of Alzheimer’s disease

Llorente-Ovejero A, Martínez-Gardeazabal J, Moreno-Rodríguez M, Lombardero L, González de San Román E, Manuel I, Giralt MT, Rodríguez-Puertas R (2021) Specific phospholipid modulation by muscarinic signaling in a rat lesion model of Alzheimer's disease. ACS Chem Neurosci 12(12):2167-2181. doi: 10.1021/acschemneuro.1c00169

Objective: To evaluate the lipid composition and muscarinic signaling in brain areas related to cognitive processes.

Summary: Using a rat model of BFCN lesion, this study evaluated the lipid composition and muscarinic signaling in brain areas related to cognitive processes. Results suggest that the modulation of specific lipid metabolic routes could represent an alternative therapeutic strategy to potentiate cholinergic neurotransmission and preserve cell membrane integrity in AD.

Usage: 192-IgG-SAP was dissolved in aCSF under aseptic conditions to a final concentration of 130 ng/ml. aCSF or 192-IgG-SAP was bilaterally injected (1 ml/hemisphere) at a constant rate of 0.2 ml/min. to selectively eliminate BFCN in the NBM.

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Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data

Nazmuddin M, Philippens IHCHM, van Laar T (2021) Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data. Sci Rep 11(1):11751. doi: 10.1038/s41598-021-91391-0

Objective: Review the design of stimulation experiments on the nucleus basalis of Meynert (NBM) and its effects on behavioral and neurophysiological aspects.

Summary: Deep brain stimulation (DBS) of the NBM (nucleus basalis of Meynert) in animal studies and the effects on behavioral and neurophysiological aspects are systematically reviewed. Translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, and most animals were stimulated unilaterally. Lee et al. (2016) addressed both of these issues using 192-IgG-SAP to lesion the NBM, which was stimulated thereafter.

Usage: Lee et al. lesioned the basal forebrain of rats through bilateral injections totaling 5 μg of 192-IgG-SAP into the lateral ventricle.

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Forebrain cholinergic plasticity in rats with chronic epilepsy induced by status epilepticus

da Costa C, Soares JI, Lukoyanov NV (2021) Forebrain cholinergic plasticity in rats with chronic epilepsy induced by status epilepticus. . 14th U.PORTO Young Researchers Meeting

Summary: This poster had the following aims: 1) Evaluate the GABAergic population in the MS/DB in a chronic epilepsy model of kainic acid (KA)-treated rats. 2) Assess the GABAergic and cholinergic interconnectivity in the MS/DB in a chronic epilepsy model of kainic acid (KA)-treated rats. Results showed that outcomes were improved in rats receiving 192-IgG-SAP treatment as compared to Sham. Mortality: Sham - 50%; SAP - 0%.Recurrent motor seizures: Sham - 83%; SAP - 40%. Recurrent motor + EEG seizures: Sham - 100%; SAP - 50%.

Usage: 192-IgG-SAP was used to produce a moderate, but significant loss of septohippocampal cholinergic cells and to suppress their plasticity.

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Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions

Madrid LI, Jimenez-Martin J, Coulson EJ, Jhaveri DJ (2021) Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions. Int J Biochem Cell Biol 134:105969. doi: 10.1016/j.biocel.2021.105969

Summary: In this review, the authors appraise the evidence linking the contribution of cholinergic signalling to the regulation of adult hippocampal neurogenesis and hippocampus-dependent functions.

Usage: A hallmark feature of all basal forebrain cholinergic neurons is the expression of high levels of the p75 neurotrophin receptor which can be precisely targeted using 192-IgG-SAP. Administration of 192-IgG-SAP (icv, 2.5 µg, Mohapel et al., 2005) resulted in significant impairment in adult hippocampal neurogenesis in rats. In contrast, a study which lesioned MS cholinergic neurons in mice reported no effect on baseline proliferation in the hippocampus. Mice received 3.6 µg of mu p75-SAP into each lateral ventricle (Ho et al., 2009). Although the number of surviving neurons was similar in both lesioned and control animals, most of the progenitor cells in the lesioned animals could not survive without cholinergic input.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

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Placenta: A gold mine for translational research and regenerative medicine

Pethe P, Kale V (2021) Placenta: A gold mine for translational research and regenerative medicine. Reprod Biol 21(2):100508. doi: 10.1016/j.repbio.2021.100508

Objective: To review recent studies regarding the therapeutic potential of human placenta-derived mesenchymal stromal/stem cells (hPMSCs) and their extracellular vesicles (EVs).

Summary: These studies demonstrate salutary effects of hPMSC-EVs on a range of different difficult-to-treat conditions like Duchenne Muscular Dystrophy, Parkinson's disease, acute kidney injury, etc., and therefore, it is imperative that these leads should be taken forward to clinical trials.

Usage: 8 µL of 192 IgG-saporin (0.63 µg/µL) were bilaterally injected into the ventricle to induce a dementia rat model.

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Cholinergic signaling, neural excitability, and epilepsy

Wang Y, Tan B, Wang Y, Chen Z (2021) Cholinergic signaling, neural excitability, and epilepsy. Molecules 26(8):2258. doi: 10.3390/molecules26082258

Summary: In this review, the authors briefly describe the distribution of cholinergic neurons, muscarinic, and nicotinic receptors in the central nervous system and their relationship with neural excitability and epilepsy. intraventricular administration of 192-IgG-SAP, which inhibits cholinergic projection to the hippocampus and cortex respectively, facilitates seizure induced by amygdala kindling

Usage: Ferencz et al. used 192-IgG-SAP (2.5 μg icv) to investigate the effect of eliminating cholinergic projections to the hippocampal formation and cerebral cortex on the induction of epilepsy through electrical stimulation of the rat brain. They determined that the loss of specific projections to the amygdala accelerates development of seizures.

See: Ferencz I et al. Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats. Eur J Neurosci 12:2107-2116, 2000.

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Medial parabrachial nucleus is essential in controlling wakefulness in rats

Xu Q, Wang DR, Dong H, Chen L, Lu J, Lazarus M, Cherasse Y, Chen GH, Qu WM, Huang ZL (2021) Medial parabrachial nucleus is essential in controlling wakefulness in rats. Front Neurosci 15:645877. doi: 10.3389/fnins.2021.645877

Summary: Lesions of the LC with 192-IgG-SAP have no significant effect on wakefulness in rats (Blanco-Centurion et al.). Only the Orexin-SAP lesion involved in the MPB region resulted in the dramatic decrease of wakefulness in rats (Fuller et al.).

Related Products: 192-IgG-SAP (Cat. #IT-01), Orexin-B-SAP (Cat. #IT-20)

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Preferential neuronal responses to snakes in the monkey medial prefrontal cortex support an evolutionary origin for ophidiophobia

Dinh HT, Nishimaru H, Le QV, Matsumoto J, Setogawa T, Maior RS, Tomaz C, Ono T, Nishijo H (2021) Preferential neuronal responses to snakes in the monkey medial prefrontal cortex support an evolutionary origin for ophidiophobia. Front Behav Neurosci 15:653250. doi: 10.3389/fnbeh.2021.653250

Summary: Ophidiophobia (snake phobia) is one of the most common specific phobias. Noninvasive imaging studies of patients with specific phobia reported that the medial prefrontal cortex (mPFC), especially the rostral part of the anterior cingulate cortex (rACC), and amygdala are activated during the presentation of phobogenic stimuli. Attentional bias to specific animals promotes anxiety and phobia. The mPFC is reported to be involved in attentional allocation to various salient visual stimuli. The findings suggest that the rACC focuses attention on snakes, and promotes aversive conditioning to snakes, which may lead to anxiety and ophidiophobia.

Usage: Prior work has demonstrated that lesions of the cortical cholinergic system of the basal forebrain impair performance in attentional tasks. 192-IgG-SAP (50 or 100 ng) was infused into the PFC of rats.

See: Dalley JW et al. Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-Saporin-induced lesions of the medial prefrontal cortex. Cereb Cortex 14(8):922-932, 2004.

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Nanobody: a small antibody with big implications for tumor therapeutic strategy

Sun S, Ding Z, Yang X, Zhao X, Zhao M, Gao L, Chen Q, Xie S, Liu A, Yin S, Xu Z, Lu X (2021) Nanobody: a small antibody with big implications for tumor therapeutic strategy. Int J Nanomedicine 16:2337-2356. doi: 10.2147/IJN.S297631

Summary: This Journal Club commentary focuses on the publication by Kalinchuk et al.

Usage: The author refers to work with 192-IgG-SAP published by Blanco-Centurion et al. This group investigated whether basal forebrain cholinergic neurons are involved in adenosine regulation of sleep. 6 µg of 192-IgG-SAP was administered to the lateral ventricle of rats.

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Fluoxetine and ketamine reverse the depressive but not anxiety behavior induced by lesion of cholinergic neurons in the horizontal limb of the diagonal band of broca in male rat

Chen L, Ke Y, Ma H, Gao L, Zhou Y, Zhu H, Liu H, Zhang F, Zhou W (2021) Fluoxetine and ketamine reverse the depressive but not anxiety behavior induced by lesion of cholinergic neurons in the horizontal limb of the diagonal band of broca in male rat. Front Behav Neurosci 15:602708. doi: 10.3389/fnbeh.2021.602708

Summary: A lesion of horizontal limb of the diagonal band of Broca (HDB) cholinergic neurons and followed hippocampus damage may be involved in the pathogenesis of depression.

Usage: Injections of 192-IgG-SAP were made bilaterally into the HDB in a volume of 0.5 µL per side with a concentration of 0.5 µg/µL.

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Disruption of basal forebrain cholinergic neurons after traumatic brain injury does not compromise environmental enrichment-mediated cognitive benefits.

Moschonas EH, Leary JB, Memarzadeh K, Bou-Abboud CE, Folweiler KA, Monaco CM, Bondi CO (2021) Disruption of basal forebrain cholinergic neurons after traumatic brain injury does not compromise environmental enrichment-mediated cognitive benefits. Brain Res 1751:147175. doi: 10.1016/j.brainres.2020.147175

Objective: To determine if basal forebrain cholinergic neurons are important mediators of environmental enrichment (EE)-induced benefits after traumatic brain injury.

Summary: These data show that despite significant medial septal ChAT+ cell loss, the EE-mediated benefit in cognitive recovery is not compromised.

Usage: 0.22 μg/1.0 μL 192-IgG-SAP was infused over 5 min at a rate of 0.2 μL/min.

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Lesions of the nucleus basalis magnocellularis (Meynert) induce enhanced somatosensory responses and tactile hypersensitivity in rats.

Dezawa S, Nagasaka K, Watanabe Y, Takashima I (2021) Lesions of the nucleus basalis magnocellularis (Meynert) induce enhanced somatosensory responses and tactile hypersensitivity in rats. Exp Neurol 335:113493. doi: 10.1016/j.expneurol.2020.113493

Summary: The authors used 192-IgG-SAP to produce a selective cholinergic lesion in the nucleus basalis of Meynert (NBM) of rats and investigated whether the NBM lesion led to tactile hypersensitivity in the forepaw. Results suggest that neuronal loss in the NBM diminishes acetylcholine actions in the S1, thereby enhancing the cortical representation of sensory stimuli, which may in turn lead to behavioral hypersensitivity.

Usage: The lesion group received injection of 0.3 μL of 192-IgG-SAP into the left nucleus basalis of Meynert (NBM).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Aberrant functional connectivity of basal forebrain subregions with cholinergic system in short-term and chronic insomnia disorder

Ma X, Fu S, Yin Y, Wu Y, Wang T, Xu G, Liu M, Xu Y, Tian J, Jiang G (2021) Aberrant functional connectivity of basal forebrain subregions with cholinergic system in short-term and chronic insomnia disorder. J Affect Disord 278:481-487. doi: 10.1016/j.jad.2020.09.103

Summary: Previous animal studies have identified the cholinergic basal forebrain (CBF) as a crucial structure in sleep-wake cycle modulation and lesion or inactivation of the BF has been found to increase delta electroencephalogram activity, disturb behavioral arousal, and reduce sleep. They reference Kaur et al. using 192-IgG-SAP to lesion the CBF to examine the role of these neurons in sleep behavior.

See: Kaur S et al. Effects of ibotenate and 192IgG-saporin lesions of the nucleus basalis magnocellularis/substantia innominata on spontaneous sleep and wake states and on recovery sleep after sleep deprivation in rats. J Neurosci 28:491-504, 2008.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Measuring attention in rats with a visual signal detection task: Signal intensity vs. signal duration

Holloway Z, Koburov R, Hawkey A, Levin ED (2020) Measuring attention in rats with a visual signal detection task: Signal intensity vs. signal duration. Pharmacol Biochem Behav 199:173069. doi: 10.1016/j.pbb.2020.173069

Summary: Drug-induced effects have been used to demonstrate the construct validity of operant attention tasks, as well as to assess the pharmacological systems that underlie cognitive processes, such as attention, short-term memory and reaction time, either by interrupting or enhancing performance.

See: McGaughy J et al. Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112(6):1519-1525, 1998.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Extracellular levels of the sleep homeostasis mediator, adenosine, are regulated by glutamatergic neurons during wakefulness and sleep

Sun MJ, Tang Y (2020) Extracellular levels of the sleep homeostasis mediator, adenosine, are regulated by glutamatergic neurons during wakefulness and sleep. Purinergic Signal 16(4):475-476. doi: 10.1007/s11302-020-09758-3

Summary: Blanco-Centurion et al. investigated the role of cholinergic neurons in the BF by administering 192–IgG–SAP to lesion them, but surprisingly the results indicated that adenosine from cholinergic neurons in BF are not essential to sleep induction.

See: Blanco-Centurion C et al. Adenosine and sleep homeostasis in the Basal forebrain. J Neurosci 26(31):8092-8100, 2006.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Characterizing the neural substrate of reward with the use of specific brain lesions

Cromwell HC (2021) Characterizing the neural substrate of reward with the use of specific brain lesions. Fakhoury M (Ed.): The Brain Reward System. Neuromethods. 165. Humana, New York, NY doi: 10.1007/978-1-0716-1146-3_3

Summary: This review is focused on experimental lesions and work using the rodent model examining the neural substrates of reward processing. Saporin is listed as a neurotoxin used to target selective neuronal populations with success.

See: Pappas BA et al. Neonatal 192 IgG-saporin lesion of forebrain cholinergic neurons: focus on the life span?. Neurosci Biobehav Rev 27(4):365-376, 2003.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Long-term potentiation in the hippocampal CA3 to CA1 synapses may be induced in vivo by activation of septal cholinergic inputs.

Dobryakova YV, Stepanichev MY, Markevich VA, Bolshakov AP (2020) Long-term potentiation in the hippocampal CA3 to CA1 synapses may be induced in vivo by activation of septal cholinergic inputs. Int J Neurosci 23:1-7. doi: 10.1080/00207454.2020.1822834

Objective: To clarify the role of septal input in the development of long-term potentiation (LTP) in this synapse.

Summary: Elimination of septal cholinergic neurons by 192-IgG-SAP abolished LTP development in both experimental series. This suppression of LTP in animals with a cholinergic deficit was not due to loss of hippocampal neurons.

Usage: Rats received intraseptal injections of 192-IgG-SAP (1.5 μg).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Evaluation of the adverse effects of chronic exposure to donepezil (an acetylcholinesterase inhibitor) in adult zebrafish by behavioral and biochemical assessments.

Audira G, Ngoc Anh NT, Ngoc Hieu BT, Malhotra N, Siregar P, Villalobos O, Villaflores OB, Ger TR, Huang JC, Chen KH, Hsiao CD (2020) Evaluation of the adverse effects of chronic exposure to donepezil (an acetylcholinesterase inhibitor) in adult zebrafish by behavioral and biochemical assessments. Biomolecules 10(9):1340. doi: 10.3390/biom10091340

Objective: The authors use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays.

Summary: Chronic waterborne exposure to donepezil (DPZ) can severely induce adverse effects on normal zebrafish in a dose-dependent manner.

See: Cutuli D et al. Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res Ther 5(5):50, 2013.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Identification of multiple targets in the fight against Alzheimer’s disease

Giannoni P, Fossati S, Claeysen S, Marcello E, eds (2020) Identification of multiple targets in the fight against Alzheimer’s disease. Front Aging Neurosci 12:169. doi: 10.3389/fnagi.2020.00169

Summary: A collection of 20 articles that depict a broad representation of the most impactful advances in Alzheimer’s disease (AD) comprehension and therapeutic openings.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

Acetylcholine and spontaneous recognition memory in rodents and primates.

Easton A, Barros M, Lever C (2020) Acetylcholine and spontaneous recognition memory in rodents and primates. Curr Top Behav Neurosci 45:29-45. doi: 10.1007/7854_2020_132

Summary: Review of lesioning designed to specifically target cells that express acetylcholine as a transmitter.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic signaling dynamics and cognitive control of attention.

Parikh V, Bangasser DA (2020) Cholinergic signaling dynamics and cognitive control of attention. Shoaib M., Wallace T (Ed.): Behavioral Pharmacology of the Cholinergic System. Current Topics in Behavioral Neurosciences. 45:71-87. Springer, Cham doi: 10.1007/7854_2020_133

Summary: A plethora of studies conducted in rodents demonstrated that selective lesions of BF cholinergic neurons and their cortical inputs produced by the immunotoxin 192-IgG-SAP impair performance in various tasks of attention.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Intracerebroventricular administration of 192IgG-saporin alters the state of microglia in the neocortex.

Volobueva MN, Dobryakova YV, Manolova AO, Stepanichev MY, Kvichansky AA, Gulyaeva NV, Markevich VA, Bolshakov AP (2020) Intracerebroventricular administration of 192IgG-saporin alters the state of microglia in the neocortex. Neurochem J 14(1):37-42. doi: 10.1134/S1819712420010213

Objective: The effect of intracerebroventricular (icv) immunotoxin administration on the state of microglia in tissues adjacent to the ventricle (striatum and parietal cortex) and remotely located but receiving innervation from the medial septal region and diagonal band of Broca (entorhinal cortex and olfactory bulbs).

Summary: 1.5 months after the administration of immunotoxin, microglia are activated only in the neocortical areas, not in the striatum or olfactory bulbs.

Usage: Injected bilaterally at a dose of 4 μg in each ventricle.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model.

Shin J, Kong C, Lee J, Choi BY, Sim J, Koh CS, Park M, Na YC, Suh SW, Chang WS, Chang JW (2019) Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res Ther 11(1):110. doi: 10.1186/s13195-019-0569-x

Objective: To investigate the decrease of adult hippocampal neurogenesis (AHN) in Alzheimer’s disease (AD).

Summary: This work studied the effect of FUS on AHN in a cholinergic degeneration rat model of dementia.

Usage: 192-IgG-SAP was injected bilaterally into the lateral ventricle (4 μl at a concentration of 0.63 μg/μl at a rate of 1 μl/min).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effect of medial septal selective and non selective lesions on exploratory behavior and recognition memory

Kruashvili L, Beselia G, Chkhikvishvili N (2019) Effect of medial septal selective and non selective lesions on exploratory behavior and recognition memory. Neuroscience 2019 Abstracts 336.01. Society for Neuroscience, Chicago, IL.

Summary: Investigation of cholinergic system and memory interaction has especially become the object of scientific attention due to the clinical and experimental data, in which the severity of dementia in Alzheimer's disease (AD) was found to have a positive correlation with the extent of the cholinergic loss. The septum is connected to the hippocampus via the fimbria-fomix, which carries projections from the medial septum (MS), and the vertical limb of the diagonal band of Broca. These projections are predominantly cholinergic and GABAergic. Lesions of the fimbria-fomix, or electrolytic lesions of the MS, impair hippocampal- dependent learning and memory. The purpose of this study was to investigate ability to acquire and use spatial (or non-spatial) information as well as to habituate exploratory activity over time in sham-operated, electrolytic, neuro or immunotoxic MS lesioned rats. Methods: A total of 39 male rats were used. For electrolytic lesions a stainless steel was inserted in the MS. All injections were performed stereotaxically. Rats were individually given five 3-min sessions in the open field. All experiments were approved by the Animal Care and Use Committee of the Center and were in accordance with the principles of laboratory animal care. Results: Examination of the AChE stained sections showed that after injections of 192 IgG saporin into the MS, animals exhibited significantly less AChE staining in MS and hippocampus as compared to sections obtained from control animals. The MS electrolytic and ibotenic acid lesioned rats showed an increase in their exploratory activity to the objects and were impaired in habituating to the objects in the repeated spatial environment, rats with immunolesions of the MS did not differ from control rats. Electrolytic lesions of the MS disrupt spatial recognition memory, rats with immuno- or neurotoxic lesions of the MS were normal in detecting spatial novelty. The MS lesioned and control rats clearly reacted to the object novelty by exploring the new object more than familiar ones. Conclusions: MS is sufficient for spatial recognition, but is not sufficient for object recognition memory, the selective loss of septohippocampal cholinergic or noncholinergic projections does not disrupt the function of the hippocampus to a suffi cient extent to impair spatial recognition memory. Therefore, the present study demonstrates dissociation between the two major components (cholinergic and noncholinergic) of the septohippocampal pathway in exploratory behavior assessed in the open field.

Related Products: 192-IgG-SAP (Cat. #IT-01)

How to stimulate: Basal forebrain DBS parameters to restore the attentional performance of rats with cholinergic losses

Nazmuddin M, Rao HA, Van Laar T, Sarter MF (2019) How to stimulate: Basal forebrain DBS parameters to restore the attentional performance of rats with cholinergic losses. Neuroscience 2019 Abstracts 377.10. Society for Neuroscience, Chicago, IL.

Summary: The degeneration of basal forebrain (BF) cholinergic neurons is an index of the severity of cognitive impairment in Alzheimer disease (AD) and Parkinson’s disease (PD). Moreover, in PD patients, gait and balancing deficits, and an increased propensity for falls have been attributed to cholinergic losses. Thus, Deep Brain Stimulation (DBS) of the BF has been considered a potential therapeutic intervention to improve cognition and movement control in these patients. However, efficacy of BF DBS in clinical populations has yet to be conclusively demonstrated. Likewise, the demonstration of beneficial effects of BF DBS in rodent models has been hampered by uncertainties about useful animal models and behavioral tasks and, importantly, a lack of consensus concerning DBS parameters (duration, frequency, current, intermittent versus continuous, prior and/or during task, etc.). Here we assessed various DBS parameters in rats with a partial loss of the cortical cholinergic input system. In rats, such cholinergic losses have been frequently demonstrated to impair the detection of cues during the performance of a Sustained Attention Task (SAT) and to attenuate performance recovery following a distractor challenge (dSAT). In PD patients with cholinergic losses, attentional impairments were also attributed to cortical and thalamic cholinergic losses (Kim et al., 2017). The attribution of SAT impairments to cholinergic losses is consistent with evidence showing that the detection of cues and associated attentional control parameters depend on cortical cholinergic signaling (e.g., Howe et al., 2017). Here, rats acquired the SAT, received infusions of the cholino-specific neurotoxin 192-IgG-saporin into the BF, and were implanted bilaterally with BF unipolar stimulation electrodes. Initial DBS parameters consisted of continuous high (130 Hz) versus low (20 Hz) frequency stimulation, intermittent (20-s ON at 80 Hz and 40-s OFF) stimulation, with pulse width and amplitude kept constant at 100 µs and 100 µA, respectively. We first assessed the effects of these DBS parameters on the behavior of rats in an open field space and then when administered during, or only prior to (for 1 hr), SAT and dSAT performance. Ongoing experiments indicate that these stimulation parameters are well tolerated as indicated by the absence of effects on locomotor and exploratory activity. We predict that BF DBS will be particularly effective in restoring attentional performance in the dSAT condition. If confirmed, this finding will suggest that demonstration of efficacy in patients will require measures indicating their attentional capacities in response to taxing performance challenges.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effects of an orexin-2 receptor agonist on attention in rats following loss of cortical cholinergic projections

Blumenthal SA, Maness EBL, Fadel JR, Burk JA (2019) Effects of an orexin-2 receptor agonist on attention in rats following loss of cortical cholinergic projections. Neuroscience 2019 Abstracts 418.06. Society for Neuroscience, Chicago, IL.

Summary: Deterioration to the basal forebrain cholinergic system (BFCS) is linked to age-related cognitive impairment, specifically to the pathology of Alzheimer’s disease (AD). Animals with BFCS damage perform poorly on learning, memory, and attention tasks, indicating cognitive deficits. The orexin neuropeptide system, comprised of two neuropeptides (orexin A and orexin B), has also been implicated in the cognitive decline associated with aging, likely due to the role of orexins in promoting attention. Two orexin receptor subtypes exist, orexin 1 (Ox1R) and orexin 2 (Ox2R). Studies have examined the effects of stimulation and blockage of both receptors together and Ox1R alone on attention; but no studies have examined the role of Ox2Rs in attention through the use of Ox2R agonists. Ox2Rs may be implicated in attentional processes and the loss of orexin neurons seen in age-related cognitive decline. In order to examine the role of Ox2Rs in attention following BFCS deterioration, the present study administered the Ox2R agonist, YNT-185, to rats given intrabasalis infusions of either saline (n = 12) or 192 IgG saporin (n=11), an immunotoxin which selectively destroys the BFCS. Animals received infusions of YNT-185 to the lateral ventricle (LV) in doses of 0, 1, 10, and 100nM across four separate sessions and performance was then assessed on a sustained attention task requiring discrimination between signal and non-signal trials through lever presses. The 100nM dose of YNT-185 improved attentional performance, as compared to the 0nM dose, for rats given the immunotoxin, but worsened performance for rats given saline lesions. YNT-185 may be efficacious in aiding attentional function in animals with vulnerable cholinergic systems but may lead to overexcitation for those with intact cholinergic function.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Dissociable attentional effects of dopaminergic and cholinergic lesions to the anterior cingulate cortex

Clement MK, Pimentel CS, Swaine JA, Pimentel AJ, Hutchins D, McGaughy JA (2019) Dissociable attentional effects of dopaminergic and cholinergic lesions to the anterior cingulate cortex. Neuroscience 2019 Abstracts 418.11. Society for Neuroscience, Chicago, IL.

Summary: Prior work from our lab has shown that excitotoxic lesions to the anterior cingulate cortex (ACC) impairs the ability of rats to filter certain types of distracting stimuli (Newman and McGaughy 2011). Specifically, rats with lesions of the ACC cannot filter distractors that have been made salient through pairing with reinforcement. In contrast, these same subjects can filter distracting stimuli that have not been predictive of reward. The present study investigates the effects of neuromodulator specific lesions of the same region to determine how specific neuromodulators contribute to the attentional function of ACC. Cholinergic or dopaminergic deafferentation of the ACC was achieved using either 192 IgG saporin (n=10) or dopamine transporter saporin (n=10). Lesions were restricted to the rostral portion of the area and did not spread to nearby prefrontal sub-regions e.g prelimbic cortex. After lesioning, subjects were tested in an attentional set-shifting task (Birrell and Brown 2000). While both cholinergic and dopaminergic lesions increased distractibility, these deficits were not as severe as those produced after excitotoxic lesions (n= 8). In contrast to excitotoxic lesions, both cholinergic and dopaminergic lesions also impeded formation of an attentional set. Because dopaminergic lesions produced impairments in many stages of the tasks, we hypothesized that these subjects had a more general impairment in stimulus processing. In order to address these broader processing impairments, we analyzed the data to determine whether lesioned rats showed more sensitivity to novel stimuli, or made more perseverative errors. The implications of these data for understanding the unique contributions of acetylcholine and dopamine to attentional processing in the ACC will be discussed.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DAT-SAP (Cat. #IT-25)

Medial septum cholinergic signaling regulates gastrointestinal-derived vagus sensory nerve communication to the hippocampus

Suarez AN, Liu CM, Cortella AM, Noble EN, Kanoski SE (2019) Medial septum cholinergic signaling regulates gastrointestinal-derived vagus sensory nerve communication to the hippocampus. Neuroscience 2019 Abstracts 601.19. Society for Neuroscience, Chicago, IL.

Summary: The vagus nerve delivers bi-directional communication between feeding-relevant gastrointestinal (GI) signals and the brain. Vagal sensory-mediated GI satiation signals, including gastric distension and intra-gastric nutrient infusion, activate neurons in the hippocampus (HPC). Recent work from our lab revealed that selective GI-derived vagal sensory signaling is required for HPC-dependent episodic and visuospatial memory, effects accompanied by reduced dorsal HPC (dHPC) expression of neurotrophic and neurogenic markers. To investigate the neural pathways mediating gut regulation of hippocampal-dependent memory, here we investigate the hypothesis that GI-derived signals communicate to dHPC neurons via cholinergic input from the medial septum, a memory-promoting pathway that is vulnerable to disruption in various degenerative dementia diseases. To explore this putative gut-to-brain pathway, we administered 192IgG-saporin, a neurotoxin that selectively kills cholinergic neurons via apoptosis, in the medial septum to determine whether septal cholinergic neurons regulate vagally-mediated neuronal activation in dHPC. Results revealed that elimination of cholinergic neurons in the MS reduced peripherally-administered cholecystokinin (CCK)-induced c-Fos expression in the dHPC, suggesting that cholinergic inputs from the MS transmit GI-derived signaling to the dHPC. Consistent with this interpretation, dHPC protein expression of vesicular acetylcholine transporter (VAChT), which promotes memory function and acetylcholine release without disrupting other co- released molecules, was significantly reduced in rats with GI-specific vagal sensory ablation via nodose ganglion injections of CCK conjugated to saporin. Collectively these results suggest that GI-derived vagal sensory signaling infuences memory function via enhancement of MS cholinergic signaling to the dPHC.

Related Products: 192-IgG-SAP (Cat. #IT-01), CCK-SAP (Cat. #IT-31)

The role of subcortical hippocampal inputs in contextual memory formation

Grayson VS, Han Y, Guedea AL, Jovasevic V, Gao C, Apkarian A, Radulovic JM (2019) The role of subcortical hippocampal inputs in contextual memory formation. Neuroscience 2019 Abstracts 786.03. Society for Neuroscience, Chicago, IL.

Summary: The role of cortical efferents to the hippocampus in the formation of episodic-like memory is well established, however, less is known about the contribution of subcortical memory circuits to memory. In the present study, we studied the roles of several subcortical inputs into the dorsal hippocampus in mouse models of contextual fear conditioning, extinction, and reinstatement. Fear conditioning was induced by a single exposure of mice to a context followed by foot shock. Subsequently, mice were exposed to daily extinction trials. After significant reduction of freezing, indicating successful extinction, mice were exposed to a brief reminder shock and re-tested in the conditioning context. Circuit manipulations were performed by chemogenetic silencing with the inhibitory designer receptor exclusively activated by designer drugs (DREADD) hM4(Gi) or targeted cholinergic depletion induced by 192 IgG-saporin, at different stages of fear conditioning, extinction, and reinstatement. We identified projection- and neurotransmitter-specific roles of discrete circuits, indicating complex regulation of fear-inducing memories by subcortical afferents.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Selective loss of septohippocampal cholinergic projections is associated with more circuitous homeward progressions

Osterlund JR, BLackwell AA, Lipton M, Castillo V, Kartje GL, Tsai S-Y, Wallace DG (2019) Selective loss of septohippocampal cholinergic projections is associated with more circuitous homeward progressions. Neuroscience 2019 Abstracts 789.11. Society for Neuroscience, Chicago, IL.

Summary: Rodents rely on self-movement cues as a source of information to maintain spatial orientation during exploration. The vestibular system provides a source of self-movement cues that are processed by the septohippocampal cholinergic system, and when damaged, disruptions in movement organization are observed. The current study examined the effects of medial septum infusion of 192 IgG-saporin on movement organization during a single exploratory session that limited rats to using only self-movement cues. Rats organize their exploratory behavior into stops and progression. Although stops occur throughout the environment, they tend to cluster within a restricted area indicative of home base establishment. In the current study, movement organization characteristics and home base stability were similar between the lesion and sham groups. However, the lesion group exhibited greater path circuity during progressions returning to the home base. Increases in path circuitry have been implicated in spatial disorientation, indicating a role for medial septum cholinergic projections in processing self-movement cues to maintain spatial orientation. These results provide a foundation for future work to investigate the efficacy of interventions that enhance neuroplasticity within the septohippocampal cholinergic system.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Increased transplantation efficacy of mesenchymal stem cell by focused ultrasound and improvement of the spatial memory in the 192 IgG-saporin rat model

Lee J, Seo Y, Shin J, Kong C, Na Y, Chang W, Chang J (2019) Increased transplantation efficacy of mesenchymal stem cell by focused ultrasound and improvement of the spatial memory in the 192 IgG-saporin rat model. Neuroscience 2019 Abstracts 048.01. Society for Neuroscience, Chicago, IL.

Summary: Introduction: Stem cell therapy has been found to have therapeutic effects in neurodegenerative disease, but traditional transplant methods, such as parenchymal or intravenous injection, possess limitations like secondary injuries, infection, and low survival rate of stem cells in the brain. Meanwhile, recently the focused ultrasound(FUS) was found to have promising results regarding transplantation of stem cells into the rat brain. However, the mechanism of stem cell transplantation with FUS and possibility of cognitive recovery remain elusive. Therefore, this study investigates a possibility for non-invasive focused ultrasound use in stem cell transplantation into the brain of dementia rat model. Materials & methods: We divided rats into five groups: Normal, Lesion, Cell only, FUS + Cell, and FUS only. We used 192 IgG-saporin for degeneration of basal forebrain cholinergic neuron and it was injected into all rats except for the normal group. After a week, 5p mesenchymal stem cells (MSC: 3*106/200ul) were injected in the tail vein of all rats of the cell only and FUS + Cell group, and the FUS + Cell group received the FUS three hours before cell transplantation. FUS was applied with parameters of 0.25Mpa, 300s (Targeted hippocampal region: AP -3.5, ML ±2). And last, FUS only group was received only FUS without any treatment. Five weeks after transplantation, rats performed the Morris water maze test. Results: MSC were detected in both cell only and FUS + Cell group of the hippocampus region. After comparing FUS+MSC & cell only rats, it was confirmed that FUS increases MSC homing in the sonicated rat’s brain. In addition, the most effective memory restoration occurred in the FUS + Cell group. Moreover, the FUS + Cell group exhibited better recall of the platform position than the other groups. And FUS only group did not recover. Conclusion: Noninvasive FUS can increase the efficacy of stem cell delivery. And memory impairment due to cholinergic denervation can be effectively improved by cell transplantation with FUS. The results of this study suggest possibility of stem cell homing and therapeutic effects of the FUS in dementia rat model. However, further study regarding the function of stem cells transplanted in the brain and a more detailed mechanism of stem cell homing by FUS is needed.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Sign-trackers deploy perceptual, but not cholinergic-attentional, mechanisms to respond to salient cues

Phillips KB, Avila C, Sarter M (2019) Sign-trackers deploy perceptual, but not cholinergic-attentional, mechanisms to respond to salient cues. Neuroscience 2019 Abstracts 331.10. Society for Neuroscience, Chicago, IL.

Summary: Sign-trackers (STs) attribute incentive value to stimuli that predict food and drug rewards and therefore have emerged as a model for studying vulnerability for addiction-like behaviors. Relative to goal-trackers (GTs), who do not imbue discrete predictive stimuli with motivational value, STs also show a reduced capacity for engaging forebrain cholinergic signaling for the processing of behaviorally significant and attention-demanding cues. The greater power of Pavlovian drug cues in STs has been attributed in part to their relatively poor attentional control of such cues. However, when tested in an operant Sustained Attention Task (SAT), STs exhibit only a minor impairment in hit rates but, more robustly, unstable performance over time. These observations raised the question as to the neuro-behavioral or -cognitive mechanisms via which STs perform the SAT. Male and female STs were trained on SAT. The SAT requires the reporting of cues as well as non-cue events via separate levers, yielding four response categories (hits and misses, and correct rejections and false alarms). After reaching criterion, half of STs received bilateral infusions of the cholino-selective neurotoxin 192-IgG saporin while the remaining STs received sham-lesions. Following recovery, performance was assessed on the SAT and a version of SAT incorporating a flashing house light distractor (dSAT). Goal-directed (or top-down) attention is thought to maintain and recover performance during dSAT and mediated via increases in cortical cholinergic activity. In STs, neither SAT nor dSAT performance depended on the integrity of the cholinergic system. We therefore hypothesized that STs perform the SAT using model-free, non-attentional mechanisms, perhaps relying largely on trial-biased perceptual processes to detect salient cues. To test this hypothesis, separate STs and GTs were trained on SAT. The salience of the cue light relative to the house light was varied across operant chambers. In STs, greater perceptual sensitivity reductions were observed as a function of relatively weaker cue salience. In contrast, GTs’ perceptual sensitivity did not relate to cue salience. Associated with their relatively unresponsive cholinergic system, STs rely on perceptual mechanisms, rather than attentional mechanisms, to perform the SAT. The relative absence of (top-down) attentional control of behaviorally significant cues, combined with a propensity to attribute incentive value to such cues, renders STs less likely to reject such cues from guiding their behavior and engaging in alternative action.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Astroglia in Alzheimer’s Disease.

Verkhratsky A, Parpura V, Rodriguez-Arellano J, Zorec R (2019) Astroglia in Alzheimer’s Disease. (eds. Verkhratsky A, Ho M, Zorec R, Parpura V). In: Advances in Experimental Medicine and Biology: Neuroglia in Neurodegenerative Diseases. 1175:273-324. Springer, Singapore. doi: 10.1007/978-981-13-9913-8_11

Summary: A review of the tools for creating animal models of Alzheimer's Disease. 192-IgG-SAP binds selectively and irreversibly to low-affinity nerve growth factor receptor interrupting cholinergic neuronal protein synthesis was employed. Anti-DBH-SAP binds dopamine-β-hydroxylase, which is not only localized mainly in the cytosol, but also at the plasma membrane surface of noradrenergic neurons. Anti-DBH-SAP produced specific and dose-dependent depletions of locus coeruleus neurons, with no effects on other cholinergic, dopaminergic or serotonergic neuronal populations. The possibility to induce a partial or total noradrenergic loss (by varying the injected dose) makes this immunotoxic approach an ideal model to study events within the noradrenergic projection system, as they occur during age-related demise of locus coeruleus in humans.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03)

Micro- and macro-psychological analyses of attention and the role of cholinergic systems

Phillips K (2019) Micro- and macro-psychological analyses of attention and the role of cholinergic systems. University of Michigan Thesis. doi: 2027.42/151673

Objective: To determine the validity of behavioral tasks used to reveal neurobehavioral and neurocognitive mechanisms of attention.

Summary: The opposing cognitive-motivational styles of sign-trackers and goal-trackers, while originating in different approaches to food and drug cues, provide us with a crucial insight into the individual differences and specific vulnerabilities for attentional processing and performance.

Usage: Bilateral bolus infusions of 192-IgG-SAP (0.8 μl/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer’s disease.

Veening-Griffioen DH, Ferreira GS, van Meer PJK, Boon WPC, Gispen-de Wied CC, Moors EHM, Schellekens H (2019) Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer's disease. Eur J Pharmacol 859:172524. doi: 10.1016/j.ejphar.2019.172524 Related Products: 192-IgG-SAP (Cat. #IT-01)

Partial depletion of septohippocampal cholinergic cells reduces seizure susceptibility, but does not mitigate hippocampal neurodegeneration in the kainate model of epilepsy.

Soares JI, Da Costa C, Ferreira MH, Andrade PA, Maia GH, Lukoyanov NV (2019) Partial depletion of septohippocampal cholinergic cells reduces seizure susceptibility, but does not mitigate hippocampal neurodegeneration in the kainate model of epilepsy. Brain Res 1717:235-246. doi: 10.1016/j.brainres.2019.04.027

Objective: To examine how the inhibition of epilepsy-related cholinergic plasticity may be reflected in seizure susceptibility and/or in the development of chronic epilepsy and its neurological consequences.

Summary: These data suggest that seizure-induced plasticity of cholinergic cells may indeed enhance seizure susceptibility and contribute to epileptogenic processes. They do not support the hypothesis that epilepsy-related hypertrophy of cholinergic neurons may potentiate hippocampal cell loss and respective behavioral impairments.

Usage: Bilateral lesions of cholinergic cells were made by infusing 0.5 μl of 192-IgG-saporin (0.08 μg/μl saline solution) into the hippocampus.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic deficit induced by central administration of 192IgG-Saporin is associated with activation of microglia and cell loss in the dorsal hippocampus of rats

Dobryakova YV, Volobueva MN, Manolova AO, Medvedeva TM, Kvichansky AA, Gulyaeva NV, Markevich VA, Stepanichev MY, Bolshakov AP (2019) Cholinergic deficit induced by central administration of 192IgG-Saporin is associated with activation of microglia and cell loss in the dorsal hippocampus of rats. Front Neurosci 13:146. doi: 10.3389/fnins.2019.00146

Objective: To study the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression.

Summary: Cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus.

Usage: 192-IgG-SAP was injected bilaterally into both ventricles (i.c.v.) at a dose of 4 μg/site.

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Basal forebrain chemogenetic inhibition disrupts the superior complex movement control of goal-tracking rats.

Kucinski A, Kim Y, Sarter M (2019) Basal forebrain chemogenetic inhibition disrupts the superior complex movement control of goal-tracking rats. Behav Neurosci 133:121-134. doi: 10.1037/bne0000290

Usage: Basal forebrain cholinergic neurons situated in the nucleus basalis and substantia innominata were targeted with 192-IgG-SAP in aCSF infused bilaterally (200 ng/μL; 0.8 μL/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson’s disease.

Koshy Cherian A, Kucinski A, Wu R, deJong IEM, Sarter M (2019) Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson’s disease. Psychopharmacology 236:1701–1715. doi: 10.1007/s00213-018-5150-y

Objective: The authors used a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with rivastigmine.

Summary: The results extend the prediction that the combined treatment with idalopirdine and an AChE inhibitor improves complex movement control and reduces propensity for falls in patients with movement disorders.

Usage: Basal forebrain cholinergic neurons situated in the nucleus basalis and substantia innominata were targeted with 192-IgG-SAP in aCSF infused bilaterally (200 ng/μL; 0.8 μL/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic input to the hippocampus is not required for a model of episodic memory in the rat, even with multiple consecutive events.

Seel S, Eacott M, Langston R, Easton A (2018) Cholinergic input to the hippocampus is not required for a model of episodic memory in the rat, even with multiple consecutive events. Behav Brain Res 354:48-54. doi: 10.1016/j.bbr.2017.06.001

Summary: The authors use 192-IgG-SAP (Cat. #IT-01) to examine episodic memory. Continual trials versions of an episodic memory task are unimpaired by cholinergic lesions of the medial septum. In contrast continual trial versions of a location-context (where-which) task are impaired in the same animals. The results replicate the effects of lesions on one-trial a day versions of the same tasks. Increasing the amount of interference between trials by increasing the overlap of features in consecutive events has no effect on the behavioural outcome of these lesions. The result is interpreted in light of models of acetylcholine function centered around pattern separation.

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Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

Moreno-Rodriguez M, Martinez-Gardeazabal J, Llorente-Ovejero A, Lombardero L, Manuel I, Rodriguez-Puertas R (2018) Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction. Neuroscience 2018 Abstracts 049.05 / S3. Society for Neuroscience, San Diego, CA.

Summary: The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer’s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert have been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes. The animal models of cholinergic impairment mimic the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits. Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p < 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p < 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec; p < 0.001). The CB1 receptor activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD. International application patent PCT/EP2018/054525.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Improvements of cognitive function by focused ultrasound associated with adult hippocampal neurogenesis in immunotoxin 192-Saporin rat model of cholinergic degeneration

Kong C, Shin J, Lee J, Koh C, Sim J, Na Y, Chang W, Chang J (2018) Improvements of cognitive function by focused ultrasound associated with adult hippocampal neurogenesis in immunotoxin 192-Saporin rat model of cholinergic degeneration. Neuroscience 2018 Abstracts 174.27 / JJJ31. Society for Neuroscience, San Diego, CA.

Summary: Introduction: Alzheimer’s disease is irreversible, progressive neurodegenerative disorder that destroys memory and cognitive function. Recently, focused ultrasound (FUS) has been demonstrated that FUS-mediated BBB opening induces an increase in hippocampal neurogenesis in adult rodents. In this study, we investigated the effects of FUS on memory and cognitive function after 192 IgG-saporin lesion. Materials and Methods: The present study utilized adult male Sprague-Dawley rats (200-250 g). Animals were divided into the three groups: Sham group (PBS injection), Lesion group (saporin injection), FUS group (saporin + FUS treatment). Lesion groups were injected bilaterally into the lateral ventricle. Rats were sonicated using a single-element transducer with microbubble. The acoustic parameters used for each sonication are: pressure amplitude 0.3 MPa, pulse length 10 ms, burst repetition frequency 1 Hz, and a duration of 120 s. BrdU was intraperitoneally injected two times per day for 4 consecutive days starting 24 hours after sonication. Two weeks after IgG-saporin administration, spatial memory was tested with the Morris water maze training. Results: In the water maze test, the FUS groups were significantly increased in number of crossing and platform zone, compared to the lesion group. We confirmed that the number of BrdU+, DCX+, and NeuN+ were significantly increased in the dentate gyrus following FUS sonication, compared to the lesion groups. Also, we found that the expression level of BDNF and TrkB increased in FUS group. Conclusion: Our results suggest that FUS treatments led to spatial memory improvement in cholinergic deficits rat model. Therefore, this provides evidence that the behavior changes may be mediated by increased acetylcholine activity and neuronal plasticity. Furthermore, FUS may represent a promising treatment for neurodegenerative disease, including Alzheimer’s disease because neurogenesis is associated with memory and cognitive function.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Lifespan and cholinergic changes in cognitive flexibility in rats

Cammarata C, DeRosa ED, Anderson AK (2018) Lifespan and cholinergic changes in cognitive flexibility in rats. Neuroscience 2018 Abstracts 512.05 / GGG8. Society for Neuroscience, San Diego, CA.

Summary: The ability to update one’s mental schemas in order respond flexibly and adaptably - i.e. cognitive flexibility - is crucial to navigating a dynamic environment. Proactive interference (PI) is a phenomenon wherein prior memory impedes the formation of new memories for similar information, biasing behavior toward no-longer-relevant schemas. Thus, overcoming PI is an important aspect of cognitive flexibility. PI is exacerbated during aging, and in turn contributes to age-related deficits in cognitive flexibility. In young animals and young adult humans, resolution of PI has been found to rely on neuromodulatory activity via Acetylcholine (ACh), and ACh levels are known to decline in aging, however it has yet to be demonstrated whether these age-related changes in ACh directly contribute to age-related increase in PI. Here, we first compared PI resolution in middle-aged (13 months, n = 8) and old (23 months, n= 11) male Long Evans rats, finding that old animals were more inefficient in resolving PI when compared to the middle-aged animals. Furthermore we performed cholinergic deafferentation, with the immunotoxin 192-IgG saporin (SAP; 0.2 µl of 0.3 µg/µl dissolved in sterile phosphate buffered sale in each of four locations targeting bilateral anterior and posterior basal forebrain), in our older rats (N= 5 SAP and N=6 Sham) which had no effect on the floor performance of older rats. This suggests that the inability to resolve PI seen in the aged rats may be due to already-depleted levels of ACh. We are currently collecting local field potential data in the prelimbic and posterior parietal cortices in behaving older and younger rats and will combine this with central administration of muscarinic cholinergic pharmacology to continue to examine age-related changes in the cortical dynamics that support cognitive flexibility. Based on prior findings in our laboratory examining similar attentional flexibility, we predict the young animals will demonstrate increased beta band LFP activity in the posterior parietal cortex, and potentially increased beta coherence between prefrontal and posterior parietal cortices, related to successful resolution of PI. We expect such activity to be mitigated by cholinergic antagonists and in the older animals.

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Lacrimal gland denervation alters tear protein composition and impairs ipsilateral eye closures and corneal nociception

Hegarty DM, David LL, Aicher SA (2018) Lacrimal gland denervation alters tear protein composition and impairs ipsilateral eye closures and corneal nociception. Invest Ophthalmol Vis Sci 59:5217-5224. doi: 10.1167/iovs.18-25267

Objective: To evaluate spontaneous and evoked ocular sensory responses in rats after denervation of the lacrimal gland, as well as protein changes in tears that may mediate functional changes.

Summary: Denervation of the lacrimal gland causes long-lasting hypoalgesia, impairs the blink response, and alters tear proteins.

Usage: 192-IgG-SAP (5 μL, 0.5 μg/μL) was microinjected into the left extraorbital lacrimal gland. In a separate group, 192-IgG-SAP was applied directly and unilaterally to the corneal surface.

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Neuropharmacology of attention

Burk JA, Blumenthal SA, Maness EB (2018) Neuropharmacology of attention. Eur J Pharmacol 835:162-168. doi: 10.1016/j.ejphar.2018.08.008

Objective: This review focuses on the knowledge gained about neurotransmitter systems with respect to attentional processing, with emphasis on the functions mediated within the medial prefrontal cortex.

Summary: Future research needs to facilitate a better comprehension of the neural circuitry engaged by different subcategories of attention. Such information will be useful in allowing for more targeted treatments for conditions characterized by attentional deficits.

Usage: Several citations using 192-IgG-SAP;. The specific role of ACh in attentional function can be examined with lesions to cholinergic inputs to the mPFC, using the immunotoxin 192 immunoglobulin G (IgG) saporin. Increases in mPFC ACh efflux related to attention are no longer present following cholinergic lesions. These cholinergic lesions lead to severe deficits in performance on both sustained attention and 5CSRTT-related tasks.

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Molecular, cellular and circuit basis of cholinergic modulation of pain

Naser PV, Kuner R (2018) Molecular, cellular and circuit basis of cholinergic modulation of pain. Neuroscience 387:135-148. doi: 10.1016/j.neuroscience.2017.08.049

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic modulation of spatial learning, memory and navigation.

Solari N, Hangya B (2018) Cholinergic modulation of spatial learning, memory and navigation. Eur J Neurosci 48:2199-2230. doi: 10.1111/ejn.14089

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

The hot ‘n’ cold of cue-induced drug relapse

Pitchers KK, Sarter M, Robinson TE (2018) The hot 'n' cold of cue-induced drug relapse. Learn Mem 25:474-480. doi: 10.1101/lm.046995.117 Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate

Lelkes Z, Abdurakhmanova S, Porkka-Heiskanen T (2018) Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate. J Sleep Res 27:e12605. doi: 10.1111/jsr.12605

Objective: Discover to what extent the cholinergic versus non‐cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate.

Summary: Destruction of the basal forebrain cholinergic neurons did not abolish the wake‐enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate.

Usage: 0.23 μg 192 IgG‐SAP was administered into the basal forebrain.

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Effects of cholinergic lesions and cholinesterase inhibitors on aromatase and estrogen receptor expression in different regions of the rat brain

Li J, Rao D, Gibbs RB (2018) Effects of cholinergic lesions and cholinesterase inhibitors on aromatase and estrogen receptor expression in different regions of the rat brain. Neurosci 384:203-213. doi: 10.1016/j.neuroscience.2018.05.033

Objective: To determine if effects of cholinergic inputs on synaptic plasticity and neuronal function are mediated by effects on local estrogen production or ER expression. 

Summary: Selectively destroying cholinergic projections to the hippocampus had little effect on ARO and ER expression in many regions of the rat brain.

Usage: Rats received intraseptal injections of 2.0 ml (0.2 mg/ml) or icv injections of 0.4 mcg.  Lesions resulted in loss of ChAT-positive cells in the septum, and ChAT activity in the hippocampus.  Septal infusions eliminated most of the ChAT-IR cells in MS; ChAT activity in hippocampus also significantly decreased.  ChAT activity in the frontal cortex was not significantly affected.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Improvements in cognitive function after focused ultrasound are associated with changes in hippocampal cholinergic activity and neurogenesis.

Shin J, Kong C, Lee J, Na YC, Chang WS, Chang JW (2018) Improvements in cognitive function after focused ultrasound are associated with changes in hippocampal cholinergic activity and neurogenesis. FENS 2018 Abstracts C038. Federation of European Neuroscience Societies, Berlin, Germany.

Summary: Introduction: Alzheimer’s disease is irreversible and progressive neurodegenerative disorder that destroys memory and cognitive function. Recently, focused ultrasound (FUS) has been demonstrated that FUS- mediated BBB opening induces an increase in hippocampal neurogenesis in adult rodents. In this study, we investigated the effects of FUS on memory and cognitive function after 192 IgG-saporin lesioning. Materials and Methods: The present study utilized adult male Sprague-Dawley rats (200-250 g). Animals were divided into the three groups: Sham group (PBS injection), Lesion group (saporin injection), FUS group (saporin + FUS treatment). Lesion groups were injected bilaterally into the lateral ventricle. Rats were sonicated by using a single-element transducer with microbubble. The acoustic parameters for each sonication are: pressure amplitude 0.3 MPa, pulse length 10 ms, burst repetition frequency 1 Hz, and a duration of 120 s. BrdU was intraperitoneally injected 2 times per day for 4 consecutive days starting 24 hours after sonication. Two weeks after IgG-saporin administration, spatial memory was tested with the Morris water maze training. Results: In the water maze test, the FUS groups were significantly increased in number of crossing and platform zone, compared to the lesion group. We confirmed that the number of BrdU+, DCX+, and NeuN+ were significantly increased in the dentate gyrus following FUS sonication, compared to the lesion groups. Conclusion: Our results suggest that FUS treatments led to spatial memory improvement in cholinergic deficits rat model. These provided evidences indicate that reason of the behavior change may be induced by increase of acetylcholine activity and neuronal plasticity.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Expression of NR2B subunit of the NMDA receptor and spatial long-term memory in medial septal lesioned rats

Kruashvili L, Dashniani M, Beselia G, Chkhikvishvili N (2018) Expression of NR2B subunit of the NMDA receptor and spatial long-term memory in medial septal lesioned rats. FENS 2018 Abstracts F038. Federation of European Neuroscience Societies, Berlin, Germany.

Summary: The present study was designed to investigate the effect of selective immunolesions of cholinergic and GABA- ergic SH projection neurons (using 192 IgG-saporin and GAT-1 saporin, respectively) on spatial memory assessed in water maze and the N-methyl-D-aspartate (NMDA) receptor GluN2B subunit expression in the rat hippocampus. Animals were tested in a standard Morris water maze. We found that immunolesion of medial septal cholinergic neurons did not affect spatial learning as exhibited by a decreased latency to find the hidden platform across the eight training trials. In contrast, rats with immunolesions of medial septal GABAergic neurons did not show a decreased latency across training trials in water maze. Trained control rats spent significantly longer than chance (15 s) performances such as swimming time in test sector (where the hidden platform was located). Moreover, they spent significantly longer in test sector than in the opposite sector, confirming the establishment of long-term memory. In contrast, the preference for test sector was abolished in medial septal immunolesioned rats. Because Saporin treated rats learned the location of the hidden platform during training, the results suggest that saporin treated rats could not remember the training a day later. We found that the expression level of NR2B subunit of NMDA receptor in the hippocampus was decreased significantly in the GAT-1 treated group compared with the control and saporin treated groups. In conclusion, our findings suggest that immunolesion of medial septal GABAergic neurons can interrupt hippocampus-dependent spatial learning, possibly through modulation of NMDA receptor subunit expression in the hippocampus.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Effects of lesions of medial septal area on spatial short-term memory

Rusadze K, Sakandelidze R, Chighladze M (2018) Effects of lesions of medial septal area on spatial short-term memory. FENS 2018 Abstracts F044. Federation of European Neuroscience Societies, Berlin, Germany.

Summary: In the present study electrolytic and the immunotoxins (192 IgG saporin and GAT1-SAP) lesions of medial septal area (MS) were used to investigate the importance of cholinergic and GABAergic MS neurons in spatial working memory using spatial alternation task. In our experiments electrolytic lesions destroyed on average 69% of the intact MS. Examination of the AChE stained sections showed that after injections of 192 IgG saporin into the MS, animals exhibited significantly less AChE staining in MS as compared to sections obtained from control animals. Intraseptal GAT1-SAP preferentially reduced GABAergic neurons as compared to cholinergic neurons in the MS. The results of present study indicate that spatial short-term memory is affected only by electrolytic but not 192 IgG saporin or GAT1-SAP lesions. The behavioral testing showed that 192 IgG saporin treated rats, relative to control rats, had a significantly lower level in the number of arms entered during the testing session. However, the groups did not differ in the level of alternation behavior. GAT1-SAP lesioned rats showed that the percent alternation scores and the number of arms that the rat entered in the maze were not significantly different from control rats.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Neuronal activity-dependent control of postnatal neurogenesis and gliogenesis

Káradóttir RT, Kuo CT (2018) Neuronal activity-dependent control of postnatal neurogenesis and gliogenesis. Annu Rev Neurosci 41:139-161. doi: 10.1146/annurev-neuro-072116-031054 Related Products: 192-IgG-SAP (Cat. #IT-01)

Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory.

Staib JM, Della Valle R, Knox DK (2018) Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory. Learn Mem 152:71-79. doi: 10.1016/j.nlm.2018.05.009

Objective: To determine which efferent projections are critical for contextual fear memory discrimination and extinction memory.

Summary: The results of this study suggest that MS/vDBB cholinergic neurons are critical for fear and extinction memory.

Usage: 192-IgG saporin was infused into all brain regions at a concentration of 0.2 μg/μL dissolved in 0.2 M PBS. The total volume of each injection was 0.5 μL. Sham surgeries were accomplished using the same volume (0.5 μL) of PBS.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effect of placenta-derived mesenchymal stem cells in a dementia rat model via microglial mediation: A comparison between stem cell transplant methods

Cho JS, Lee J, Jeong DU, Kim HW, Chang WS, Moon J, Chang JW (2018) Effect of placenta-derived mesenchymal stem cells in a dementia rat model via microglial mediation: A comparison between stem cell transplant methods. Yonsei Med J 59:406-415. doi: 10.3349/ymj.2018.59.3.406

Objective: To study the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in a dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyze their mechanisms of therapeutic action.

Summary: ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons.

Usage: Dementia modeling was established by bilateral ventricle infusion of 192 IgG-SAP to lesion cholinergic neurons. 8 μL of 192 IgG-saporin (0.63 μg/μL) were bilaterally injected into the lateral ventricle at a rate of 1 μL/min and was left to diffuse for 5 min after injection. Rats were subjected to the Morris water maze and subsequent immunostaining analyses.

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Cholinergic modulation of frontoparietal cortical network dynamics supporting supramodal attention

Ljubojevic V, Luu P, Gill PR, Beckett L-A, Takehara-Nishiuchi K, De Rosa E (2018) Cholinergic modulation of frontoparietal cortical network dynamics supporting supramodal attention. J Neurosci 38:3988-4005. doi: 10.1523/JNEUROSCI.2350-17.2018

Objective: To examine whether neurochemical acetylcholine (ACh) contributes to a state of readiness for target detection, by engaging frontoparietal cortical attentional networks independent of modality.

Summary: ACh supported alerting attention to an impending presentation of either visual or olfactory targets. Enhanced stimulus detection was associated with an anticipatory increase in power in the beta oscillation range prior to the target’s appearance within the posterior parietal cortex (PPC) as well as increased synchrony. In beta, this was also detected between the prefrontal cortex and PPC. ACh may act, in a supramodal manner, to prepare frontoparietal cortical attentional networks for target detection.

Usage: The ACh-NBM-lesioned rats received an injection of 0.2 μl of 0.3 μg/μl 192 IgG-SAP

Related Products: 192-IgG-SAP (Cat. #IT-01)

Ontogenetic and phylogenetic approaches for studying the mechanisms of cognitive dysfunctions

Zhuravin IA, Dubrovskaya NM, Tumanova NL, Vasilev DS, Nalivaeva NN (2018) Ontogenetic and phylogenetic approaches for studying the mechanisms of cognitive dysfunctions. Evolutionary Physiology and Biochemistry - Advances and Perspectives: InTech 714-741. doi: 10.5772/intechopen.73666

Summary: The effectiveness of the studies of the pathogenesis of AD and search for the strategies of its prevention and treatment depend on appropriate modeling of the pathological conditions in the brain leading to AD. Traditionally, the main focus on designing animal models of AD was related to the identification of brain areas and mediator systems related to memory. One model employed injections of a monoclonal antibody against growth factor receptor conjugated with saporin (192 IgG-saporin), which also resulted in the loss of cholinergic neurons and cognitive disorder

Related Products: 192-IgG-SAP (Cat. #IT-01)

The role of the supramammillary area of the hypothalamus in cognitive functions

Shim HS, Park H-J, Lee M-S, Ye M, Shim I (2018) The role of the supramammillary area of the hypothalamus in cognitive functions. Animal Cells and Systems 22:37-44. doi: 10.1080/19768354.2018.1427627 Related Products: 192-IgG-SAP (Cat. #IT-01)

Intracerebroventricular administration of 192IgG-saporin alters expression of microglia-associated genes in the dorsal but not ventral hippocampus

Dobryakova YV, Kasianov A, Zaichenko MI, Stepanichev MY, Chesnokova EA, Kolosov PM, Markevich VA, Bolshakov AP (2018) Intracerebroventricular administration of 192IgG-saporin alters expression of microglia-associated genes in the dorsal but not ventral hippocampus. Front Mol Neurosci 10:429. doi: 10.3389/fnmol.2017.00429

Objective: To analyze the postponed consequences of cholinergic deficit in different parts of the hippocampus.

Summary: Disturbance of memory-associated behavior after administration of 192-IgG-SAP is associated with upregulation of microglia-associated genes in the dorsal but not ventral hippocampus.

Usage: Rats received bilateral i.c.v.infusions of 192-IgG-SAP (4 mcg/site).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Modulation of GluN2B subunit-containing NMDA receptors expression and spatial long-term memory in medial septal immunolesioned rats

Beselia G, Dashniani M, Burjanadze M, Solomonia R, Kruashvili L, Chkhikvishvili N (2017) Modulation of GluN2B subunit-containing NMDA receptors expression and spatial long-term memory in medial septal immunolesioned rats. Neuroscience 2017 Abstracts 428.01 / UU39. Society for Neuroscience, Washington, DC.

Summary: The hippocampus is important in the formation of spatial memory in both humans and animals. The N-methyl-D-aspartate (NMDA) type of glutamate receptors in the hippocampus has been reported to be essential for spatial learning and memory as well as for the induction of synaptic plasticity. Evidence accumulated from recent studies suggest that GluN2A and GluN2B subunit-containing NMDA-Rs preferentially contribute to the induction of hippocampal LTP and LTD. Using a Morris water maze (MWM) task, the LTP- blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation.1The present study was designed to investigate the effect of selective immunolesions of cholinergic and GABA-ergic1septohippocampal projection neurons [using 192 IgG-saporin (SAP) or GAT1-1 saporin (GAT), respectively] on spatial memory assessed in MWM and NMDA receptor GluN2B subunit expression in the rat hippocampus. We used MWM training protocol with eight training trials. One day after training, probe test with the platform removed was performed to examine long-term spatial memory retrieval. We found that immunolesions of medial septal cholinergic or GABAergic neurons did not affect spatial learning as exhibited by a decreased latency to find the hidden platform across the eight training trials. Trained control and SAP treated rats spent significantly longer than chance (15 s) performances such as swimming time in test sector (where the hidden platform was1located). Moreover, they spent significantly longer in test sector than the opposite sector, confirming the establishment of long-1term memory. In contrast, the preference for test sector was abolished in medial septal GAT treated rats. Because GAT treated rats learned the location of the hidden platform during training, the result suggest that GAT level of NR2B subunit of NMDA receptor in the hippocampus was decreased significantly in the GAT treated group compared with the control and SAP treated groups.1In conclusion, our findings suggest that immunolesion of medial septal GABAergic neurons can interrupt hippocampus dependent1spatial memory, possible through modulation of NMDA receptor subunit expression in the hippocampus. Moreover, our finding that selective lesions of medial septal GABAergic neurons affect probe-test performance but not spatial learning, suggests that septohippocampal GABAergic projections are involved specifically in the consolidation or retrieval, but not in the acquisition of long- term memory.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Improvements in memory after focused ultrasound are associated with changes in hippocampal cholinergic activity and neurogenesis

Kong C, Shin J, Lee J, Koh C-S, Yoon M-S, Na Y, Chang J, Chang W (2017) Improvements in memory after focused ultrasound are associated with changes in hippocampal cholinergic activity and neurogenesis. Neuroscience 2017 Abstracts 201.12 / C29. Society for Neuroscience, Washington, DC.

Summary: Abstract Introduction: Alzheimer’s disease is characterized pathologically by neurofibrillary tangles, amyloid plaques, gliosis, synaptic loss and cholinergic deficits. Recently, cell proliferation and neurogenesis was reported to have increased when the blood brain barrier (BBB) was disrupted by Focused ultrasound (FUS) with microbubbles. Previously, we have demonstrated that the cholinergic cell decreases in 192 IgG-saporin rat model, and that decrease in cholinergic cell is associated to decrease in cognitive behavior. The purpose of this study was to determine if the learning and memory abilities of the 192 IgG-saporin rat model are improved by FUS. Materials and Methods: Animals were divided into the four groups: Sham group (PBS injection), Lesion group (saporin injection), FUS-3 and FUS-10 groups (After 3 and 10 days after saporin injection, FUS treatment). Sprague-Dawley rats (200-250g) were injected bilaterally with 192 IgG-saporin into the ventricle. Rats were sonicated using a single-element transducer (frequency 0.5 MHz) with microbubble. The acoustic parameters used for each sonication are: pressure amplitude 0.3 MPa, pulse length 10 ms, burst repetition frequency 1 Hz, and a duration of 120 s. To confirm cell proliferation, BrdU was intraperitoneally injected 2 times per day for 4 consecutive days starting 24 hours after FUS sonication. Two weeks after IgG-saporin administration, spatial memory was tested with the Morris water maze training for 5 days and the final test was performed. Results: In the water maze test, the FUS groups had a higher number of crossing times and staying time in the platform zone than the lesion group. Also, the FUS-3 group was higher than for the FUS-10 group. We confirmed that the amounts of DCX , NeuN , and BrdU were different between the FUS group and the lesion group. Conclusion: Our results suggest that FUS sonication facilitates recovery of memory and learning abilities in cholinergic deficits rat model. Moreover, the results suggest that neurogenesis is correlated with the mechanism of cognitive behavior recovery.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Basal forebrain cholinergic neurons are vital for cortical desynchronization and behavioral arousal observed after nicotine consumption

Sharma A, Sharma R, Mackey C, Sahota P, Thakkar M (2017) Basal forebrain cholinergic neurons are vital for cortical desynchronization and behavioral arousal observed after nicotine consumption. Neuroscience 2017 Abstracts 241.1 / LL2. Society for Neuroscience, Washington, DC.

Summary: Purpose: Nicotine is an addictive constituent of tobacco which severely affects behavior. Sleep disruptions including reducing total sleep time, increasing sleep fragmentation and reducing sleep efficiency are very common in nicotine users. However, the underlying neuronal mechanism of how nicotine promotes desynchronization and disrupts sleep is unknown. We have shown that the basal forebrain (BF) is a key brain region, mediating nicotine’s effects on sleep-wakefulness (SFN 2015; Poster#166). The BF contains multiple neuronal phenotypes including cholinergic, GABAergic and glutamatergic subtypes. Thus, this study was designed to examine the neuronal subtype responsible for nicotine effects on sleep-wakefulness. As a first step, we focused on BF cholinergic neurons because BF cholinergic neurons are wake-promoting, express nicotinic receptors and supply acetylcholine to the prefrontal cortex, hippocampus and amygdala. We hypothesized that lesions of BF cholinergic neurons will attenuate nicotine induced cortical arousal/desynchronization. Methods: To test our hypothesis, adult male Sprague-Dawley rats were implanted with sleep recording electrodes and were divided into two groups: Lesion: Selective lesion of the BF cholinergic neurons was performed by bilateral administration of immunotoxin, 192-IgG-Saporin (SAP; 0.28 µg/0.5µL/side) in the BF; Sham (controls): Rats were bilaterally infused with saline (0.5µL/side). After injections, animals were left undisturbed for 3 weeks. Day 1: saline was administered subcutaneously at light/sleep onset. Day 2: Nicotine (0.3 mg/Kg) was administered at the same time. Sleep- wakefulness was examined for next 6 hours. On completion, animals were euthanized and the brains were processed for choline acetyltransferase (ChAT) immunohistochemistry to verify BF cholinergic lesions. Results: Our preliminary results: As compared to controls, lesioned rats, with a 64% reduction in cholinergic neurons, displayed attenuated nicotine induced cortical desynchronization and behavioral arousal. Conclusions: Our results suggest that the BF cholinergic neurons mediate nicotine induced cortical arousal/desynchronization that may be the cause of sleep disruptions in nicotine users.

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Glutamate and adenosine, basal forebrain and cortex: Cross-talk during prolonged wakefulness

Larin AA, Karpova SA, McCarley RW, Basheer R, Kalinchuk AV (2017) Glutamate and adenosine, basal forebrain and cortex: Cross-talk during prolonged wakefulness. Neuroscience 2017 Abstracts 72.2 /KK24. Society for Neuroscience, Washington, DC.

Summary: Recently we described a biochemical cascade which is critical in promoting recovery sleep (RS) after sleep deprivation (SD). It is initially triggered in the basal forebrain (BF) and later in the prefrontal cortex (PFC). This cascade includes production of inducible nitric oxide synthase (iNOS)-dependent NO followed by an increase in adenosine (AD). We hypothesized that iNOS induction is triggered by an increase in extracellular glutamate (Glu), and that the increase in AD prevents further rise in Glu via its inhibitory action on AD A1 receptor (A1R). To test this hypothesis, during 8h of SD, we first examined the time course of Glu and AD in BF/PFC. Further, to investigate the role of BF Glu receptors (GluRs) in this cascade, we measured the changes in BF/PFC AD and NREMs/delta after: a) stimulating BF GluRs by NMDA or AMPA without SD; b) blocking BF GluRs during SD by NMDAR or AMPAR selective antagonists. Finally, we measured Glu in the BF/PFC after blocking A1R. Furthermore, to determine the cellular target of glutamate effects, we examined the effects BF AMPA infusion on BF/PFC AD and NREMs/delta after BF cholinergic (ChBF) lesions using 192 IgG-saporin. Male rats were implanted with EEG/EMG recording electrodes and microdialysis guide cannulae targeting the BF and PFC. Microdialysis samples were collected during 8h SD and/or drug infusion. AD and Glu were measured using high performance liquid chromatography (HPLC) and ultra HPLC. To block NMDAR/AMPAR/A1R we used dizoclipine (MK-801)/6,7- dinitroquinoxaline-2,3-dione (DNQX)/8 cyclopentyltheophylline (CPT), respectively. 1) In the BF, Glu dramatically increased at the beginning of SD, followed by increase in AD at 2 h of SD. When AD maximized at 4 h of SD, Glu concurrently decreased to baseline. High AD levels were maintained till the end of SD. In the PFC, Glu significantly increased within 2h of SD. When AD increased at 5 h of SD, Glu returned to the baseline. 2) BF AMPA mimicked the effects of SD by increasing AD in both BF and PFC. NREMs/delta increased post AMPA-infusion. NMDA was not effective. 3) BF DNQX prevented AD increase during SD in BF/PFC and attenuated RS. MK-801 did not show any effect. 4) CPT Infusion to the BF/PFC induced dramatic increase in Glu till the end of SD. 5) Lesion of ChBF prevented BF/PFC AD increase during AMPA infusion and attenuated NREMs/delta post-infusion. A rapid increase in Glu during SD may be a trigger for the induction of iNOS-NO-AD cascade in both the BF and PFC. AD via A1R exerts a negative feedback on Glu neurotransmission, preventing its further rise and potential toxicity during long-term SD. The effect of Glu on SDinduced changes is primarily mediated via AMPAR, located on ChBF cells.

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Increase in cortical endocannabinoid signaling in a rat model of basal forebrain cholinergic dysfunction

Llorente-ovejero A, Manuel I, Giralt MT, Rodríguez-puertas R (2017) Increase in cortical endocannabinoid signaling in a rat model of basal forebrain cholinergic dysfunction. Neuroscience 362:206-218.. doi: 10.1016/j.neuroscience.2017.08.008

Objective: To evaluate the eCB signaling in relation to the memory impairment induced in adult rats following a specific cholinergic lesion of the basal forebrain.

Summary: CB1 receptors present in presynaptic GABAergic terminals in the hippocampus are down regulated, but not those in cortical glutamatergic synapses.

Usage: 192-IgG-SAP was dissolved in aCSF under aseptic conditions to a final concentration of 130 ng/ml. aCSF or 192-IgG-SAP was bilaterally injected (1 ml/hemisphere) at a constant rate of 0.2 ml/min.

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Lesion of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption.

Sharma R, Sahota P, Thakkar M (2017) Lesion of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption. J Neurochem 142:710-720.. doi: 10.1111/jnc.14054

Summary: This project examined the sleep-promoting effect of alcohol and which neurons in the brain are involved in the process. 192-IgG-SAP (Cat. #IT-01; 0.3 µg/500 nL/side) was administered through bilateral basal forebrain infusions in rats. Based on the results, the authors suggest that alcohol promotes sleep by increasing extracellular adenosine via its action on cholinergic neurons of the basal forebrain.

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Acute effects of alcohol on sleep are mediated by components of homeostatic sleep regulatory system: An Editorial Highlight for ‘Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption’ on page 710.

Alam M, McGinty D (2017) Acute effects of alcohol on sleep are mediated by components of homeostatic sleep regulatory system: An Editorial Highlight for 'Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption' on page 710. J Neurochem 142(5):620-623.. doi: 10.1111/jnc.14100

Summary: In the study published in 2017, Sharma and colleagues report that the wake-promoting BF cholinergic neurons are critically involved in the acute alcohol-induced sleep promoting response and that extracellular adenosine buildup in the BF mediates this response. Using 192-IgG-SAP (Cat. #IT-01), they ablated BF cholinergic neurons unilaterally and compared extracellular adenosine levels on lesioned versus non-lesioned sides after local delivery of alcohol via reverse microdialysis. They found that adenosine levels were significantly lower (nearly 50%) on the side with a loss of cholinergic neurons.

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See Also:

Impact of chronic stress on the spatial learning and GR-PKAc-NF-κB signaling in the hippocampus and cortex in rats following cholinergic depletion.

Lee S, Cho W, Lee Y, Han J (2018) Impact of chronic stress on the spatial learning and GR-PKAc-NF-κB signaling in the hippocampus and cortex in rats following cholinergic depletion. Mol Neurobiol 55:3976-3989. doi: 10.1007/s12035-017-0620-5

Objective: Examine the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex.

Summary: The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer’s disease to stress since activation of NF-κB is associated with stress.

Usage: Male Sprague-Dawley rats received injections of 192 IgG-SAP dissolved in sterile 0.01 M PBS) at a concentration of 0.25 μg/μl.

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Sigma-1 (σ1) receptor in memory and neurodegenerative diseases

Maurice T, Goguadze N (2017) Sigma-1 (σ1) receptor in memory and neurodegenerative diseases. Handb Exp Pharmacol 244:81-108. doi: 10.1007/164_2017_15

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Identifying the appropriate time for deep brain stimulation to achieve spatial memory improvement on the Morris water maze.

Jeong D, Lee J, Chang W, Chang J (2017) Identifying the appropriate time for deep brain stimulation to achieve spatial memory improvement on the Morris water maze. BMC Neuroscience 18:29.. doi: 10.1186/s12868-017-0345-4

Summary: This study was performed to determine the stage of memory affected by medial septum deep brain stimulation (MS-DBS). Memory impairment due to cholinergic denervation can be improved by DBS. The improvement is significantly correlated with the up-regulation of BDNF expression and neurogenesis. Based on the results of this study, the use of MS-DBS during the early stage of disease may restore spatial memory impairment.

Usage: Rats were injected bilaterally with 8 μl of 192-IgG-SAP (0.63 μg/μl) at the cerebroventricle.

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Lipid mapping of the rat brain for models of disease.

Martínez-Gardeazabal J, González de San Román E, Moreno-Rodríguez M, Llorente-Ovejero A, Manuel I, Rodríguez-Puertas R (2017) Lipid mapping of the rat brain for models of disease. Biochim Biophys Acta Biomembr 1859:1548-1557.. doi: 10.1016/j.bbamem.2017.02.011

Objective: To map the spatial distribution of different lipid species in the rat central nervous system (CNS) using IMS to find a possible relationship between anatomical localization and physiology. The data obtained were subsequently applied to a model of neurological disease, the 192IgG-saporin lesion model of memory impairment.

Summary: The specific distribution of different lipids supports their involvement not only in structural and metabolic functions but also as intracellular effectors or specific receptor ligands and/or precursors. Moreover, the specific localization in the CNS described here will enable us to analyze lipid distribution to identify their physiological conditions in rat models of neurodegenerative pathologies, such as Alzheimer’s disease.

Usage: 192 IgG-SAP in aCSF (135 ng/1 μl/hemisphere; 0.25 μl/min) was administered.

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Chronic lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration.

Gelfo F, Cutuli D, Nobili A, De Bartolo P, D'Amelio M, Petrosini L, Caltagirone C (2017) Chronic lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration. J Alzheimers Dis 56:1505-1518.. doi: 10.3233/JAD-160892

Objective: To evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes.

Summary: The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Usage: Neurodegeneration was induced by injecting the immunotoxin 192 IgG-SAP in the medial septum (0.5 ug/side) and nucleus basalis magnocellularis (0.4 ug/side).

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Impact of altered cholinergic tones on the neurovascular coupling response to whisker stimulation.

Lecrux C, Sandoe C, Neupane S, Kropf P, Toussay X, Tong X, Lacalle-Aurioles M, Shmuel A, Hamel E (2017) Impact of altered cholinergic tones on the neurovascular coupling response to whisker stimulation. J Neurosci 37:1518-1531. doi: 10.1523/JNEUROSCI.1784-16.2016

Summary: The authors assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex. ACh depletion was achieved via unilateral icv injection (4 mcg/2 mcl) with 192 IgG-SAP (Cat. #IT-01) or saline. They conclude that ACh is not only a facilitator, but also a prerequisite for the full expression of sensory-evoked NVC responses.

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Cholinergic-dependent shifts to cue-directed behavior.

Phillips KB, Sarter M (2016) Cholinergic-dependent shifts to cue-directed behavior. Neuroscience 2016 Abstracts 833.11 / HHH30. Society for Neuroscience, San Diego, CA.

Summary: Successful cue detection requires cortical cholinergic signaling. Recent evidence has elucidated the role of phasic, short-timescale, regionally-specific cholinergic signals, termed “cholinergic transients”, in cue detection. Cholinergic transients in the right prefrontal cortex were exclusively observed in trials in which cues were detected and when such trials followed non-cued trials yielding correct rejections or falsely perceived non-cued trials (cues that were missed). Thus, these cholinergic transients were interpreted as mediating shifts from performance guided by internally-guided attention to cued-directed behavior (Howe et al., 2013). In contrast to cholinergic transients mediating shift-hits, such transients were not observed during consecutive hits. Transients may be actively suppressed during consecutive hits in order to constrain a potential detection bias and maintain behavioral flexibility (Sarter et al., 2015). Here we removed cholinergic innervation to the right prefrontal cortex in rats to test the hypothesis that the right hemispheric cortical cholinergic projection system is necessary for shift-hits. Rats were trained on a sustained attention task (SAT) consisting of a random sequence of signal trials and non-signal trials, both requiring a distinct lever response from the subject. Following stable task performance, half of the subjects received right unilateral cholino-selective lesions of the basal forebrain by infusions of the immunotoxin 192 IgG-saporin, while the remaining subjects received sham surgeries. Rats were then familiarized with performing a modified version of SAT which consisted of engineered trial sequences to provide an “aggressive” test of the hypothesis based on the performance of pre-defined trials. In particular, the modified SAT included long strings of non-cued trials that were followed by a cued trial, with lesioned animals expected to miss specifically that latter trial. Conversely, neither hits during long strings of cued trials, nor correct rejections during non-cued trials that followed long strings of consecutive hits were expected to be affected by the lesion. Results indicate that right cholinergic losses selectively impair shift-hits. These findings are consistent with recent results from our optogenetic studies showing that cortical cholinergic transients are necessary and sufficient for the detection of cues (Gritton et al., 2016) and they extend these findings by specifying that in the absence of cortical cholinergic activity, subjects remain arrested in a state of perceptual or intrinsic attention.

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Effects of N-desmethylclozapine on attentional performance following loss of basal forebrain corticopetal cholinergic inputs.

Maness EBL, Leong CS, Burk JA (2016) Effects of N-desmethylclozapine on attentional performance following loss of basal forebrain corticopetal cholinergic inputs. Neuroscience 2016 Abstracts 833.15 / HHH34. Society for Neuroscience, San Diego, CA.

Summary: Corticopetal cholinergic neurons play a vital role in attentional processing, and dysregulation of this system contributes to central nervous system disorders whose main attributes include an inability to engage in sustained attention, such as Alzheimer’s disease. The cholinergic muscarinic-1 (M1) receptor is known to be necessary for normal attentional processing. In general, there has been a trend towards supporting drugs that provide allosteric agonism of cholinergic receptors as an approach that may yield greater benefits than drugs that act at orthosteric receptor sites. There exists contention in the literature regarding the action of N-desmethylclozapine (NDMC), a partial M1-preferring agonist, that is thought to act at an allosteric site on the M1 receptor. The goal of the present experiment is to further evaluate NDMC’s activity at these sites in a lesion model of cholinergic dysfunction using an operant task assessing attentional capacity. After training in an attention-demanding task requiring differentiation between signal trials (500, 100, and 25ms illumination of a central panel light) and non-signal trials (no light illumination), Sprague Dawley rats received intrabasalis infusions of either saline or the cholinergic neurotoxin 192 IgG-saporin, and attentional performance was later measured following intracerebroventricular infusions of NDMC. In general, NDMC impaired attentional performance, particularly for lesioned animals. These findings suggest that NDMC may functionally decrease acetylcholine stimulation of M1 receptors or that the actions of NDMC at other receptor sites disrupt any beneficial effects of NDMC at the M1 receptor.

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Preventing falls in PD in a rat model of impaired cognitive control of complex movements by a pro-cholinergic combination treatment.

Kucinski AJ, De Jong IEM, Sarter M (2016) Preventing falls in PD in a rat model of impaired cognitive control of complex movements by a pro-cholinergic combination treatment. Neuroscience 2016 Abstracts 835.15 / III34. Society for Neuroscience, San Diego, CA.

Summary: Parkinson's disease (PD) patients, in addition to primary motor symptoms resulting from extensive losses of striatal dopamine (DA), suffer from an interrelated group of motor-control symptoms including postural instability, gait deficits, and a propensity for falls. These levodopa-insensitive symptoms are associated with losses of cortically-projecting cholinergic neurons of the basal forebrain (BF), as well as cognitive impairments such as poor attention. Given the high prevalence and severe consequences of falls in levodopa-treated patients, alternative treatment options are urgently needed. To assess potential treatments we have developed behavioral models of falls in rats including a test system (Michigan Complex Motor Control Task, MCMCT) that requires persistent control of gait, limb coordination, and carefully timed and placed steps during traversals of dynamic surfaces (rotating square rods). Rats with bilateral cholinergic lesions of the BF using 192 IgG-saporin and 6-OHDA lesions to the dopaminergic dorsomedial striatum (dual lesions, DL) exhibit falls while traversing rotating rods and these falls correlate with impaired performance of a sustained attention task. DL rats’ falls have been hypothesized to result from interactions between disruption of normally cholinergically-driven transfer of extero- and interoceptive cue information from cortex to striatum and impaired striatal action sequencing. Here we tested the hypothesis that falls are reduced by co-treatment with acetylcholinesterase inhibitor donepezil and a 5-HT6 receptor antagonist. This combination treatment was previously reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease. Overall, drug-treated rats fell less frequently from the rotating rods and were particularly more efficient at reinstating forward movement after sudden stoppages of forward movement with a passive (doorframe) distractor task. This treatment combination may benefit fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait. The neuropharmacological interactions of this treatment may involve diverse signaling pathways converging onto striatal output neurons. Results from current experiments using microdialysis and HPLC-mass spectrometry to simultaneously assess release of striatal ACh, animo acids and monoamines during rotating rod traversals will assist in elucidating potential targets for therapeutic prevention of falls. Supported by a grant from H. Lundbeck A/S

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Developmental disturbances in thalamocortical connection are sufficient to produce almost all features of schizophrenia.

Rajakumar R (2016) Developmental disturbances in thalamocortical connection are sufficient to produce almost all features of schizophrenia. Neuroscience 2016 Abstracts 845.01 / LLL41. Society for Neuroscience, San Diego, CA.

Summary: Partial ablation of subplate of the developing frontal cortex was achieved by two different approaches in PD1 S-D rat pups: infusions of either P75 receptor antibody-conjugated to saporin or β-nerve growth factor, and both resulted in identical changes: ~20% loss of subplate and aberrant distribution of thalamocortical fibers within the cortex. Control littermates received similar infusions of vehicle. Pups were allowed to grow under standard care. All animals survived, and showed no noticeable differences in milestones or activities. No differences were observed between lesioned and control groups in standard behavioral tests at 6-8 weeks of age. However, lesioned group showed significantly increased stress- or amph-induced locomotor activity, PPI deficit, social interaction deficits, and executive functional deficits after 9 weeks of age. A month-course of haloperidol or risperidon completely ameliorated locomotor abnormalities but did not affect social interaction deficit. Histological examination revealed several interesting changes: (1) 18% loss of gray matter thickness in the mPFC and no change in thickness in other cortical areas at 12 weeks, while at 20 weeks PFC loss remained at 18% but parietal and temporal cortices showed progressive thinning (20-36%); (2) significant loss of neuropil in the mPFC characterized by loss of synaptophysin and spinophilin labeling; (3) no changes in the number of neuronal cell bodies in PFC; (4) significantly increased lateral and third ventricular volume; (5) significant loss of dopaminergic fibers in lower layers of the PFC; (6) significant loss of GAD67-IR terminals in PFC; (6) significant decrease in the intensity of PAR labeling and abnormal distribution of PAR-IR terminals/cell bodies without loss of neurons; (7) significant loss of GAT-1-IR terminals only in upper layers of the PFC; (8) loss of PAR-IR terminals and cell bodies in the hippocampus; (9) abnormal distribution but no loss of CR-IR neurons in the entorhinal cortex; and (10) significantly reduced volume of basolateral amygdala. No changes were seen in ChAT neurons of the septum or N. basalis. All structural changes noted above were seen as early as 12 weeks and were not affected by antipsychotic treatment between 12 and 16 weeks. Results suggest that disturbances in thalamocortical pathfinding (due to genetic or other mechanisms) are sufficient to cause features of schizophrenia in normal animals.

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Enhanced motor recovery by vagus nerve stimulation requires cholinergic innervation in a rat model of ischemic stroke.

Ruiz AD, Hays S, Berry A, Vallejo S, Barron L, Carrier X (2016) Enhanced motor recovery by vagus nerve stimulation requires cholinergic innervation in a rat model of ischemic stroke. Neuroscience 2016 Abstracts 807.20 / HH11. Society for Neuroscience, San Diego, CA.

Summary: Stroke is a debilitating neurological insult that affects approximately 795,000 people in the U.S. each year. Following a stroke, many patients are left with impairment in upper extremity function, even after intensive rehabilitation therapy. Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitative training significantly enhances recovery of forelimb function in models of ischemic stroke, intracerebral hemorrhage, and traumatic brain injury. Nevertheless, the mechanisms that underlie VNS-dependent enhancement recovery are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry. Previous studies demonstrated that cholinergic innervation of the motor cortex is required for VNS-dependent enhancement of cortical plasticity. In this study we examine whether cholinergic innervation is required for VNS-dependent enhanced recovery in a rat model of ischemic stroke. A cohort of rats was trained to proficiency on the isometric force task, an automated and qualitative measure of forelimb function and then received a cortical ischemic lesion to impair the trained forelimb. Rats then received injections of the highly selective immunotoxin IgG-192-saporin into the nucleus basalis to deplete cortical cholinergic innervation (NB-) or control injections (NB+). Two weeks after stroke and immunolesion, rats underwent rehabilitative training for 6 weeks with or without VNS paired with forelimb movement. At the conclusion of behavioral testing, pseudorabies virus labelling was performed to assay anatomical plasticity in motor circuits controlling the forelimb. Preliminary findings indicate that VNS-dependent enhancement of stroke recovery requires cholinergic innervation.

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Effects of protein kinase C activation on attention deficits following loss of corticopetal cholinergic neurons.

Leong CS, Maness EB, Baraki DI, Burk JA (2016) Effects of protein kinase C activation on attention deficits following loss of corticopetal cholinergic neurons. Neuroscience 2016 Abstracts 833.03 / HHH22 . Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a neurodegenerative dementia characterized by memory loss, cognitive impairment, and attention deficits. Damage to corticopetal cholinergic neurons originating in the basal forebrain is thought to contribute to the attention deficits. Recent evidence had identified G-protein decoupling at the M1 muscarinic acetylcholine receptor as well as decreased levels of protein kinase C (PKC) in rat AD models and the human AD brain. PKC is a signaling kinase that can affect neurite outgrowth, synaptic formation, and neurotransmitter release. PKC activation additionally may affect voltage-gated calcium currents. Previous research in this lab has shown that inhibition of PKC by chelerythrine chloride decreased signal detection in a sustained attention task. The present experiment evaluates the effect of PKC activation on sustained attention following loss of cortical cholinergic projections induced by infusions of 192 IgG-saporin into the basal forebrain. Male and female Sprague-Dawley rats were trained to discriminate between signals (illumination of a central panel light) and nonsignals (no panel light illumination) in a two-lever sustained attention task. Each rat received intraventricular infusions of the PKC activator bryostatin-1 (0, 0.5, 2.0, and 4.0pM) prior to testing. In the middle block of trials, a flashing houselight distracter was included to increase attentional demands. Compared to sham-lesioned animals, lesioned animals showed poorer signal detection in the distracter block of the task, but no differential effects of lesion on nonsignal trials. Distracter scores (initial block of trials with no distracter - distracter block) were calculated for each behavioral measure. For signal detection, there was a dose × group interaction (F(3,30) = 3.069, p = 0.043). Bryostatin-1 attenuated signal detection deficits in lesioned animals. Sham-treated animals showed decreased performance with increased bryostatin-1 dosage. Following the highest bryostatin-1 dose, there were no difference in signal detection between the sham and lesioned animals. The present results support the hypothesis that Bryostatin-1 can improve performance in a visual attention task following damage to corticopetal cholinergic neurons.

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Cerebral cholinergic mechanisms in pain: CBF lesions vs systemic scopolamine.

Wiley RG, Yezierski R, Vierck Jr CJ (2016) Cerebral cholinergic mechanisms in pain: CBF lesions vs systemic scopolamine. Neuroscience 2016 Abstracts 525.15 / SS2. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic inputs to the cerebral cortex and limbic system, originating primarily from the cholinergic basal forebrain (CBF), play an important role in cortical sensory processing, largely through modulation of inhibitory interneurons. Cholinergic agonists given spinally, intracerebroventricularly (ICV) or systemically depress reflex nocifensive responses, but systemic cholinergic antagonists also depress some affective responses to pain and impair attention to aversive stimuli and stress reactions. In the present study, we determined the effects of selective cerebral cholinergic denervation, using ICV microinjection of 4 ug of 192-saporin in 10 μl (Advanced Targeting Systems, San Diego, CA) on operant thermal escape responses to aversive thermal stimuli (10° C, 44.5° C) and hyperalgesic effect of sound stress (ten X 30 sec bursts of 100 dB white noise over a 15 min period, 20 mins prior to thermal escape testing) in normal and CBF-lesioned rats compared to effects of systemic cholinergic antagonism (0.1 mg/kg, i.p., scopolamine, 20 minutes prior to thermal escape testing) in intact, normal rats. All rats were on the thermal escape task prior to either scopolamine, or sound stress testing and prior to ICV 192-saporin. At the conclusion of behavioral testing, choline acetyltransferase immunohistochemistry confirmed that 192-sap produced 62-81% loss of CBF cholinergic neurons. CBF-lesioned rats showed decreased thermal escape responses to both temperatures (10°C and 44.5°C) for >19 weeks. There also was no increase in escape responding (hyperalgesia) after sound stress as seen in normal rats. Scopolamine in normal rats produced decreased thermal escape responses to cold (2° C, 6°C and 10° C) and to heat (44.5° C). These results suggest that systemic scopolamine mimics the effects of CBF destruction on pain and together the overall results are interpreted to indicate an important role for the CBF in cerebral pain processing. These findings may be relevant to clinical pain care in patients with cerebral cholinergic dysfunction, such as Alzheimer’s disease.

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The role of cholinergic input from the medial septum in cued and contextual fear extinction memory.

Staib JM, Knox D (2016) The role of cholinergic input from the medial septum in cued and contextual fear extinction memory. Neuroscience 2016 Abstracts 262.11 / III7. Society for Neuroscience, San Diego, CA.

Summary: In classical fear conditioning, a neutral stimulus (CS) is paired with an aversive stimulus (US), causing the animal to associate the US with CS, and display a fear response to the CS. Fear extinction occurs when the CS is presented without the US and the animals learn that the CS no longer predicts the US, thus learning to no longer show fear with CS presentation. Ventral medial prefrontal cortex inhibition of neural activity in basolateral and central amygdala nuclei is critical for extinction memory formation. Recently, we observed that cholinergic lesions in the Medial Septum and Diagonal Bands of Broca (MS/DBB), induced with 192-IgG saporin results in fear extinction memory deficits and contextual fear memory generalization between the conditioning and extinction contexts. While this suggests that MS/DBB cholinergic neurons may be a component of the fear extinction circuit, these neurons project to many brain regions. As a result, the MS/DBB cholinergic efferents that are critical for mediating extinction memory and contextual fear memory discrimination are unknown. The goal of the present study is to isolate the exact MS/DBB efferents that mediate extinction memory and contextual fear memory discrimination. While the study is in progress, some results have been collected. Cholinergic lesions in the dorsal hippocampus, ventral hippocampus, and medial prefrontal cortex have no effects on fear extinction memory or contextual fear memory discrimination. This is surprising because all of these regions are components of the fear extinction circuit and the dorsal hippocampus is critical for contextual learning during acquisition of fear and extinction memory. The MS/DBB also projects to habenula nuclei, and there are cholinergic interneurons in the MS/DBB as well. For the remainder of the study, we explore the potential role of MS/DBB cholinergic input to the habenula and MS/DBB cholinergic interneurons in mediating extinction memory and contextual fear memory discrimination. Isolating a region that has a direct role in mediating extinction memory could help focus future research in fear memory disorders like post traumatic stress disorder.

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Placenta-derived mesenchymal stem cells facilitate neural and cognitive recovery in dementia rat model.

Cho J, Lee J, Jeong D, Kim H, Chang W, Moon J, Chang J (2016) Placenta-derived mesenchymal stem cells facilitate neural and cognitive recovery in dementia rat model. Neuroscience 2016 Abstracts 38.10 / G29. Society for Neuroscience, San Diego, CA.

Summary: Introduction: Dementia is a term that encompasses various types of neurodegenerative diseases of the brain that cause a gradual decline in mental abilities. Loss of cholinergic neurons in the brain cholinergic system including the hippocampus is a hallmark of many dementia cases. In this study, we report the therapeutic effects of administration of human placenta-derived mesenchymal stem cells (pMSCs) in dementia model Sprague-Dawley (SD) rats using two different cell injection methods: intracerebroventricular (ICV) and intravenous (IV) injections. Methods: Dementia modeling was carried out by intraventricular injection of 192 IgG saporin, which causes lesion of cholinergic neurons. Fifty male SD rats were divided into four groups: normal (n=9), lesion (n=9), ICV (n=12) and IV (n=12). All rats were then subject to Morris water maze test and subsequent immunostaining analyses using markers for human cytoplasm, acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and microglial cells at the hippocampus. Results: Lesioned rats showed poor performance in the Morris water maze test compared to the normal rats. Both ICV and IV pMSC administration allowed significant cognitive recovery compared to the lesioned rats. AChE was also significantly recovered back to normal levels at the hippocampus in rats injected with pMSCs post-lesion. ChAT did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Stem cell count showed a significantly greater number of pMSCs at the hippocampal dentate gyrus in IV group rats compared to ICV group rats. Number of microglial cells increased in lesioned rats, and was significantly reduced back to normal levels after pMSC injection. Discussion: Our results demonstrate that injection of pMSCs facilitates recovery of cholinergic neuronal population and function, as well as cognitive behavior. The mechanism through which such recovery happens does not seem to be direct differentiation of injected pMSCs into cholinergic neurons, but rather seems to be through paracrine effects that resemble microglial function. Further research will be necessary for elucidation of the exact mechanisms involved and establishment of optimal parameters for successful cell homing. Acknowledgements: This study was supported by the grant from the Yonsei University Future-leading Research Initiative (Yonsei Challenge) of 2015 (2015-22-0137) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1C1A1A02036851).

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Neuronal and glial changes in rat hippocampal formation after cholinergic deafferentation

Paban V, Valable S, Baril N, Gilbert V, Chambon C, & Alescio-Lautier B (2016) Neuronal and glial changes in rat hippocampal formation after cholinergic deafferentation. J Biomol Res Ther 5(3):1000147. doi: 10.4172/2167-7956.1000147

Summary: The effects of cholinergic insult were studied in the hippocampal formation of cholinergic lesioned rats at metabolic and cellular levels by in vivo nuclear magnetic resonance spectrometry and immuno-histochemical approaches.

Usage: Cholinergic deafferentation was induced by injection of the cholinergic immunotoxin 192-IgG-SAP into the medial septum (37.5 ng/side).

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Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements

Kucinski A, de Jong IEM, Sarter M (2017) Reducing falls in Parkinson's disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci 45:217-231.. doi: 10.1111/ejn.13354

Objective: To assess the effects of treatment on MCMCT performance and attention in DL rats. The combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was use because it has been reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease.

Summary: This treatment may reduce fall propensity in patients.

Usage: 192-IgG-SAP aCSF infused bilaterally (120 ng/uL; 0.5 uL/hemisphere).

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Featured Article: Cerebral cholinergic lesion reduces operant responses to unpleasant thermal stimuli

Wiley RG (2016) Featured Article: Cerebral cholinergic lesion reduces operant responses to unpleasant thermal stimuli. Targeting Trends 17(2)

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Read the featured article in Targeting Trends.

Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat.

Vierck C, Yezierski R, Wiley R (2016) Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat. Neuroscience 319:23-34. doi: 10.1016/j.neuroscience.2016.01.038

Objective: There is a large amount of research on the involvement of cholinergic mechanisms on spinal transmission of pain signals, indicating that cholinergic agonists can attenuate this kind of pain. In contrast, some studies have shown affective reactions to pain are suppressed by cholinergic antagonists. The authors investigated the disagreement between reflexive and affective reactions.

Summary: Lesioned rats displayed decreased escape from thermal stimulation, as well as loss of the normal hyperalgesic effect of sound stress. Results indicate that the basal forebrain cholinergic system plays a role in central processing of pain.

Usage: Administration of 192-IgG-SAP with a 4-μg injection into the left lateral ventricle of rats. Animals were tested in temperature escape and sound stress models.

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Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets.

Wang L, Conner J, Nagahara A, Tuszynski M (2016) Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets. Proc Natl Acad Sci U S A 113:2750-2755. doi: 10.1073/pnas.1514682113

Summary: Rehabilitation is often prescribed after brain injury, but the basis for how training can influence brain plasticity and recovery is unclear. In this study, the authors show that intense rehabilitation training after focal brain injury drives significant structural changes in brain cells located adjacent to the injury. Importantly, a key brain modulatory system, the basal forebrain cholinergic system, is required for enabling rehabilitation to impact brain structure. Rats underwent cholinergic ablations by injecting 192-IgG-Saporin (Cat. #IT-01) into the nucleus basalis (0.2-0.25 mcl of 0.375 mg/ml solution in artificial CSF). Damage to the cholinergic system, which can occur naturally during aging, completely blocks brain plasticity mediated by rehabilitation and significantly attenuates functional recovery. These results provide new insights into how rehabilitation may promote recovery and suggest that brain cholinergic systems may be a possible therapeutic target for influencing recovery.

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Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.

Vazquez-DeRose J, Schwartz M, Nguyen A, Warrier D, Gulati S, Mathew T, Neylan T, Kilduff T (2016) Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain. Brain Struct Funct 221:923-940. doi: 10.1007/s00429-014-0946-y

Summary: The basal forebrain (BF) is one of the regions receiving excitatory input from orexin neurons. The authors investigated the hypothesis that orexin antagonists induce sleep at least in part by interfering with the facilitation of BF neurons. Rats received bilateral 500-ng injections of 192-IgG-SAP (Cat. #IT-01) into the BF. Lesioned animals displayed no abnormal responses to a benzodiazepine agonist or vehicle. An orexin antagonist, however, was less effective than the control at inducing sleep in lesioned rats.

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Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task.

Köppen J, Stuebing S, Sieg M, Blackwell A, Blankenship P, Cheatwood J, Wallace D (2016) Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task. Behav Brain Res 299:97-104. doi: 10.1016/j.bbr.2015.11.021

Summary: The memory impairments experienced in neurodegenerative disorders such as Alzheimer’s disease have been well documented. One theory attributes these impairments to the loss of cholinergic basal forebrain neurons, a hallmark of Alzheimer’s disease. Some patients experience a retrograde amnesia, in which older memories are relatively stable and more recent memories are frequently lost. The temporal relationship of memories to disease onset has not been definitively established. In this work the authors administered either 150 ng or 200 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats. Using a string-pulling task, a model for temporal learning was established. The results indicate that cholinergic projections originating in the medial septum are involved in long-term memory retrieval, and that loss of these neurons does not create a temporal type of amnesia.

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Neuroteratology and animal modeling of brain disorders

Archer T, Kostrzewa RM (2016) Neuroteratology and animal modeling of brain disorders. Curr Top Behav Neurosci 29:1-40. doi: 10.1007/7854_2015_434

Summary: This work covers development and use of the neurotoxins that are most commonly used as neuroteratologic agents - producing permanent, lifelong destruction of specific groups of neurons. Saporin conjugates are discussed, in terms of animal models of human neurodegenerative, neuropsychiatric, and neurological conditions. In contrast to 192 IgG-SAP treatment of adult rats,which also destroys cerebellar Purkinje cells, perinatal 192 IgG-saporin spares Purkinje cells which have a lower expression of p75NGF

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The effect of nucleus basalis magnocellularis deep brain stimulation on memory function in a rat model of dementia.

Lee J, Jeong D, Lee J, Chang W, Chang J (2016) The effect of nucleus basalis magnocellularis deep brain stimulation on memory function in a rat model of dementia. BMC Neurol 16:6. doi: 10.1186/s12883-016-0529-z

Objective: Deep brain stimulation (DBS) is the application of electrical impulses to specific parts of the brain for treating disorders such as Parkinson’s disease, chronic pain, and obsessive-compulsive disorder. This study investigated whether stimulation of brain structures associated with memory can enhance cognitive function.

Summary: Results indicate that DBS has beneficial effects on consolidation and retrieval of visuospatial memory.

Usage: The authors lesioned the basal forebrain of rats through bilateral injections totaling 5 μg of 192-IgG-SAP into the lateral ventricle. Animals then received DBS to the nucleus basalis magnocellularis and were tested in a Morris water maze task.

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Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation.

Hulsey D, Hays S, Khodaparast N, Ruiz A, Das P, Rennaker R, Kilgard M (2016) Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation. Brain Stimul 9:174-181. doi: 10.1016/j.brs.2015.12.007

Summary: Recent work has suggested that vagus nerve stimulation (VNS) can enhance neuroplasticity, and coupled with other training can drive motor cortex reorganization. These findings highlight the potential of VNS to support recovery from neurological disease. Pretrained rats received bilateral injections totaling 3.75 μg of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis (NB). Mouse-IgG-SAP (Cat. #IT-18) was used as control. Control animals displayed a substantial increase in proximal limb representation, lesion of the NB prevented this increase. Motor performance was similar between lesion and control groups, indicating that the difference in representation was not due to altered limb function.

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Basal forebrain cholinergic deficits reduce glucose metabolism and function of cholinergic and gabaergic systems in the cingulate cortex.

Jeong D, Oh J, Lee J, Lee J, Cho Z, Chang J, Chang W (2016) Basal forebrain cholinergic deficits reduce glucose metabolism and function of cholinergic and gabaergic systems in the cingulate cortex. Yonsei Med J 57:165-172. doi: 10.3349/ymj.2016.57.1.165

Summary: A common result of cholinergic neuron loss in the hippocampus and cortical regions due to Alzheimer’s disease is a reduction in glucose metabolism. The authors examine the interaction between the cell loss and metabolic changes. Rats received 5-μg bilateral cortical injections of 192-IgG-SAP (Cat. #IT-01), were subject to water maze testing, and analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. Lesioned animals displayed decreased learning performance and reduced metabolic activity in the cingulate cortex.

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Perinatal 192 IgG-saporin as neuroteratogen.

Petrosini L, De Bartolo P, Cutuli D, Gelfo F (2016) Perinatal 192 IgG-saporin as neuroteratogen. Curr Top Behav Neurosci 29:111-123. doi: 10.1007/7854_2015_418

Summary: The authors discuss the effects of perinatal administration of 192-IgG-SAP (Cat. #IT-01) and areas of research that have been investigated through the use of these lesions. The chapter covers a description of 192-IgG-SAP, lesioning methods, and outlines the short- and long-term biochemical, structural, behavioral, and cognitive effects of 192-IgG-SAP administration.

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Treatment efficacy of NGF nanoparticles combining neural stem cell transplantation on Alzheimer’s Disease model rats.

Chen Y, Pan C, Xuan A, Xu L, Bao G, Liu F, Fang J, Long D (2015) Treatment efficacy of NGF nanoparticles combining neural stem cell transplantation on Alzheimer's Disease model rats. Med Sci Monit 21:3608-3615. doi: 10.12659/msm.894567

Summary: NSC (neural stem cell) transplants into animals have been shown to compensate for the loss of cholinergic cells in the basal forebrain, a hallmark of Alzheimer’s disease. One hurdle to overcome is the actuation of NSC differentiation into the specific replacement cells needed. NGF has been shown to induce this differentiation, but it has a very short half-life and does not permeate tissue very effectively. In this work the authors administered 5 mcl of icv 192-IgG-SAP (Cat. #IT-01) to rats, followed by a graft of NCSs in the presence of NGF nanoparticles with a polymer coating. Rats receiving both NCSs and NGF nanoparticles showed significantly improved memory and learning functions as compared to control animals.

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Cognitive and motor deficits in a rodent model of Parkinson’s disease displaying concurrent dopamine and acetylcholine loss

Ostock CY, Conti MM, Larose T, Meadows S, Bishop C (2015) Cognitive and motor deficits in a rodent model of Parkinson’s disease displaying concurrent dopamine and acetylcholine loss. Neuroscience 2015 Abstracts 676.26/D33. Society for Neuroscience, Chicago IL.

Summary: Dopamine (DA) loss in Parkinson’s disease (PD) is frequently accompanied by degeneration of acetylcholine neurons within the basal forebrain (BF) and the pedunculopontine nucleus (PPN). Recently, Ach neurons in these nuclei have been implicated in both the motor and non-motor symptoms of PD. However, few rodent models of PD actually account for Ach loss in both the BF and PPN. Here, we evaluated the effects of concurrent BF and PPN Ach loss alone and in combination with striatal DA loss on motor and cognitive performance in a rat model of PD. Sprague-Dawley rats (N = 44) received bilateral: striatal 6-OHDA lesions to deplete DA (DA-lesioned; n = 14), BF (192 IgG-Saporin) and PPN (anti-ChAT Saporin) saporin lesions to deplete Ach (Ach-lesioned; n = 10), combined 6-OHDA + saporin lesions (dual-lesioned; n = 6) , or sham lesions (n = 14). Following recovery from surgery, rats underwent a battery of motor and cognitive behavioral tests. Results indicated that Ach-lesioned and dual-lesioned rats displayed spatial memory deficits on the Morris Water Maze and Spontaneous Alternation tests. DA and Ach lesions alone impaired stepping for the forepaw adjusting steps and vibrissae-elicited paw placement tests and this deficit was exacerbated in dual-lesioned rats. However, only rats with Ach or dual lesions showed motor deficits on the rotarod tests. Collectively, these findings demonstrate that Ach loss may exacerbate cognitive and motor symptoms in PD and highlight the importance of including Ach loss in preclinical models of PD.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-ChAT-SAP (Cat. #IT-42), Saporin (Cat. #PR-01)

Neuroprotective effects of placenta-derived mesenchymal stem cell for rat model of dementia

Lee J, Jeong D, Chang W, Chang J (2015) Neuroprotective effects of placenta-derived mesenchymal stem cell for rat model of dementia. Neuroscience 2015 Abstracts 626.12/AA3. Society for Neuroscience, Chicago IL.

Summary: Introduction: The neuroprotective effects of mesenchymal stem cell (MSC) in neurodegenerative disease have been recently reported. In contrast of the transplantation effect of MSC derived from bone marrow, adipose tissue and human umbilical cord blood, the study of placenta-derived mesenchymal stem cell (pMSC) is still little known. In this study, we studied the effective method of placenta-derived mesenchymal stem cell (pMSC) transplantation by comparing intracerebroventrical (icv) with intravenous (iv) injection. In addition, we also tried to compare the effect of pMSC transplantation and standard treatment for dementia. Materials and Methods: We used the rat model of dementia by damaging basal forebrain cholinergic neurons using 192 IgG-saporin. 1 week after administration of 192 IgG-saporin, pMSC was injected via intraventricular route (icv, 1.2 x 106 cells/ul) or intravenous route (iv, 5 x 106 cells/200 ul) and Cyclosporine (immunosuppressant drug) were administrated at peritoneal cavity for preventing immune reaction by innate immunity (daily / 5 weeks). To compare the effect of stem cell therapy and standard therapy, some rats were treated with donepezil and 5 weeks after transplantation, all animals were tested visuo-spatial cognitive functions by Morris water maze. Results: The probe test of water maze, performance of pMSC transplantation group and donepezil group increased time spent in target quadrant and in platform zone. Also acetylcholinesterase(AChE) activity was increased in the hippocampus and medial prefrontal cortex(mPFC). Interestingly, iv group showed more improved behavior performance and acetylcholinesterase(AChE) activity than icv group. Immunohistochemistry of stem121 marker of stem cell and iba1 maker of microglia and Western blot of DCX and BDNF were also suggested the beneficial effect of both stem cell therapy and standard donepezil treatment. Conclusions: Our result show that pMSC recover spatial memory of dementia model by increasing acetylcholinesterase(AChE) activity. Intravenous injection of pMSC seemed to be more beneficial route for both risk managing and symptom improvement. And pMSC transplantation also showed similar efficacy of the donepezil for improving cognitive function. For determining the superiority of both treatment, further investigation should be needed. Acknowledgements: This work was supported (YonseiChallenge) by the Yonsei University Future-leading Research Initiative of 2014 and CABMC (Control of Animal Brain using MEMS Chip) funded by Defense Acquisition Program Administration (UD140069ID).

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Compensatory cortical sprouting across the lifespan of the rat

Carnes B, DeLacalle S (2015) Compensatory cortical sprouting across the lifespan of the rat. Neuroscience 2015 Abstracts 391.10/C34. Society for Neuroscience, Chicago IL.

Summary: To investigate the plastic capacity of the cholinergic system in a partial animal model of Alzheimer’s disease, adult and aged rats received unilateral lesions of the horizontal diagonal band of Broca (HDB) using the cholinergic-specific toxin 192-IgG-saporin. The rats were sacrificed at 2, 4, 8, 12, or 24 weeks post lesion. Immuno- and histochemical techniques were used to quantify the effects of the lesion. Tissues were stained using an acetylcholinesterase technique. A 230µm by 200µm grid was used to indirectly measure the density of cholinergic fibers in the Entorhinal Cortex (EC). We compared our data to a young (3 month old) control group (Hartonian, 2005) in which the maximal loss of fiber density occurred by 8 weeks post-lesion and recovered to 75% of the intact contralateral EC by 12 weeks. All groups (young adult: 12-15; adult: 18; aged: 24-27 month old rats at the start of the experiment) exhibited a decrease in cortical fiber density after the lesion, which was more pronounced in the young adult group. All groups showed a recovery in fiber density to 60-80% of the intact side by 24 weeks post lesion. Interestingly, the loss occurred faster and more intense in the young adult group (to 25% of the intact side at 8 weeks post-lesion) than in the older ones (to 60% of the intact side by week 12 post lesion). Twenty four weeks after the lesion, the young adult group had recovered fiber density to 70%. The adult group also reached 70%, and the aged group reached 80% of the contralateral intact side. We conclude that following a cholinergic specific lesion, a compensatory mechanism is activated in the basal forebrain such that surviving neurons, projecting to the same target, are able to extend terminals and occupy the denervated area. It remains to be investigated whether the sprouts are able to establish proper synaptic connections and make a functional recovery.

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Basal forebrain cholinergic lesions attenuate the reinstatement of cocaine-seeking produced by a discriminative stimulus in goal-trackers but not sign-trackers

Jones JL, Pitchers KK, Robinson TE, Sarter M (2015) Basal forebrain cholinergic lesions attenuate the reinstatement of cocaine-seeking produced by a discriminative stimulus in goal-trackers but not sign-trackers. Neuroscience 2015 Abstracts 411.15/L-15. Society for Neuroscience, Chicago IL.

Summary: Goal-trackers (GTs), compared to sign-trackers (STs), express higher levels of acetylcholine when performing a cue detection and processing task. We hypothesized, therefore, that GTs utilize their basal forebrain cholinergic systems differently and to a greater extent than STs, such that this system may be critical for signal-induced behavior in GTs but not STs. The purpose of this experiment was to investigate individual variation in the reinstatement of drug-seeking behavior produced by a signal indicating cocaine availability (a discriminative stimulus), as well as the influence of the basal forebrain cholinergic system. STs and GTs were trained to self-administer cocaine using an intermittent access (IntA) procedure. The IntA procedure involved allowing animals access to cocaine for discrete 5-min drug available periods indicated by a light signal (DS+) separated by 25-min no drug available periods indicated by a different signal (DS-) in a different location than the DS+. This procedure results in ‘spiking’ brain levels of cocaine. Once stable performance was achieved on this procedure, animals underwent extinction training where the context remained similar to the IntA procedure but was now devoid of both DSs and an active response no longer had any consequence. STs and GTs did not differ in the acquisition or expression of self-administration or extinction training. After behavior was stably extinguished, half of the subjects received bilateral infusions of the cholinotoxic immunotoxin 192 IgG-saporin into the basal forebrain, while the other half received sham surgeries. Animals underwent 5 days of re-extinction. Finally, they underwent a reinstatement test during which the DS+ was presented non-contingently for 2 sec on a variable time schedule. Current results show that the ST-lesion group and both sham groups reinstated responding upon exposure to the DS+, compared to the last day of extinction. In contrast, the GT-lesion group did not reinstate responding, relative to the last day of extinction and, additionally, showed fewer active responses during the reinstatement test than the GT-sham group. Our findings suggest that the basal forebrain cholinergic system is involved in the reinstatement of drug-seeking behavior produced by a signal indicating drug availability in some animals (GTs), but not others (STs), further supporting the notion that drug cues are processed very differently in STs and GTs.

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Cholinergic contributions to PASA and functional compensation in rats

Yegla B, Francesconi JA, Forde JC, Parikh V (2015) Cholinergic contributions to PASA and functional compensation in rats. Neuroscience 2015 Abstracts 253.11/V29. Society for Neuroscience, Chicago IL.

Summary: Neuroimaging studies have indicated increased recruitment of prefrontal regions coupled to reduced activation of posterior regions in task-performing older adults. This shift of activity in cortical networks is described as posterior-anterior shift in aging (PASA). What cellular mechanisms contribute to PASA and how it provides functional compensation for age-related decline in cognitive capacities remains unknown? Cortically-projecting forebrain cholinergic neurons modulate cortical networks and facilitate attentional processes. Here we examined whether cortical cholinergic inputs contribute to PASA expression and maintenance of attentional capacities in aging. Young (3 months) and aged (24 months) Wistar rats were trained in a sustained attention task (SAT) that requires them to distinguish between signal and non-signal events. After attaining criterion performance (_70% correct responses for 3 consecutive sessions), rats received bilateral infusions of cholinoselective immunotoxin 192-IgG SAP either into the prefrontal cortex (PFC) or posterior parietal cortex (PPC) to produce partial cholinergic deafferentation. Control animals were infused with saline. Following behavioral testing 4 weeks post-surgery, animals were perfused 45-min after the last session to examine changes in neuronal activity in the PFC and PPC using c-fos immunohistochemistry. Partial prefrontal cholinergic deafferentation in aged rats produced robust deficits in response accuracy on signal trials as compared to aged sham (p=0.04) and young lesion (p=0.03) rats. In general, c-fos expressing neurons were higher in the PFC of aged rats as compared to young rats. Although prefrontal neuronal activity did not differ between the aged sham and PFC lesion group, there was a trend for a higher neuronal activity in the PPC of the latter. Surprisingly, attentional performance displayed a negative correlation with the prefrontal activity. Neuronal activity in the PPC did not correlate with performance. PPC-infused aged rats displayed no lesion effect on SAT and performed better than aged rats infused with 192 IgG-SAP into the PFC (p=0.04). Moreover, partial loss of cholinergic inputs into the PPC reduced PFC recruitment as compared to PFC lesioned aged rats. Collectively, these data suggest that reduced cortical activity in young rats compared to aged rats may represent better neural capacity, or the efficient utilization of normal brain regions, for task performance. Moreover, PASA is not triggered by prefrontal cholinergic inputs, but these inputs may regulate the reciprocal interactions between the PFC and PPC networks to maintain optimal performance in aging.

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Preliminary investigation on the antidepressive effect of chronic oxotremorine treatment in a rodent model of Alzheimer’s disease

Nair DV, Al-Badri MM, Peng H, Pachego-Quinto J, Eckman CB, Iacono D, Eckman EA (2015) Preliminary investigation on the antidepressive effect of chronic oxotremorine treatment in a rodent model of Alzheimer’s disease. Neuroscience 2015 Abstracts 40.29/C34. Society for Neuroscience, Chicago IL.

Summary: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the rate of progression varies from individual to individual. A great deal of evidence supports the idea that depression and other neuropsychiatric conditions co-exist with cognitive decline. However, the neurobiological basis of these symptoms and their influence on the clinical course of AD remain unclear. Our lab has shown previously that the 192-IgG saporin rat model of AD-like basal forebrain cholinergic cell loss exhibits a depression-like phenotype that develops months after the well-described impairment in spatial working memory. Furthermore, we have shown that chronic intracerebroventricular administration of the muscarinic agonist oxotremorine reverses both spatial working memory deficits and the depression-like behavior triggered by cholinergic denervation, and induces hippocampal neurogenesis. Current experiments are focused on determining additional pathological correlates of depression in this model and how they may be modulated by muscarinic agonists. To induce AD-like basal forebrain cholinergic cell loss, adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP) or saline as control (SHAM). After a 5 week recovery period, the rats received either 2 or 6 weeks of icv infusion of either oxotremorine or vehicle (saline) via osmotic minipump. Behavioral testing to assess the depressive phenotype was carried out using the sucrose consumption test every 2 weeks during oxotremorine treatment. The phenotype was further confirmed by forced swim test. The levels of ChAT, tryptophan hydroxylase (TPH), muscarinic receptors and FosB and ΔFosB were assessed in the hippocampus, basal forebrain, and orbitofrontal cortex by western blot and immunohistochemistry. Our preliminary results show increases in TPH, M1 receptors and FosB in the hippocampus, basal forebrain, and orbitofrontal cortex of a subset of treated animals, but no changes ChAT or ΔFosB. Further experiments are in progress to determine if there are changes in the expression of these and additional proteins in other brain regions including the nucleus accumbens, an area involved in activational aspects of motivation which also contributes to behavioral disorders such as to depression. The results of these studies may provide new insight in understanding the molecular basis of depression and antidepressant action of oxotremorine thereby defining new targets for possible therapeutic intervention for depressive symptoms in AD.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Denervation of the lacrimal gland leads to corneal hypoalgesia in a novel rat model of aqueous dry eye disease.

Aicher S, Hermes S, Hegarty D (2015) Denervation of the lacrimal gland leads to corneal hypoalgesia in a novel rat model of aqueous dry eye disease. Invest Ophthalmol Vis Sci 56:6981-6989. doi: 10.1167/iovs.15-17497

Summary: One result of functional disruption of the tear gland is dry eye disease (DED), which represents a group of disorders rather than a singular one. DED manifests itself in altered responses to noxious corneal stimulation, but many of these patients do not actually have dry eyes or tear gland dysfunction. In order to investigate what circuits are involved in DED the authors created two models, one of which used the ablation of p75 receptor-expressing neurons innervating the extraorbital lacrimal gland. Rats received 2.5 μg of 192-IgG-SAP (Cat. #IT-01) directly into the left extraorbital lacrimal gland. Tear production in the lesioned animals was normal, and responses to noxious cold stimuli were impaired. This accompanied by unchanged fiber density indicates that the nociceptive signaling was affected on a molecular level.

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Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats.

McHugh S, Francis A, McAuley J, Stewart A, Baxter M, Bannerman D (2015) Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats. Behav Neurosci 129:491-501. doi: 10.1037/bne0000072

Summary: It is unclear whether cholinergic lesions in the hippocampus affect both learning and behavior, or learning only. In this study the authors lesioned cholinergic neurons in the medial septum/vertical limb of the diagonal band of Broca of rats with bilateral 30-ng injections of 192-IgG-SAP (Cat. #IT-01). Although hippocampal cholinergic innervations were significantly reduced, with a concomitant reduction in choline acetyltransferase activity, the lesioned animals did not perform differently in several behavioral tests. The data do not provide evidence that the septo-hippocampal cholingeric projections play a role in anxiety, spatial novelty preference, or differential reward for low rates of responding tests.

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Exploratory behavior and recognition memory in medial septal electrolytic, neuro- and immunotoxic lesioned rats.

Dashniani M, Burjanadze M, Naneishvili T, Chkhikvishvili N, Beselia G, Kruashvili L, Pochkhidze N, Chighladze M (2015) Exploratory behavior and recognition memory in medial septal electrolytic, neuro- and immunotoxic lesioned rats. Physiol Res 64:755-767. doi: 10.33549/physiolres.932809

Summary: To investigate recognition memory that incorporates a spatial or temporal component, the authors lesioned the medial septum of rats using several techniques. For specific lesioning of cholinergic neurons rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01, 500 ng total) into the medial septum. Saporin (Cat. #PR-01) was used as a control. While electrolytic lesions produced disruptions of spatial recognition memory, immunotoxin lesions did not, indicating that the cholinergic neurons of the septohippocampal pathway are not essential to processing this type of learning.

Related Products: 192-IgG-SAP (Cat. #IT-01), Saporin (Cat. #PR-01)

Effects of immunotoxic and electrolytic lesions of medial septal area on spatial short-term memory in rats.

Dashniani M, Kruashvili L, Rusadze K, Matatradze S, Beselia G (2015) Effects of immunotoxic and electrolytic lesions of medial septal area on spatial short-term memory in rats. Georgian Med News 239:98-103.

Summary: In this work the authors investigated how essential septohippocampal projections are in a spatial working memory model. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01, 600 ng total) or GAT-1-SAP (Cat. #IT-32, 195 ng total) into the medial septum. Saporin (Cat. #PR-01) was used as a control.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32), Saporin (Cat. #PR-01)

Chronic oxotremorine treatment ameliorates depressive phenotype in a rodent model of Alzheimer’s disease

Nair DV, Al-Badri MM, Peng H, Schenkman N, Pacheco-Quinto J, Eckman CB, Iacono D, Eckman EA (2014) Chronic oxotremorine treatment ameliorates depressive phenotype in a rodent model of Alzheimer’s disease. Neuroscience 2014 Abstracts 670.03. Society for Neuroscience, Washington, DC.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative condition that is characterized by changes to brain structure and function. It is estimated that depression and other neuropsychiatric symptoms occur in up to 90% of AD patients, yet the neurobiological basis of these symptoms and their influence on the clinical course of AD remain unclear. Using a rat model of AD-like basal forebrain cholinergic cell loss, our lab has previously shown that central administration of a muscarinic receptor agonist, oxotremorine, for 4 weeks could induce hippocampal neurogenesis and reverse the spatial working memory deficit triggered by cholinergic denervation. Preliminary experiments conducted with this model in our lab also revealed a depressive phenotype emerging between 11 and 15 weeks after cholinergic denervation. The depressive phenotype was detected using a sucrose consumption test and further confirmed by forced swim test. The goal of the present study was to determine whether effects of chronic oxotremorine treatment could ameliorate the depressive phenotype observed after selective cholinergic cell loss in the basal forebrain. Adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP), to induce AD-like basal forebrain cholinergic cell loss. After a 5 week recovery period, the rats then received 8 weeks of icv infusion of either oxotremorine or vehicle (saline) via osmotic minipump. Behavioral testing to assess the depressive phenotype was carried out using the sucrose consumption test every 2 weeks during oxotremorine treatment. The phenotype was further confirmed by forced swim test. Biochemical analysis of a range of markers including tryptophan hydroxylase, the rate limiting enzyme for synthesis of serotonin, was performed after extraction of the brains following the behavioral tests. Results of these experiments demonstrate that oxotremorine treatment prevents the development of the depressive phenotype in SAP-lesioned rats. A number of oxotremorine-treated rats showed increases in tryptophan hydroxylase, suggesting a possible mechanism for the improved behavioral phenotype Based on these data, we propose that 192-IgG saporin lesioned rats may be an effective model for studying the pathophysiology and therapeutic modulation of age- and neurodegeneration-related neuropsychiatric symptoms such as depression.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The role of the basal forebrain cholinergic neurons in cued extinction memory

Schreiber WB, Keller S, Knox D (2014) The role of the basal forebrain cholinergic neurons in cued extinction memory. Neuroscience 2014 Abstracts 748.01. Society for Neuroscience, Washington, DC.

Summary: Fear extinction learning and memory requires inhibition of neural activity in amygdala (AMY) nuclei driven by neural substrates in the ventromedial prefrontal cortex (vmPFC), resulting in the behavioral phenotype of a decreased fear response (e.g. low levels of conditioned freezing). Fear extinction memory retrieval is sensitive to contextual feature manipulations, rendering extinction memory retrieval sensitive to hippocampal (HIPP) input to the AMY. Function of the vmPFC and HIPP requires cholinergic innervation from basal forebrain cholinergic neurons (BFCNs), including neurons in the nucleus basalis (NB), horizontal diagonal band of Broca (hDBB), vertical diagonal band of Broca (vDBB), and medial septum (MS). Given the importance of the vmPFC and HIPP for extinction memory, we hypothesized that intact BFCNs would be critical for extinction memory. We found that complete BFCN lesions using 192 IgG-saporin disrupted acquisition of cued fear extinction memory (Experiment 1). Follow-up studies examining more restrictive cholinergic lesions of the MS/vDBB (Experiment 2) or the NB/hDBB (Experiment 3) suggest these two clusters of BFCNs may differentially modulate acquisition and retention of cued extinction memory. The overall results of this study suggest that BFCNs are a component of the fear extinction circuit and a potential target for the pharmacological treatment of psychological disorders thought to stem from extinction memory deficits (e.g. PTSD).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Is selective hippocampal cholinergic deafferentation sufficient to produce temporally graded retrograde amnesia?

Köppen JR, Stuebing SS, Sieg M, Blackwell AA, Blankenship P, Grisley ED, Cheatwood JL, Wallace DG (2014) Is selective hippocampal cholinergic deafferentation sufficient to produce temporally graded retrograde amnesia?. Neuroscience 2014 Abstracts 749.20. Society for Neuroscience, Washington, DC.

Summary: Dementia of the Alzheimer’s type (DAT) is a neurodegenerative disorder marked by degeneration of basal forebrain structures and is associated with significant mnemonic deficits. The current study used a rat string-pulling task to evaluate whether selective cholinergic deafferentation of the hippocampus is sufficient to produce temporally graded retrograde amnesia. Female rats were pre-trained to pull strings to obtain reinforcement (cashew). Subsequently, rats were trained to discriminate between two scented strings. One scented string was consistently reinforced (+A), while the other scented string was never reinforced (B). After rats met criterion, they either waited two weeks (recent) or six weeks (remote) prior to receiving a sham surgery or infusion of 192-IgG-Saporin into the medial septum. Two weeks later rats were given four days of reversal training during which they experienced the same scented strings; however, the cashew was at the end of the string that was not previously reinforced. Following reversal training, rats were trained on a novel discrimination (+C/D). The results of the current study are consistent with selective cholinergic deafferentation of the hippocampus being sufficient to produce retrograde amnesia that was not temporally graded. First, all rats met criterion in a similar number of days. Rats receiving infusion of 192-IgG-Saporin into the medial septum had a higher number of correct responses during reversal training, relative to sham rats; however, no group differences were observed between recent and remote groups. Next, there were no group differences in the ability to learn a new discrimination. Finally, no group differences we observed in the latency to approach and pull up the string. The results were not caused by deficits in motivation or motor function, but they do reflect impairments in mnemonic function. The current study provides a novel behavioral assessment technique that models the retrograde amnesia characteristics observed in DAT.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The galantamine prodrug, Memogain®, reverses deficits in hippocampal neurogenesis associated with the loss of basal forebrain cholinergic neurons

Van Kampen JM, Kay DG, Maelicke A (2014) The galantamine prodrug, Memogain®, reverses deficits in hippocampal neurogenesis associated with the loss of basal forebrain cholinergic neurons. Neuroscience 2014 Abstracts 789.21. Society for Neuroscience, Washington, DC.

Summary: Loss of basal forebrain cholinergic innervation of the hippocampus and severe neuronal loss within the hippocampal CA1 region are early hallmarks of Alzheimer's disease (AD), and are strongly correlated with cognitive status. This loss of cholinergic innervation is a key factor underlying alterations in hippocampal neurogenesis, which are also characteristic of AD. We have previously reported the effects of various cholinergic compounds on hippocampal neurogenesis indicating that acetylcholine serves as a potent neurogenic regulator. Memogain® (GLN 1062) is an inactive galantamine pro-drug with 15 fold higher brain availability than galantamine. It is designed to provide improved blood brain barrier penetration, greater potency, and fewer side effects than the cholinesterase inhibitors currently used for the treatment of Alzheimer's dementia. This would serve both to promote patient adherence and permit the use of higher doses. Galantamine is unique among the cholinesterase inhibitors in that it also has allosteric actions at α-7 nicotinic receptors, activation of which has been linked to both disease-modifying and cognitive enhancing effects, as well as effects on hippocampal cell proliferation. Here, we describe the neurogenic actions of Memogain® in a rodent model of cholinergic depletion. Infusion of the immunotoxin, 192IgG saporin (SAP), used to induce selective basal forebrain cholinergic cell loss reminiscent of that found in AD, resulted in a pronounced loss of basal forebrain cholinergic neurons and hippocampal ChAT fiber density. Consistent with earlier reports, SAP-lesioned animals had significantly fewer BrdU+ and PCNA+ cells in both the dentate gyrus and CA1 region of the hippocampus, when compared to sham-operated control animals. These animals also displayed significant impairments in spatial working memory, as assessed by a T-maze and the radial arm maze. By contrast, animals treated with Memogain® displayed a restoration of hippocampal cell proliferation, increased neuronal cell counts, normalized neuronal migration, and improvements in cognitive function. Thus, the beneficial effects of Memogain® may extend beyond acute cognitive enhancement, to include disease modification through support of hippocampal neurogenesis.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The role of the supramammillary area in spatial learning and memory

Shim H, Park H-J, Lee H, Shim I (2014) The role of the supramammillary area in spatial learning and memory. Neuroscience 2014 Abstracts 652.05. Society for Neuroscience, Washington, DC.

Summary: The supramammillary area (SuM) of the hypothalamus, although small in size, has wide spread connection with numerous brain structures. It is known that the SuM can control the frequency of the hippocampal theta rhythm, which plays a role in the cognitive functions of the hippocampal formation. In order to examine the role of the specific cells of the SuM in learning and memory, selective cholinergic neurotoxic or excitotoxic lesioned rats of the SuM were tested for spatial memory on the Morris water maze (MWM) test. After the behavior tests, the expression of acetylcholine esterase (AChE) in the hippocampus was studied using the immunohistochemistry. In the MWM test, both lesion of the SuM with 192 IgG-saporin and ibotenic acid produced the impairment of spatial learning and memory. In the immunohistochemistry, the SuM-lesioned rat model by selective cholinergic neurotoxin showed decrease in the AChE expression in the hippocampal CA3. These findings suggest that cholinergic cells of the SuM area play a critical role in the process of consolidation of memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Vagus nerve stimulation dependent enhancement of cortical plasticity requires cholinergic innervation of the cortex

Hulsey D, Hays S, Khodaparast, N, Casavant R, Ruiz A, Das P, Nutting E, Carrier X, Iyengar M, Quareshi I, Sultana S, Rennaker R, Kilgard M (2014) Vagus nerve stimulation dependent enhancement of cortical plasticity requires cholinergic innervation of the cortex. Neuroscience 2014 Abstracts 542.20. Society for Neuroscience, Washington, DC.

Summary: Primary motor cortex (M1) transiently reorganizes in response to motor skill learning. Pairing forelimb movements with Vagus Nerve Stimulation (VNS) drives enhanced and robust analogous plasticity within M1. These changes occur outside of the typical period for motor plasticity and are independent of new skill learning. The mechanism by which VNS enhances M1 plasticity is not well understood. Skill learning and the associated cortical plasticity is dependent on cholinergic innervation of the cortex. VNS may enhance plasticity by engaging neuromodulatory systems necessary for plasticity. We hypothesize that cholinergic innervation of M1 is necessary for motor plasticity associated with VNS pairing. To test this hypothesis, we trained female Sprague Dawley rats on a skilled lever pressing task emphasizing use of the proximal forelimb. After task acquisition, one group of rats received a lesion to the cholinergic neurons of the basal forebrain using 192-IgG-Saporin, while another group received a control injection. All subjects also received a VNS cuff implant during the surgery. After one week of recovery, all subjects receive VNS paired to successful task performances for five days. Intracortical microstimulation was performed to derive M1 maps of each group 24 hours after their final VNS paired session. Subjects with an intact cholinergic system show significant expansion of proximal forelimb representation over naïve animals within the cortex. Subjects without cholinergic innervation of the cortex show no difference in M1 organization when compared to naïve animals. We conclude that cholinergic innervation is necessary for the effects of VNS on motor plasticity.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic regulation of aromatase in brain

Li J, Nelson D, Gibbs R (2014) Cholinergic regulation of aromatase in brain. Neuroscience 2014 Abstracts 640.10. Society for Neuroscience, Washington, DC.

Summary: Our goal is to understand mechanisms by which estrogens can influence brain function and cognition. Estrogens have been shown to influence neuronal plasticity and cognitive performance. Recent studies suggest that, in some cases, local estrogen synthesis can have a greater impact on neuronal survival and plasticity than systemic estrogen administration. Cholinergic projections also have a significant impact on neuronal plasticity in the brain, and recent studies demonstrate critical links between effects of estrogens and effects mediated by cholinergic inputs. In this project we are investigating whether aromatase expression and activity in specific regions of the adult brain are regulated by cholinergic activity. In one experiment, ovariectomized (OVX) rats were treated with the cholinesterase inhibitors donepezil (3 mg/Kg) or galantamine (5 mg/Kg) daily for one week prior to tissue collection. In a second experiment, OVX rats received intraseptal infusions of 192IgG-saporin (SAP) to selectively destroy cholinergic inputs to the hippocampus. Tissues were collected two weeks following the infusions. Different groups of rats were used to evaluate effects on aromatase mRNA and aromatase activity. Effects on aromatase mRNA were evaluated using qRT-PCR. Effects on aromatase activity were evaluated using a novel microsomal assay in which brain tissue microsomes were extracted and activity was measured in vitro by measuring conversion of testosterone to estradiol. Results show an increase in aromatase mRNA in the preoptic area following treatment with galantamine, but no effect in the hippocampus, frontal cortex, or amygdala. Galantamine also produced an increase in aromatase activity in the amygdala, but no significant effect in other brain regions. Donepezil had no significant effects on either aromatase mRNA or activity. Effects of the cholinergic lesions are still being evaluated; however, preliminary results suggest no significant effect on relative levels of aromatase mRNA in the hippocampus. These results indicate that cholinergic manipulations can affect aromatase expression and activity in specific regions of the brain such as the preoptic area and amygdala, with little or no effect in the hippocampus and frontal cortex. This could have important implications for the effects of cholinergic and anticholinergic medications on local estrogen production in the brain.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Spatial long-term memory and modulation of NMDA receptor subunit expression in medial septal immunolesioned rats

Kruashvili L, Mepharishvili M, Dashniani M, Burjanadze M, Demurishvili M (2014) Spatial long-term memory and modulation of NMDA receptor subunit expression in medial septal immunolesioned rats. Neuroscience 2014 Abstracts 463.19. Society for Neuroscience, Washington, DC.

Summary: The present study was designed to investigate the effect of selective immunolesions of cholinergic and GABA-ergic SH projection neurons (using 192 IgG-saporin and GAT-1 saporin, respectively) on spatial memory assessed in water maze and the N-methyl-D-aspartate (NMDA) receptor GluN2B subunit expression in the rat hippocampus. We used water maze training protocol with eight training trials. One day after training, probe test with the platform removed was performed to examine long-term spatial memory retrieval. We found that immunolesion of medial septal cholinergic neurons did not affect spatial learning as exhibited by a decreased latency to find the hidden platform across the eight training trials. In contrast, rats with immunolesions of medial septal GABAergic neurons did not show a decreased latency across training trials in water maze. Trained control rats spent significantly longer than chance (15 s) performances such as swimming time in test sector (where the hidden platform was located). Moreover, they spent significantly longer in test sector than in the opposite sector, confirming the establishment of long-term memory. In contrast, the preference for test sector was abolished in medial septal immunolesioned rats. Because Saporin treated rats learned the location of the hidden platform during training, the results suggest that saporin treated rats could not remember the training a day later. We found that the expression level of NR2B subunit of NMDA receptor in the hippocampus was decreased significantly in the GAT-1 treated group compared with the control and saporin treated groups. In conclusion, our findings suggest that immunolesion of medial septal GABAergic neurons can interrupt hippocampus[[unable to display character: ‐]]dependent spatial learning, possibly through modulation of NMDA receptor subunit expression in the hippocampus. Moreover, our finding that selective lesions of medial septal cholinergic neurons affects probe-test performance but not spatial learning, suggests that septohippocampal cholinergic projections are involved specifically in the consolidation or retrieval, but not in the acquisition of long-term spatial memory.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

The role of acetylcholine in learning: Cholinergic MSDB lesions retard trace eyeblink conditioning and decrease adult neurogenesis

Anderson ML, Nokia MS, Shors TJ (2014) The role of acetylcholine in learning: Cholinergic MSDB lesions retard trace eyeblink conditioning and decrease adult neurogenesis. Neuroscience 2014 Abstracts 177.10. Society for Neuroscience, Washington, DC.

Summary: Decades ago, acetylcholine was considered intrinsic to processes related to attention and/or learning and memory. However, in the last decade or so, this relationship has been questioned and with good reason. That said, only a few studies have addressed the involvement of acetylcholine in tasks that require an animal to associate stimuli separated in time, such as trace eyeblink conditioning. Trace eyeblink conditioning is associated with hippocampal theta rhythmic activity and dependent on adult neurogenesis in the hippocampus, both of which are thought to be mediated by cholinergic activity. In the present study, 192 IgG-Saporin (SAP) was infused into the medial septum diagonal band (MSDB) complex of Sprague-Dawley rats to selectively kill cholinergic neurons bilaterally or unilaterally. Each side of the MSDB predominantly projects to the ipsilateral hippocampal formation. Animals were considered to have a bilateral lesion if the number of neurons that express choline acetyltransferase was reduced by at least 80% compared to sham animals or a unilateral lesion if the difference in the reduction between hemispheres was greater than 30%. Animals with bilateral, unilateral or sham lesions were trained with trace eyeblink conditioning at least 14 days after the SAP infusion. Animals were given 200 trials for four days for 800 trials in total. Animals with a sham lesion made more conditioned responses over all 800 trials compared to animals with bilateral and unilateral lesions. Conditioned responses increased over time in all groups. Taken together, bilateral and unilateral lesions both retard but do not drastically impair learning. In two separate experiments, the effect of bilateral and unilateral lesions on adult neurogenesis and theta rhythms was assessed. Animals were injected with 5-bromo-2’-deoxyuridine (BrdU) to label dividing cell at least 14 days after the SAP infusion. Seven days later, the number of BrdU-positive cells in the dentate gyrus of the hippocampus of animals with bilateral and unilateral lesions was reduced by ~40% in both hemispheres. Hippocampal local field potentials were recorded from another group of animals. Seven days following the SAP infusion, relative theta power was reduced in the bilateral but not unilateral group. However, by Day 14 relative theta power was similar in all three groups. This data suggests that a reduction in the number of new neurons in the hippocampus may be a contributing factor to a trace learning deficit as a result of a MSDB lesion. Moreover, disrupting septohippocampal cholinergic activity even in one hemisphere only is enough to reduce hippocampal adult neurogenesis and retard learning.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Prefrontal cholinergic overload and attentional capacities in aging

Yegla B, Kelbaugh A, Mookhtiar A, Parikh V (2014) Prefrontal cholinergic overload and attentional capacities in aging. Neuroscience 2014 Abstracts 211.25. Society for Neuroscience, Washington, DC.

Summary: The cognitive reserve hypothesis of aging posits that brain activity attempts to cope with functional age-related changes. Individuals with lower cognitive reserve are considered more susceptible to cognitive decline and age-related pathologies. However, what neuronal mechanisms underlie cognitive reserve, and how these mechanisms provide compensation for age-related decline in attentional capacities remains unknown. The basal forebrain cortical cholinergic input system is a critical component of the brain’s attentional system. Healthy older adults show attentional load-dependent posterior-anterior shift in aging (PASA) characterized by higher activation of the prefrontal regions. However, it is not known whether prefrontal cortex (PFC)-driven cholinergic mechanisms compensate for age-related decline in attentional capacities. Here, we investigated the impact of partial cholinergic deafferentation of the PFC on attentional capacities in young and aged rats. The impact of cholinergic depletion on neuronal activation in the PFC and posterior parietal cortex (PPC) was also investigated using a semi-quantitiative c-fos immunohistochemistry procedure. Young and aged rats were trained in an operant sustained attention task (SAT) that required the animals to distinguish between signal and non-signal events to attain a reward. After attaining criterion (70% correct responses on both trial types), animals either received bilateral infusions of 192-IgG saporin or sterile saline into the PFC and the performance was monitored for 4 weeks. Aged rats required more training sessions to acquire criterion than young rats. However, post-criterion performance prior to lesion surgeries remained similar between the two age groups. Saline-infused aged rats show a greater number of c-fos expressing cells in the PFC but not PPC as compared to the young animals. Restricted loss of prefrontal cholinergic inputs produced attentional impairments in aged rats (SAT scores: 0.43±0.08 vs. 0.63±0.05 in young lesioned rats). Moreover, lesioned aged rats show reduced c-fos positive counts in the PFC as compared to aged intact rats. Collectively, these data suggest that PASA shifts and prefrontal overload foster top-down processes to maintain attentional capacities in aging. Moreover, these compensatory processes are triggered by prefrontal cholinergic inputs.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Assessing removal of illumination as a signal: Effects of loss of basal forebrain corticopetal cholinergic neurons

Burk JA, Otoya D, Leong C, Ng A, Kozikowski CT (2014) Assessing removal of illumination as a signal: Effects of loss of basal forebrain corticopetal cholinergic neurons. Neuroscience 2014 Abstracts 263.06. Society for Neuroscience, Washington, DC.

Summary: In the vast majority of experiments assessing visual attention in animal models, tasks are employed that require the detection of a stimulus that was previously absent. Relatively few experiments have employed procedures where the signal is the removal of a previously presented stimulus. In the present experiment, we modified a previously validated measure of a visual attention that required detection of a signal (illumination of a central panel light for 500, 100 or 25ms) from “blank” trials when the light was not illuminated. Loss of basal forebrain corticopetal cholinergic neurons has been shown to decrease signal detection in this task. We modified the task so that the central panel light was illuminated throughout the intertrial interval and a signal occurred when the light was turned off (4-s) whereas a blank trial occurred when the central panel light remained illuminated. Male FBNF1 hybrid rats were trained in this revised attention task and then assigned to receive infusions of 192IgG-saporin or saline into the basal forebrain. Rats were retrained in the task after surgery and then received one session with a houselight flashing in the back of the chamber throughout testing and a second session with the signal decreased from 4-to 2-s. During presurgical training, we observed that animals required a longer signal to maintain stable task performance when the signal involved turning off the central panel light. Surprisingly, loss of basal forebrain corticopetal cholinergic inputs was associated with higher rates of signal detection compared with sham-lesioned animals, although this effect was attenuated with subsequent training. Flashing the houselight decreased accuracy on blank trials, but did not differentially affect lesioned and sham-lesioned animals. Signal detection accuracy significantly declined in both lesioned and sham-lesioned animals when the signal duration was decreased. Collectively, these results suggest that task manipulations appear to have similar effects whether the signal involves turning the central panel light on or off. However, the neural mechanisms that are engaged during these two types of tasks appear to be different. Future work in our laboratory will explore the role of basal forebrain noncholinergic neurons in performance of a task with turning the central panel light off serves as a signal.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis.

Kalinchuk A, Porkka-Heiskanen T, McCarley R, Basheer R (2015) Cholinergic neurons of the basal forebrain mediate biochemical and electrophysiological mechanisms underlying sleep homeostasis. Eur J Neurosci 41:182-195. doi: 10.1111/ejn.12766

Summary: Previous work has indicated that non-rapid eye movement during recovery sleep after sleep deprivation requires cholinergic neurons in the BF. The authors examined how BF cholinergic neurons affect the levels of HSP markers during sleep deprivation. Rats received 230-ng injections of 192-IgG-SAP (Cat. #IT-01) into the horizontal limb of the diagonal band/substantia innominata/ magnocellular preoptic area. The results indicate that cholinergic neurons in the BF are important for regulating the biochemical and EEG mechanisms that contribute to HSP.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis.

Jeong D, Lee J, Lee S, Chang W, Kim S, Chang J (2014) Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis. Biomed Res Int 2014:568587. doi: 10.1155/2014/568587

Summary: Deep brain stimulation (DBS) is a technique by which electrical impulses are applied to specific areas of the brain as therapy for various disorders. In this work the authors examined the mechanisms by which DBS can treat dementia. Rats received 5.04 μg intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01); some rats also received an electrode implanted into the medial septum. Lesioned animals displayed deficits in water maze testing – this deficit was eliminated for the group that received electrical stimulation to the medial septum. The stimulated group also displayed an increase in hippocampal cholinergic activity as well as neurogenesis, indicating that DBS has therapeutic potential.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic immunotoxin 192 IgG-saporin alters subicular theta-gamma activity and impairs spatial learning in rats.

Rastogi S, Unni S, Sharma S, Laxmi T, Kutty B (2014) Cholinergic immunotoxin 192 IgG-saporin alters subicular theta-gamma activity and impairs spatial learning in rats. Neurobiol Learn Mem 114:117-126. doi: 10.1016/j.nlm.2014.05.008

Summary: The authors investigated the role of the subiculum in spatial informational processing, specifically cholinergic modulation of subicular theta-gamma activity. Rats received 50-ng injections of 192-IgG-SAP (Cat. #IT-01) into the ventral subiculum. Lesioned animals displayed altered theta and gamma activity as well as impaired spatial learning. The hippocampal cholinergic innervations remained intact, indicating that cholinergic modulation of theta-gamma activity in the subiculum plays an important role in spatial information processing.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic contributions to supramodal attentional processes in rats.

Ljubojevic V, Luu P, De Rosa E (2014) Cholinergic contributions to supramodal attentional processes in rats. J Neurosci 34(6):2264-2275. doi: 10.1523/JNEUROSCI.1024-13.2014

Summary: Previous work has shown that cholinergic transmission is important for attentional processing of visual stimuli. It is not known whether the role of the cholinergic system is specifically in visual processing, or if it is involved in all types of attentional processing. The authors administrated bilateral 40 ng injections of 192-IgG-SAP (Cat. #IT-01) to the nucleus basalis magnocellularis of rats. Animals had been previously trained on both visual and olfactory 5-choice serial reaction time tasks. Lesioned animals displayed deficits on both the visual and olfactory tasks when the attentional demand of the task was increased. The data suggest a modular cortical network that services both visual and olfactory attentional processes.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Medial septal cholinergic neurons modulate isoflurane anesthesia.

Tai SK, Ma J, Leung LS (2014) Medial septal cholinergic neurons modulate isoflurane anesthesia. Anesthesiology 120(2):392-402. doi: 10.1097/ALN.0b013e3182a7cab6

Summary: General anesthesia is associated with a decrease in cholinergic function. This work examines the effect of volatile anesthetics such as isoflurane or ketamine in the context of cholinergic depletion. Rats received 105-ng bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Anesthetic effects were evaluated using a loss of righting reflex test. There was no difference between lesioned and control groups in the response to ketamine. When treated with isoflurane, lesioned animals were affected for longer periods of time, and hippocampal response was reduced. The results suggest a role for septal cholinergic neurons in the sensitivity to isoflurane.

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Selective potentiation of (alpha4)3(beta2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.

Grupe M, Paolone G, Jensen AA, Sandager-Nielsen K, Sarter M, Grunnet M (2013) Selective potentiation of (alpha4)3(beta2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats. Biochem Pharmacol 86(10):1487-1496. doi: 10.1016/j.bcp.2013.09.005

Summary: Nicotinic acetylcholine receptors (nAChR) are involved in a wide range of processes in the central nervous system, many having to do with higher cognitive functions. In order to better understand how these receptors mediate attentional performance, the authors investigated glutamate release under varying conditions. In one series of experiments rats received a 160-ng injection of 192-IgG-SAP (Cat. #IT-01) into the right medial prefrontal cortex. The resulting decrease in glutamate release after the cholinergic lesion adds to the data indicating that positive modulation of nAChR may help alleviate attentional impairments caused by some brain disorders.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Activation of NF-κB signaling in the hippocampus without cholinergic input was aggravated by chronic stress

Lee S-Y, Kim M-S, Han J-S (2013) Activation of NF-κB signaling in the hippocampus without cholinergic input was aggravated by chronic stress. Neuroscience 2013 Abstracts 717.18. Society for Neuroscience, San Diego, CA.

Summary: Previous studies have demonstrated that loss of cholinergic input to hippocampus contributes dysfunction of HPA axis and alters GR-PKA-NF-κB signaling in hippocampus. In the hippocampus without cholinergic input, interactions of GR and PKA are decreased, whereas interactions of PKA and NF-κB are increased and phosphorylations on Ser276 of NF-κB p65 are increased. On the other hand, activation of NF-κB p65 is associated with behavioral action of stress and depression. The present research was conducted to examine whether NF-κB activation induced by cholinergic lesions is aggravated in response to chronic stress. Young adult rats received immunotoxic lesions of basal forebrain cholinergic neurons by intracranial injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band and substantia innominata/nucleus basalis. After 2 weeks recovery from surgery, rats with cholinergic lesions and vehicle-injected control rats were subjected to 1 hr restraint stress per day for 2 weeks. We examined that cholinergic deafferentation induced alterations in GR and NF-κB p65 expression in hippocampus and prefrontal cortex. Rats with cholinergic deafferentation and chronic stress showed more activation of NF-κB p65 signaling in the hippocampus compared with rats with cholinergic deafferentation only. Thus the loss of cholinergic integrity during aging and in AD might increase proneness to chronic stress.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Assessment of the contributions of baseline performance and prefrontal cortical cholinergic projections to orexin A-induced attentional enhancement.

Zajo KN, Fadel JR, Burk JA (2013) Assessment of the contributions of baseline performance and prefrontal cortical cholinergic projections to orexin A-induced attentional enhancement. Neuroscience 2013 Abstracts 854.02. Society for Neuroscience, San Diego, CA.

Summary: Orexinergic neurons innervate several brain regions including the basal forebrain, a structure known to be crucial for normal attentional performance in rats. Our previous research demonstrated that orexin receptor blockade impairs attention and that infusions of orexin A into the lateral ventricle enhance attentional performance in animals that have just reached criteria for stable performance levels on a sustained attention task. Our current research investigated whether more highly trained animals show orexin A-induced enhancement of attentional performance and whether basal forebrain cholinergic inputs to the medial prefrontal cortex were necessary for orexin A-induced attentional enhancement. Male FBNF1 hybrid rats were trained in a sustained attention task that required discrimination of visual signals (500, 100 or 25-ms illumination of a central panel light) from trials when no signal was presented. After stable performance levels were established, rats received both intraventricular guide cannula implantation and infusions of either the immunotoxin 192IgG-saporin or vehicle into the medial prefrontal cortex. Postsurgically, rats were retrained to stable performance levels and then received infusions of 0 (vehicle), 10, 100 or 1000pM orexin A in a counterbalanced order prior to task performance. On infusion days, rats were exposed to a version of the task which increased attentional demands by presenting a visual distracter during the middle block of trials within a testing session. In rats trained to higher performance levels, intraventricular orexin A infusions did not significantly enhance attentional performance. Loss of cholinergic projections to the medial prefrontal cortex decreased attentional performance, particularly when a visual distracter was presented. Attentional performance was unaffected in lesioned rats when orexin A was infused into the lateral ventricle. Our findings suggest that orexin A-induced attentional enhancement may be dependent upon baseline performance levels and possibly the integrity of the basal forebrain cholinergic projections to the medial prefrontal cortex.

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Increased hippocampal neurogenesis and prolonged amelioration of memory deficits by chronic oxotremorine treatment in a rodent model of Alzheimer’s disease.

Nair DV, Al-Badri MM, Rogido M, Pacheco-Quinto J, Peng H, Iacono D, Eckman CB, Eckman EA (2013) Increased hippocampal neurogenesis and prolonged amelioration of memory deficits by chronic oxotremorine treatment in a rodent model of Alzheimer’s disease. Neuroscience 2013 Abstracts 599.01. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic transmission plays a predominant role in memory processes, and loss of basal forebrain cholinergic innervation of the hippocampus has been correlated with memory impairment in Alzheimer’s disease (AD), as well as in decreased hippocampal neurogenesis in rats. Using a rat model of AD-like basal forebrain cholinergic cell loss, our lab has previously shown that central administration of a muscarinic receptor agonist, oxotremorine, for 4 weeks could reverse the spatial working memory deficit triggered by cholinergic denervation and induce hippocampal neurogenesis. The goal of the present study was to examine whether effects of chronic oxotremorine treatment persist beyond the treatment period, possibly indicating a disease-altering effect of the drug, particularly on memory function. Adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP), to induce AD-like basal forebrain cholinergic cell loss. After a 5 week recovery period, the rats then received 8 weeks of icv infusion of either oxotremorine or saline via osmotic minipump. Behavioral testing in a partially baited radial arm maze began 4 weeks after oxotremorine treatment was discontinued. To analyze cell proliferation, rats received intraperitoneal injections of BrdU either during the first 2 weeks of treatment, or at the end of behavioral testing. One month after oxotremorine treatment was discontinued, SAP-lesioned rats showed persistent improvements in radial arm maze acquisition, such that there was no difference in performance among sham/saline, sham/oxotremorine, and SAP/oxotremorine groups. SAP-lesioned rats treated with saline, however, still showed significant impairments compared to the other groups. Neuropathological and stereological analyses of these brains are ongoing, including analysis of hippocampal neurogenesis and neuronal cell counts in both basal forebrain and hippocampal regions. In a parallel cohort of rats analyzed at the end of the 8 week treatment period, initial results indicate no change in cholinergic cell density but a modest increase in the number of GABAergic cells in medial septum/diagonal band of lesioned rats treated with oxotremorine compared to saline. In the dentate gyrus (DG) of the hippocampus, increased numbers of cells labeled with BrdU during the first 2 weeks of treatment persisted to the end of the experiment, with an overall 1.5-fold increase in the number of BrdU labeled cells detected in the DG. These findings demonstrate that muscarinic stimulation is a promising target in the development of drugs to treat disorders involving cholinergic loss, such as AD.

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Loss of medial prefrontal cortical cholinergic projections increases preference for an immediately available reward in a delay discounting task.

Burk JA, Yonezaki K (2013) Loss of medial prefrontal cortical cholinergic projections increases preference for an immediately available reward in a delay discounting task. Neuroscience 2013 Abstracts 288.02. Society for Neuroscience, San Diego, CA.

Summary: Attentional control is thought to regulate numerous processes, including impulsive choices. The cholinergic projections to the medial prefrontal cortex are thought to be part of a distributed neural circuit that maintains attentional control. In the present experiment, male FBNF1 hybrid rats were trained in a delay discounting task that involved a choice between a small, immediately available reward and a larger reward. The larger reward was also immediately available at the beginning of the test session and then the delay to receive this reward was progressively increased within a session (0-40 s). After reaching stable performance levels, rats then either received infusions of the cholinergic immunotoxin, 192IgG-saporin, or vehicle into the medial prefrontal cortex. After recovering from surgery, rats were tested in the same delay discounting task that had been trained prior to surgery. Relative to sham-lesioned animals, rats with a loss of the cholinergic projections to the medial prefrontal cortex exhibited an increased preference for selecting the smaller, immediate reward. Subsequent administration of nicotine (0.0, 0.1, 0.2, 0.4 mg/kg, ip) did not substantially alter the effects of the lesion on delay discounting performance. The present results suggest that medial prefrontal cortical cholinergic projections contribute to choice behavior based upon delay to reward access and reward magnitude. Moreover, these results are consistent with the idea that disruption of attentional control can increase impulsive choices.

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Selective basal forebrain cholinergic deficits reduce glucose metabolism, cholinergic and GABAergic system in the cingulate cortex.

Lee J, Jeong D, Oh J, Lee J, Chang W, Cho Z, Chang J (2013) Selective basal forebrain cholinergic deficits reduce glucose metabolism, cholinergic and GABAergic system in the cingulate cortex. Neuroscience 2013 Abstracts 45.12. Society for Neuroscience, San Diego, CA.

Summary: Reduction of brain glucose metabolism and degeneration of cholinergic basal forebrain neurons are common features in Alzheimer’s disease and have been correlated with memory function. Although regions representing glucose hypometabolism in Alzheimer’s disease patients are target sites of cholinergic basal forebrain neurons, an interaction between cholinergic denervation and glucose hypometabolism is still unclear. To evaluate the changes in glucose metabolism in regions relevant to basal forebrain cholinergic deficits, we damaged basal forebrain cholinergic neurons of rats using 192 IgG-saporin. After 3 weeks, lesioned animals were tested by water maze test or analyzed using 18F-2-fluoro-2-deoxyglucose positron emission tomography. During the probe test in the water maze, performance of the lesion group decreased, considering time spent in both the target quadrant and platform zone. Glucose metabolism in the cingulate cortex of the lesion group decreased compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression both declined in the cingulate cortex. Our results reveal that spatial memory impairment of animals in which basal forebrain cholinergic neurons are selectively damaged is associated with a decline in functions of GABAergic, cholinergic, and glutamatergic systems associated with glucose hypometabolism in the cingulate cortex.

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Neuroprotective effects of donepezil against cholinergic depletion.

Cutuli D, De Bartolo P, Caporali P, Tartaglione AM, Oddi D, D’Amato FR, Nobili A, D’Amelio M, Petrosini L (2013) Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res Ther 5(5):50. doi: 10.1186/alzrt215

Summary: Acetylcholinesterase inhibitors appear to be one of the only pharmacological tools available to reduce cognitive deficits caused by the loss of cholinergic neurons in the basal forebrain. Here the authors pre-treated rats with the aceytlcholinesterase inhibitor donepezil before administering 0.5 μg of 192-IgG-SAP (Cat. #IT-01) into each side of the medial septum. Analysis of working memory, spatial discrimination, social novelty preference, and ultrasonic localizations, along with measuring hippocampal and neocortical caspase-3 activity indicates that donepezil pre-treatment ameliorates some effects of the cholinergic depletion.

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Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation.

Kucinski A, Paolone G, Bradshaw M, Albin RL, Sarter M (2013) Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33(42):16522-16539. doi: 10.1523/JNEUROSCI.2545-13.2013

Summary: Parkinson's disease produces a range of symptoms, some of which are unresponsive to therapies such as levodopa. These nonmotor symptoms include cognitive impairments and deficiencies in gait and balance. Here the authors develop a system to assess fall propensity in rats and examine the interaction between loss of cortical cholinergic and striatal dopaminergic afferents. Rats received 160-ng injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis and substantia innominata of the basal forebrain. The results indicate that the dual lesions result in diminished striatal control of complex movement.

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Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry.

Parent MJ, Cyr M, Aliaga A, Kostikov A, Schirrmacher E, Soucy JP, Mechawar N, Rosa-Neto P, Bedard MA (2013) Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry. EJNMMI Res 3(1):70. doi: 10.1186/2191-219X-3-70

Summary: Positron emission tomography (PET) imaging agents have been developed for the quantitative evaluation of cholinergic systems in vivo, and in this work the authors examine the concordance between the in vivo use of PET and post-mortem analysis of cholinergic damage. Rats received unilateral 0.2-0.25 μg injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. Animals were scanned using [18F]fluoroethoxybenzovesamicol, then sacrificed for cholineacetyltransferase immunohistochemistry. The results support the use of PET as an in vivo method for analyzing the loss of cholinergic neurons.

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Reprint: Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats.

Baxter MG, Bucci DJ, Gorman LK, Wiley RG, Gallagher M (2013) Reprint: Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats. Behav Neurosci 127(5):619-627 . doi: 10.1037/a0033939

Summary: In this reprint of a 1995 article, 192-IgG-SAP (Cat. #IT-01) was used to separate the depletion of cortical cholineacetyltransferase and behavioral impairment – which had previously been linked by research using less specific lesioning methods. Since the original 1995 publication, hundreds of papers have been published using a variety of lesioning techniques and a wide range of ATS products.

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See Also:

Selective immunotoxic lesions of basal forebrain cholinergic neurons: twenty years of research and new directions.

Baxter MG, Bucci DJ (2013) Selective immunotoxic lesions of basal forebrain cholinergic neurons: twenty years of research and new directions. Behav Neurosci 127(5):611-618 . doi: 10.1037/a0033781

Summary: This review covers twenty years of basal forebrain cholinergic lesioning. The initial use of 192-IgG-SAP (Cat. #IT-01) is discussed, as well as other immunotoxins such as GAT-1-SAP (Cat. #IT-32) and OX7-SAP (Cat. #IT-02). The findings generated by the use of 192-IgG-SAP and how those data have helped forward the understanding of how the cholinergic system functions in the basal forebrain are detailed. The authors also discuss new directions in the field.

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Neurotrophic factors rescue basal forebrain cholinergic neurons and improve performance on a spatial learning test.

Lee YS, Danandeh A, Baratta J, Lin CY, Yu J, Robertson RT (2013) Neurotrophic factors rescue basal forebrain cholinergic neurons and improve performance on a spatial learning test. Exp Neurol 249C:178-186. doi: 10.1016/j.expneurol.2013.08.012

Summary: It is thought that therapeutic treatments of the cholinergic system may be a viable treatment for Alzheimer's disease. In order to examine this hypothesis the authors administered a total of 160 ng of 192-IgG-SAP (Cat. #IT-01) in the form of bilateral injections into the medial septum. The lesioned animals then received 4-week infusions of nerve growth factor, neurotrophin 3, or both into the lateral ventricles. Animals treated with any neurotrophin, either alone or as a combination, retained more ChAT-positive neurons and performed better on a delayed match-to-position task than control animals. The data strengthen the theory that exogenous neurotrophic factors ameliorate the effects of Alzheimer's disease.

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Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration.

Gelfo F, Petrosini L, Graziano A, De Bartolo P, Burello L, Vitale E, Polverino A, Iuliano A, Sorrentino G, Mandolesi L (2013) Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration. Neurochem Res 38(10):2114-2123. doi: 10.1007/s11064-013-1120-2

Summary: In this work the authors investigated the connection between cholinergic depletion caused by conditions such as Alzheimer's disease and cerebral energy metabolism deficits. Rats received a 0.4-μg injection of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. Neuronal metabolic activity was measured by assaying cytochrome oxidase (CO) activity. The unilateral injection produced a bilateral deficit in CO activity throughout the cortex, and the front and parietal cortices showed CO deficits before the lesion was complete. The data suggest a link between cholinergic hypofunctionality and metabolic deficit.

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An environment-dependent modulation of cortical neural response by forebrain cholinergic neurons in awake rat.

Ariffin MZ, Chang LS, Koh HC, Low CM, Khanna S (2013) An environment-dependent modulation of cortical neural response by forebrain cholinergic neurons in awake rat. Brain Res 1513:72-84. doi: 10.1016/j.brainres.2013.03.046

Summary: Rats received 168 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum and induction of c-Fos expression in response to either familiar or novel stimuli was measured.

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Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline.

Lelkes Z, Porkka-Heiskanen T, Stenberg D (2013) Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline. J Sleep Res 22(6):721-726. doi: 10.1111/jsr.12061

Summary: Wakefulness is enhanced by the injection of noradrenaline into the basal forebrain, but it has not been clear whether cholinergic or non-cholinergic neurons are involved. 230 ng of 192-IgG-SAP (Cat. #IT-01) was administered to the horizontal diagonal band/substantia innominata/ magnocellular preoptic nucleus of rats. Upon treatment with methoxamine, lesioned animals lost the non-REM sleep-suppressing effect, but the REM sleep-suppressing effect remained intact.

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The role of visual cortex acetylcholine in learning to discriminate temporally modulated visual stimuli.

Minces VH, Alexander AS, Datlow M, Alfonso SI, Chiba AA (2013) The role of visual cortex acetylcholine in learning to discriminate temporally modulated visual stimuli. Front Behav Neurosci 7:16. doi: 10.3389/fnbeh.2013.00016

Summary: In order to examine some of the minor differences in the temporal structure of stimuli, the authors bilaterally injected 37.5 ng of 192-IgG-SAP (Cat. #IT-01) between the lambda and bregma of rats. This injection reduced acetylcholine projections to the visual cortex. Loss of that cholinergic input impaired the ability of the lesioned animals to perform fine discriminations, but previously learned discriminations remained unimpaired.

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Long-term effects of selective immunolesions of cholinergic neurons of the nucleus basalis magnocellularis on the ascending cholinergic pathways in the rat: A model for Alzheimer’s disease.

Szigeti C, Bencsik N, Simonka AJ, Legradi A, Kasa P, Gulya K (2013) Long-term effects of selective immunolesions of cholinergic neurons of the nucleus basalis magnocellularis on the ascending cholinergic pathways in the rat: A model for Alzheimer’s disease. Brain Res Bull 94C:9-16. doi: 10.1016/j.brainresbull.2013.01.007

Summary: 192-IgG-SAP (Cat. #IT-01) has been used extensively to generate models of Alzheimer's disease in rats. In this work, the authors detailed the time course of neuronal loss with an eye on potential recovery from the lesion. The nucleus basalis magnocellularis of rats was injected with 75 ng of 192-IgG-SAP (Cat. #IT-01) and long-term changes were tracked by immunohistochemistry. While some acetylcholinesterase neurons, considered cholinoceptive, were lost, choline acetyltransferase (cholinergic) neurons sustained a massive irreversible reduction in number.

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Spatial memory facilitation by electrical stimulation of the medial septum in rats.

Jeong D, Lee J, Lee S, Kim S, Chang J (2012) Spatial memory facilitation by electrical stimulation of the medial septum in rats. Neuroscience 2012 Abstracts 851.01. Society for Neuroscience, New Orleans, LA.

Summary: Recently, deep brain stimulation has been used to treat various neurological disorders. Some studies support that DBS can be a strategy to treat Alzheimer’s disease. The aim of this study was to evaluate the effect of electrical stimulation in the medial septum using rat model mimicking basal forebrain cholinergic deficits of Alzheimer’s disease. Four experimental groups were composed of normal, lesion, lesion + implantation and lesion + stimulation. 192 IgG-saporin (Selective cholinergic toxin, 8ul of 0.63ug/ul) were bilaterally injected into the lateral ventricle. Electrode was stereotactically implanted into the left medial septum (AP +0.6, ML 0.16, DV -6). Stimulation parameters are 50Hz, 120us pulse width and 1 volt. One week after implantation, Stimulation started for 2 weeks. Two weeks after surgery, water maze was performed for 1 week and rats were sacrificed immediately after behavioral test. Features were verified by immunochemistry and AChE assay. During the training trials, latencies of lesion and implantation significantly increased in day3 and day4. In contrast, latency of stimulation group had no differences as compared to normal group but it decreased significantly when compared to lesion group in day4. In the probe test, lesion group had decreases in time in target quadrant, time in platform zone and the number of platform crossing. Although they did not perform as normal group, stimulation group showed tendency of recovery. IHC and AChE assay are ongoing. Spatial memory is associated with hippocampus. We had expected activation of hippocampus by stimulation of the medial septum. We confirmed that stimulation of the medial septum facilitates acquisition and recall of spatial memory. Currently we are studying the effects of medial septal stimulation on the hippocampus.

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Cholinergic contributions to learned attentional suppression in the rat with touchscreens.

Ljubojevic V, Botly L, De Rosa E (2012) Cholinergic contributions to learned attentional suppression in the rat with touchscreens. Neuroscience 2012 Abstracts 729.13. Society for Neuroscience, New Orleans, LA.

Summary: One of the tasks of the attentional system is to filter environmental input according to its behavioral relevance. The neuromodulator acetylcholine (ACh) is thought to play a role in this process because of its ability to boost the signal-to-noise ratio of incoming sensory information. Cholinergic innervation of the attentional system has been shown to be necessary for successful selection of behaviorally-relevant stimuli (signal). However, it is not yet clear if ACh also plays a part in the attentional suppression of behaviorally-irrelevant information (noise). Thus, we examined the effect of cortical cholinergic deafferentation on attentional suppression in rats. To measure attentional suppression, we used a rat analog of the learning-to-ignore (LI) task originally designed for human participants (Dixon et al., 2009). The paradigm consisted of three stages of training (Prime1, Prime2, Probe; 10 sessions per stage), each of which involved stages of visual simultaneous discriminations between two stimuli. In both Prime conditions, individuals learned to respond to target stimuli (A+ and then C+ respectively), while ignoring the same distractor stimulus (B-). During Probe, the previously ignored stimulus became the target (B+) and a novel stimulus (D-) was introduced as a distractor. Eighteen male Long-Evans rats were trained to perform the touchscreen-based LI task. Like the human data, a behavioral decrement (lower accuracy) was observed during the Probe phase of the LI task when compared to Prime 1 and 2, which suggests that the ignored distractor stimulus was suppressed during Prime. We hypothesized that administration of the ACh-specific immunotoxin, 192 IgG-saporin, into the nucleus basalis magnocellularis (NBM) would lead to better performance during Probe condition relative to controls. Accordingly, the rats were subjected to either cholinergic immunotoxic (SAP, N=10) or sham lesion surgery (SHAM, N=8). After 2 weeks of post-surgical recovery, the rats were tested on the LI task with a new stimulus set. The two groups performed comparably during Prime1 and 2, with both SAP and SHAM rats successfully learning the discriminations. As predicted, during Probe SAP rats exhibited significantly less behavioral decrement than controls. Histological analysis revealed that the lesion was chemically and anatomically specific to cholinergic cells in the NBM. This counterintuitive finding suggests that the improved performance during Probe, due to reduced ACh input to the neocortex, was due to inefficient attentional suppression of the behaviorally-irrelevant stimulus.

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Effects of a dual hypocretin receptor antagonist on sleep and wakefulness in rats.

Schwartz MD, Dittrich L, Fisher SP, Lincoln W, Liu H, Miller MA, Warrier DR, Wilk AJ, Morairty SR, Kilduff TS (2012) Effects of a dual hypocretin receptor antagonist on sleep and wakefulness in rats. Neuroscience 2012 Abstracts 799.23. Society for Neuroscience, New Orleans, LA.

Summary: Benzodiazepine receptor agonists promote sleep by activating GABAA receptors, leading to generalized reduction in cortical activity. They are widely used as hypnotic medications, but have side effects including risk for tolerance and/or dependence, as well as cognitive impairment while under their influence. The excitatory hypocretin (HCRT) neuropeptides promote wakefulness by activating multiple subcortical wake-promoting neurotransmitter systems which, in turn, project to and regulate cortical activity. Blocking HCRT signaling should therefore promote sleep by acting specifically on subcortical brain areas regulating sleep and wake without adversely impacting cortical function. Here, we assessed the ability of the dual HCRT receptor antagonist almorexant (ALM) to promote sleep in rats following ablation of a major sleep-wake regulatory region, the cholinergic basal forebrain (BF). We predicted that ALM would be less effective at inducing sleep in BF-lesioned rats compared to neurologically-intact rats, whereas benzodiazepine-based compounds should be equally as effective in lesioned and intact rats. Male rats received bilateral stereotaxic injections of saline or the selective cholinergic neurotoxin192-IgG-saporin (SAP) directed at the BF and were implanted with telemetry for recording sleep EEG. Following recovery, animals were given increasing doses of ALM, the GABA-A receptor agonist zolpidem (ZOL), or vehicle. Spontaneous sleep/wake regulation and homeostatic recovery from sleep deprivation was also assessed. At baseline, NREM sleep in the dark (active) phase was reduced in SAP rats compared to intact rats; SAP rats also exhibited decreased NREM recovery sleep following 6 h sleep deprivation in the dark phase. Sleep in the light (rest) phase was unaffected by SAP. Analysis of ALM and ZOL administration in these animals is currently in progress.

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Positive allosteric modulation of 4 2* nicotinic acetylcholine receptors augments the amplitudes of prefrontal nicotine-evoked glutamatergic transients.

Grupe M, Paolone G, Jensen AA, Nielsen KS, Christensen JK, Grunnet M, Sarter M (2012) Positive allosteric modulation of 4 2* nicotinic acetylcholine receptors augments the amplitudes of prefrontal nicotine-evoked glutamatergic transients. Neuroscience 2012 Abstracts 696.15. Society for Neuroscience, New Orleans, LA.

Summary: α4β2* nicotinic acetylcholine receptors (nAChR) are a promising target for cognition enhancement. These receptors have been demonstrated to mediate the modulatory effects of the tonic component of cholinergic neurotransmission on fast prefrontal glutamatergic-cholinergic interactions. Specifically, α4β2* nAChR are expressed by thalamic glutamatergic afferents and amplify cue-evoked glutamatergic release events, thereby initiating a chain of neuronal events required for the detection of cues in attention tasks (Hasselmo & Sarter, 2011). In this study we investigated the effect of NS9283, a potent and selective positive allosteric modulator of low-sensitivity α4β2 nAChR (Timmermann et al., 2012), on nicotine-evoked glutamatergic release events in the mPFC of anaesthetized rats. Glutamatergic transients were recorded using amperometric measures of currents generated by the oxidation of glutamate and, subsequently, peroxide, on Platinum electrodes equipped with immobilized glutamate oxidase (see Parikh et al., 2010). Nicotine was pressure-ejected (0.040-2 nmol in 40-100 nL, respectively) into the vicinity of the recording electrode situated in the thalamic input layer of the prelimbic cortex. Systemic (i.p.) administration of NS9283 (3.0 mg/kg; administered 30 min prior to nicotine) enhanced the amplitude of glutamatergic transients evoked by the lowest dose of nicotine (40 pmol) by 72%. The modulator did not increase the efficacy of nicotine. Local pressure-ejections of NS9283 (400 pmol in 40 nL) per se were capable of evoking glutamatergic release events, presumably reflecting modulation of the effects of endogenous acetylcholine at these nAChRs. Accordingly, 192 IgG saporin-induced removal of cholinergic projections to the recording region abolished NS9283-evoked glutamatergic transients. Collectively, this evidence substantiates the identification of NS9283 as a positive modulator of nAChRs and its potency in vivo to modulate evoked glutamatergic release events. These results are consistent with the hypothesis that such compounds facilitate cue detection processes and thereby enhance attentional performance. Supported by NIH grant MH080332 and The Ministry of Science, Innovation and Higher Education, Denmark, PhD grant 10-084289.

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The effects of basal forebrain cholinergic neuron of recognition tests.

Lee J, Jeong D, Chang J (2012) The effects of basal forebrain cholinergic neuron of recognition tests. Neuroscience 2012 Abstracts 345.10. Society for Neuroscience, New Orleans, LA.

Summary: The cholinergic neurons of the Medial septum and the basal nucleus areas of the basal forebrain project to the frontal cortex and the Hippocampus, and degeneration of the cholinergic basal forebrain neuron is a common feature of Alzheimer's disease(AD) and vascular dementia and it has been correlated with cognitive decline. This research studied to verify the effects of cholinergic neuron in basal forebrain and the role of hippocampus and frontal cortex on recognition through recognition test and immunohistochemistry after damaging cholinergic neuron of the basal forebrain by intraventricular injection of 192 IgG-saporin. 192 IgG-saporin of 8ul (0.63ug/ul) was injected to the bilateral lateral ventricle of rats. After 2 weeks, Novel object recognition (NOR) test and Object in place (OIP) test was conducted to elucidate damage of cholinergic neuron. After completing the behavioral test, the ChAT cholinergic neuron in the brain was ascertained to confirm with immunohistochemistry if cholinergic neuron was damaged. In NOR test, the lesion group with 192 IgG-saporin showed 10% lower novel object preference than normal group. In OIP test, the normal group showed 50% novel object preference and the lesion group with 192 IgG-saporin showed 30% novel object preference in an hour delay test. On the other hand, the normal group and the lesion group with 192 IgG-saporin shoed 33% and 35% novel object preference respectively in a day delay test. However, this rate is not that significant value enough to elucidate behavioral difference between normal group and lesion group. In immunohistochemistry, the number of cholinergic neuron was remarkably decreased in basal forebrain. According to both of the behavioral tests, lesion group seem to less remember novel object than normal group. Also, they searched less the novel object that changed its location than normal group in the short term condition. However, there was no significant difference in the long term condition. These results suggest that the lesion with 192 IgG-saporin can damage spatial working memory.In the Immunohistochemistry result of the lesion condition, cholinergic input to hippocampus in basal forebrain affects recognition. However, the effect is not so essential.

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Effects of chronic stress on alterations of GR-PKA-NF-kappa B signaling and spatial learning in rats with cholinergic deafferentation.

Lee S-Y, Ma J, Chung C, Han J-S (2012) Effects of chronic stress on alterations of GR-PKA-NF-kappa B signaling and spatial learning in rats with cholinergic deafferentation. Neuroscience 2012 Abstracts 345.20. Society for Neuroscience, New Orleans, LA.

Summary: Aging and Alzheimer’s disease (AD) is associated with diminished integrity of the cholinergic innervations of the hippocampus and cortex. Previously, we demonstrated that removal of the cholinergic innervations impaired regulation of the HPA axis with response to acute stress and induced changes in the interaction among glucocorticoid receptor (GR), nuclear factor-κB (NF- κB) p65, and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. The current research examined effects of chronic stress on the altered signaling induced by cholinergic deafferentation. Young adult rats received immunotoxic lesions of basal forebrain cholinergic neurons by intracranial injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band and substantia innominata/nucleus basalis. After 2 weeks recovery from surgery, rats with cholinergic lesions and vehicle-injected control rats were subjected to 1 hr restraint stress per day for 2 weeks. Rats with only cholinergic deafferentation or sham-operated rats with chronic stress showed intact spatial learning. Rats with cholinergic deafferentation that received chronic stress showed impairments of spatial learning. And we examined that cholinergic deafferentation induced alterations in GR and NF- κB p65 expression in hippocampus and prefrontal cortex. Thus the loss of cholinergic integrity during aging and in AD may increase proneness to chronic stress.

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Cholinergic basal forebrain neurons contribute to the biochemical and electrophysiological changes in the cortex during sleep deprivation.

Kalinchuk AV, Kim S, Mccarley RW, Basheer R (2012) Cholinergic basal forebrain neurons contribute to the biochemical and electrophysiological changes in the cortex during sleep deprivation. Neuroscience 2012 Abstracts 486.24. Society for Neuroscience, New Orleans, LA.

Summary: Short term sleep deprivation (SD) (2-3h) increases the levels of inducible nitric oxide (NO) synthase (iNOS)-mediated NO and adenosine (AD) in the basal forebrain (BF) (Basheer et al., 1999; Kalinchuk et al., 2006). We showed recently that the prolongation of SD for 5h triggers similar biochemical changes in the prefrontal/frontal cortex (PFC/FC), the area which receives projections from the BF (Kalinchuk et al., 2010). Lesion of the BF cholinergic cells using immunotoxin 192-IgG saporin attenuates SD-induced AD increase in the BF and recovery non-rapid eye movement (NREM) sleep response (Kalinchuk et al., 2008). However, it is not known whether the cholinergic cells play a role in SD-induced biochemical changes in the cortex. In the current study we lesioned BF cholinergic cells, and compared SD-induced biochemical changes simultaneously in the PFC and BF in the same animals before and after the lesion. We correlated the changes in the biochemical markers, NO and adenosine, with the changes in electrophysiological markers of homeostatic sleep pressure, encephalogram (EEG) theta power during SD and delta power during recovery NREM sleep after SD. Male rats were implanted with electrodes for EEG/electromyogram (EMG) recording and 2 guide cannulae for microdialysis probes targeting BF and PFC. Microdialysis samples were collected simultaneously from both areas every 30 min during 8h SD. Dialysates were analyzed for AD using high performance liquid chromatography (HPLC)/fluorescent detection and for NO metabolites nitrate and nitrite (NOx) using Fluorimetric Assay Kit (Cayman). The lesion of the BF cholinergic cells was performed using the local injections of 192-IgG saporin into the BF, and similar experiment was repeated 2 weeks after the injection. Histochemical analysis confirmed the localization of the probes in the BF and PFC and the quality of the lesion procedure. Before saporin injection, SD induced increases in the levels of NOx and AD, which became significant after 1h (NOx) and 2h (AD) of SD in the BF and after 4h (NOx) and 5h (AD) of SD in the FC. EEG recording detected increases in the intensity of theta power during SD and delta power during following recovery NREM sleep. 2 weeks after saporin injection, SD-induced changes in NOx and AD were significantly attenuated both in the BF and the PFC. Also the increases in theta and delta power were significantly attenuated. We conclude that cholinergic neurons of the BF, which provide strong activating input to the PFC, contribute to the generation of homeostatic sleep pressure during SD, including its biochemical and electrophysiological correlates.

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The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

Babalola PA, Fitz NF, Gibbs RB, Flaherty PT, Li PK, Johnson DA (2012) The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract. Neurobiol Learn Mem 98(3):303-310. doi: 10.1016/j.nlm.2012.09.003

Summary: Steroid sulfatase inhibitors such as dehydroepiandrosterone (DHEAS) have memory-enhancing effects. Working with both DHEAS and the steroid sulfatase inhibitor DU-14, the authors examined cholinergic function by infusing 0.2 μg of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats. The results indicate that memory associated with contextual fear is facilitated by steroid sulfatase inhibition, but acquisition of spatial memory is impaired by these same lesions.

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Histamine release in the basal forebrain mediates cortical activation through cholinergic neurons.

Zant JC, Rozov S, Wigren HK, Panula P, Porkka-Heiskanen T (2012) Histamine release in the basal forebrain mediates cortical activation through cholinergic neurons. J Neurosci 32(38):13244-13254. doi: 10.1523/JNEUROSCI.5933-11.2012

Summary: The basal forebrain modulates many functions, among them the regulation of wakefulness and cortical arousal. Previous data has linked increases in histaminergic transmission to increases in wakefulness. In order to further investigate various facets of this system, the authors injected 230 ng of 192-IgG-SAP (Cat. #IT-01) into the horizontal diagonal band of Broca/substantia innominata/magnocellular preoptic area of rats. While control animals displayed several changes on administration of exogenous histamine, the lesioned animals had none of these changes.

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Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance.

Paolone G, Lee TM, Sarter M (2012) Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance. J Neurosci 32(35):12115-12128. doi: 10.1523/JNEUROSCI.2271-12.2012

Summary: This work examined the role that neuronal mechanisms have in cognitive performance on a fixed-time task. The authors performed bilateral 160 ng infusions of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis and substantia innominata of the basal forebrain of rats that had reached stable performance on a sustained attention task. In control animals trained in the same task, prefrontal cholinergic neurotransmission persisted at the fixed time even after the task was terminated. Both lesioning and altering the task training time impaired task performance.

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Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

Savage S, Mattsson A, Olson L (2012) Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons. Neuroscience 216:38-45. doi: 10.1016/j.neuroscience.2012.04.064

Summary: Phenylcyclidine (PCP) has been used to model aspects of schizophrenia in animals. 81 ng of 192-IgG-SAP (Cat. #IT-01) was injected into the nucleus basalis magnocellularis of rats to assess the effects of low dose PCP in a cholinergically-deprived system. Saporin (Cat. #PR-01) was used as a control. Results demonstrate basalocortical cholinergic neurons are necessary for PCP to have full effect.

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PET imaging of cholinergic deficits in rats using [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV).

Parent M, Bedard MA, Aliaga A, Soucy JP, Landry St-Pierre E, Cyr M, Kostikov A, Schirrmacher E, Massarweh G, Rosa-Neto P (2012) PET imaging of cholinergic deficits in rats using [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV). Neuroimage 62(1):555-561. doi: 10.1016/j.neuroimage.2012.04.032

Summary: In order to better understand and evaluate neurodegenerative diseases imaging agents are necessary to visualize the affected systems. [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) is one such agent that shows promise for labeling the vesicular acetylcholine transporter with positron emission tomography. The authors injected 0.2 μg of 192-IgG-SAP (Cat. #IT-01) into the left hemisphere of rats to model cholinergic terminal loss as seen in aged animals. Loss of these terminals was found to reduce [18F]FEOBV binding in the ventral frontal cortex on the lesioned side, and also in the homologous region of the contralateral hemisphere, allowing detection of both physiological and pathological reduction of cholinergic terminals.

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Control of sleep and wakefulness.

Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW (2012) Control of sleep and wakefulness. Physiol Rev 92(3):1087-1187 . doi: 10.1152/physrev.00032.2011

Summary: This review summarizes mechanisms in the brain that control sleep and wakefulness. Areas discussed include wakefulness promoting systems, non-REM sleep and REM sleep definitions, the function of each kind of sleep, and dysfunction that occurs as a result of sleep disruption. Several targeted conjugates are mentioned, such as 192-IgG-SAP (Cat. #IT-01), anti-DBH-SAP (Cat. #IT-03), and orexin-SAP (Cat. #IT-20). The review summarizes the use of these products to better understand sleep networks.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03), Orexin-B-SAP (Cat. #IT-20)

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells.

Tai SK, Leung LS (2012) Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells. Behav Brain Res 232(1):174-182. doi: 10.1016/j.bbr.2012.04.013

Summary: It is known that vestibular stimulation induces acetylcholine release in the hippocampus. The authors hypothesized that this stimulation enhances long-term potentiation (LTP) in CA1 and depends on the activation of septohippocampal cholinergic neurons. Rats received 105-ng bilateral infusions of 192-IgG-SAP (Cat. #IT-01) into the medial septum. The data suggest that LTP enhancement during vestibular stimulation is mediated by cholinergic septohippocampal cells.

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Neonatal cholinergic lesion alters the acoustic structure of infant rat vocalization but not the early cognitive development.

Kruger HS, Hanganu-Opatz IL (2013) Neonatal cholinergic lesion alters the acoustic structure of infant rat vocalization but not the early cognitive development. Dev Psychobiol 55(3):294-308. doi: 10.1002/dev.21029

Summary: The architecture of the cerebral cortex is dependent on cholinergic innervations for proper maturation and network assembly. The authors administered 0.1 μg of 192-IgG-SAP (Cat. #IT-01) to each lateral ventricle of rats on the day of birth. Although the resulting cholinergic depletion did not affect the general development of the rats during the first two weeks of life, infant ultrasonic vocalization was significantly affected. The altered vocalization did not affect maternal care of the pup, suggesting that previous results recording behavioral deficits in the pups after basal forebrain lesions were due to cholinergic depletion rather than altered mother-pup interaction.

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Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus.

Kanju PM, Parameshwaran K, Sims-Robinson C, Uthayathas S, Josephson EM, Rajakumar N, Dhanasekaran M, Suppiramaniam V (2012) Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus. PLoS One 7(2):e31073. doi: 10.1371/journal.pone.0031073

Summary: Long term potentiation (LTP) is dependent on excitatory neurotransmission in the hippocampus, which plays a major role in learning and memory. The authors examine whether cholinergic lesions in the medial septum result in LTP alteration or affect synaptic glutamate receptor subtypes. After bilateral administration of 192-IgG-SAP (Cat. #IT-01, 50 ng per injection) into the medial septum of rats, hippocampal slices were made and the LTP of the slices was measured. The data show modulation of medial septal LTP and hippocampal glutaminergic currents by cholinergic afferents.

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Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex.

Tolner EA, Sheikh A, Yukin AY, Kaila K, Kanold PO (2012) Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex. J Neurosci 32(2):692-702. doi: 10.1523/JNEUROSCI.1538-11.2012

Summary: Immature cortices in both human and rat have spontaneous activity associated with the maturation of cortical synapses and neuronal circuits. In order to investigate what cells are controlling these events the authors administered 400 ng of 192-IgG-SAP (Cat. #IT-01) to the S1 cortex hindlimb/forelimb area of rats. mu p75-SAP (Cat. #IT-16) and mouse-IgG-SAP (Cat. #IT-18) were used as controls. This lesion eliminates subplate neurons which results in a significant loss of evoked spindle burst activity.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16), Mouse IgG-SAP (Cat. #IT-18)

Recognition of novel objects and their location in rats with selective cholinergic lesion of the medial septum.

Cai L, Gibbs RB, Johnson DA (2012) Recognition of novel objects and their location in rats with selective cholinergic lesion of the medial septum. Neurosci Lett 506(2):261-265. doi: 10.1016/j.neulet.2011.11.019

Summary: This work examined object recognition and object location recognition as specific components of memory. Rats received 0.22 μg of 192-IgG-SAP (Cat. #IT-01) infused into the medial septum followed by testing in novel object recognition (NOR) and object location recognition (OLR) models. Substantial decreases in choline acetyltransferase activity in the hippocampus and frontal cortex produced no difference in NOR but caused a significant impairment in OLR – highlighting the role that septo-hippocampal cholinergic projections play in OLR.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Cholinergic control in developing prefrontal-hippocampal networks.

Janiesch PC, Kruger HS, Poschel B, Hanganu-Opatz IL (2011) Cholinergic control in developing prefrontal-hippocampal networks. J Neurosci 31(49):17955-17970. doi: 10.1523/JNEUROSCI.2644-11.2011

Summary: In this work the authors examined the role of acetylcholine in the maturation of cognitive processing due to oscillatory rhythms entraining neuronal networks. Rats received 50 ng of 192-IgG-SAP (Cat. #IT-01) into each lateral ventricle, or 25 ng directly into the medial septum. Among other results, cholinergic input was shown to reach the prefrontal cortex toward the end of the first postnatal week, initially targeting GABAergic neurons. Reduction of this activity by lesioning cholinergic neurons may cause global diminishment of neocortical activity.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Impaired visual search in rats reveals cholinergic contributions to feature binding in visuospatial attention.

Botly LC, De Rosa E (2012) Impaired visual search in rats reveals cholinergic contributions to feature binding in visuospatial attention. Cereb Cortex 22(10):2441-2453. doi: 10.1093/cercor/bhr331

Summary: Previous work established the role of acetylcholine from the nucleus basalis magnocellularis in attentional processing and visuospatial attention. In order to investigate the necessity of cortical cholinergic input for support of feature binding in visuospatial attention the authors administered bilateral intraparenchymal injections of 192-IgG-SAP (Cat. #IT-01, 4 injections, 40 ng per injection). Lesioned animals took longer to locate targets during type-specific search trials, demonstrating that cholinergic input influences feature binding during visuospatial attention tasks.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Alterations in gene expression following cortical cholinergic denervation in rats

Savage ST, Olson L, Mattsson A (2011) Alterations in gene expression following cortical cholinergic denervation in rats. Neuroscience 2011 Abstracts 790.01. Society for Neuroscience, Washington, DC.

Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. Altered function and expression of both nicotinic and muscarinic acetylcholine receptors have been reported in cortical and subcortical regions in post-mortem schizophrenic brains. Pharmacologically, dopamine-releasing compounds, such as amphetamine, can induce the psychotic symptoms in healthy volunteers and exacerbate the symptoms in schizophrenics. Furthermore, the NMDA receptor antagonist phencyclidine (PCP) induces both negative symptoms (such as social withdrawal) and cognitive deficits similar to those exhibited in schizophrenics. We have previously shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (nbm) in adult rats leads to an enhanced sensitivity to both amphetamine and PCP. The enhanced sensitivity to amphetamine, shown by a potentiated dopamine release in nucleus accumbens, along with a marked increase in locomotor activity in response to both amphetamine and PCP, suggested that the disruption of cortical cholinergic activity can lead to disturbances of glutamatergic and dopaminergic transmission. Furthermore, bilateral lesioning of nbm led to a decrease in active social interaction, as well as, impairment after an acute PCP challenge in a cognitive task (novel object recognition). To further evaluate the consequences of cortical cholinergic denervation, we are analyzing the possible changes in mRNA expression levels of selected genes in rats with unilateral removal of the cortical cholinergic innervation by 192 IgG-saporin injections into nbm following acute PCP administration. Our data indicate that the induction of c-fos mRNA expression in cortex in response to PCP administration is markedly reduced in cholinergically denervated animals as compared to controls. Other genes are under investigation to elucidate the interplay between the cholinergic, dopaminergic, and glutamatergic systems.

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Decrease of GABAergic markers and Arc protein expression in the frontal cortex by injection of intraventricular 192 IgG-saporin

Jeong D, Chang W, Lee D, Chang J (2011) Decrease of GABAergic markers and Arc protein expression in the frontal cortex by injection of intraventricular 192 IgG-saporin. Neuroscience 2011 Abstracts 878.08. Society for Neuroscience, Washington, DC.

Summary: Previous studies used 192 IgG-saporin to study cholinergic function because of its facility for selective lesioning; however, results varied due to differences in the methods of administration and behavioral tests used. We investigated whether intraventricular injections of 192 IgG-saporin were suitable to make a dementia animal model for the evaluation of therapeutic drugs or electrical stimulation techniques. We examined the effects of 192 IgG-saporin using the Morris water maze, immunochemistry, and western blotting. Animals were examined 2 weeks after intraventricular injection of 192 IgG-saporin (0.63 µg/µl, 6 µl, 8 µl, and 10 µl) or phosphate buffered saline (8 µl). In the acquisition phase of the Morris water maze, the latencies of the injection groups were significantly delayed, but recovered within 1 week. In the probe test, two of four indices (time in the platform zone and the number of crossings) were significantly different between the control group and the group injected with 8 µl of 192 IgG-saporin. Immunohistochemistry revealed the extent of cholinergic destruction that was apparent in the basal forebrain of all 192 IgG-saporin injected rats. We found significantly decreased activity-regulated cytoskeleton associated protein (Arc) and glutamate decarboxylase (GAD) expression in the frontal cortex (8 µl and 10 µl groups), but not in the hippocampus, using western blotting. Further, spatial memory impairment was associated with cholinergic basal forebrain injury as well as fronto-cortical GABAergic hypofunction and synaptic plasticity deceleration. We conclude that intraventricular injection of 192 IgG-saporin is a suitable method for making a rat model of dementia.

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The effects of basal forebrain cholinergic neuron on novel object recognition

Lee J, Jeong D, Chang J (2011) The effects of basal forebrain cholinergic neuron on novel object recognition. Neuroscience 2011 Abstracts 878.10. Society for Neuroscience, Washington, DC.

Summary: Medial septum and basal nucleus areas of the basal forebrain project cholinergic neurons to the frontal cortex and the Hippocampus.And degeneration of the cholinergic basal forebrain neurons is a common feature of Alzheimer’s disease (AD) has been correlated with cognitive decline. This research was studied to verify the effects of cholinergic neuron in basal forebrain to the role of the hippocampus and the frontal cortex on recognition through recognition test and immunohistochemistry after damaging cholinergic neuron of the basal forebrain by intraventricular injection of 192 IgG-saporin. 192 IgG-saporin of 8ul (0.63ug/ul) was injected to the bilateral lateral ventricle of rats. After 2 weeks, novel object recognition (NOR) test was conducted to elucidate damage of cholinergic neuron. In the NOR test, rats are exposed to two identical objects for 15 minutes in empty plastic box (60cmx60cmx30cm). After 3 hours, they are reintroduced to the same object and a new novel object for 10 minutes. This procedure was repeated for 4 days After completing the behavioral experiment, the ChAT of cholinergic neuron in the basal forebrain was ascertained to confirm with immunohistochemistry if cholinergic neuron was damaged. In NOR test, the lesion group with 192 IgG-saporin showed 10% lower novel object preference than normal group. However, this rate is not that significant value enough to elucidate behavioral difference between normal group and lesion group. In immunohistochemistry, the number of cholinergic neuron was remarkably decreased in basal forebrain. According to both of the NOR test and Immunohistochemistry in the condition under lesion, Cholingergic input to hippocampus and frontal cortex from basal forebrain affects recognition somewhat, however the effect is not so essential.

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P300-like event related potentials in IgG192-saporin induced rat model of Alzheimer´s disease

Clausen B, Klipec W, Bastlund J, Collins M (2011) P300-like event related potentials in IgG192-saporin induced rat model of Alzheimer´s disease. Neuroscience 2011 Abstracts 550.01. Society for Neuroscience, Washington, DC.

Summary: The P300 event-related potential (ERP) is a time-locked response to rare, response-relevant stimuli. Decreased ERP amplitude is correlated with decreased memory function. Not surprisingly, alterations in P300 ERP amplitude are commonly associated with the progressive disruption of cognitive function in human Alzheimer’s disease. Here, a rat model of Alzheimer’s disease was created by injecting the antibody-linked toxin, IgG192-saporin, into the basal forebrain, producing a progressive degeneration of cholinergic cells to mimic the cholinergic degeneration that is part of Alzheimer’s disease. The goal of this experiment was to investigate the rat model by examining the relationship between the expected degenerative deficits and possible changes in the EEG patterns. Following preliminary training that has produced reliable P300-like ERPs in prior experiments in our lab, half of the rats were injected with IgG192-saporin (lesioned), while the other half were injected with saline (controls). Recording electrodes were surgically implanted on the surface of the brain and in the prefrontal cortex (PFC) and ventral hippocampus (vHipp). Following recovery, P300-like ERP data was recorded for three weeks, after which a ChAT analysis of choline acetyltransferase activity confirmed the extent of cholinergic damage in PFC and Hipp. While no systematic increases in latency were found, surprisingly, significant increases in P300-like ERP amplitude occurred in PFC and vHipp in the lesioned compared to the control rats. The implication of these findings for a rat model of Alzheimer’s disease will be discussed.

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Cholinergic reinforcement and temporal learning in rodent visual cortex

Roach EB, Hussain Shuler MG (2011) Cholinergic reinforcement and temporal learning in rodent visual cortex. Neuroscience 2011 Abstracts 608.16. Society for Neuroscience, Washington, DC.

Summary: The idea that neuromodulators act as reinforcement signals has an intricate scientific history, including the well-characterized analogue of prediction error relayed by midbrain dopamine neurons. Neuromodulators released from discrete nuclei are poised to broadcast to many brain regions at once, and so it is an appealing concept to investigate other neuromodulatory systems within a reinforcement learning framework. Reward timing activity, a neural reflection of operantly learned stimulus-reward intervals in the primary visual cortex (V1), offers a tractable in vivo model to examine the role of candidate neuromodulators in temporal reward learning. Reward timing was first characterized in rats trained to lick a delivery tube to receive water rewards, where stimulation to one eye indicated reward availability after x licks, while stimulation to the other eye required y licks. Simultaneously recorded activity in V1 indicated that single unit responses evolve from reporting only visual characteristics to showing persistent increased/decreased firing or peak activity corresponding to the time of anticipated reward. Individual neurons report one interval or the other, even those with binocular peri-stimulus responses, arguing that reward timing is learned locally within V1. Theoretical work suggests that the local expression of reward associated intervals requires an interaction between the visually-evoked network response and a reinforcement signal conveying the time of reward. Based on anatomical and neurophysiological evidence, we hypothesized that cholinergic input from the basal forebrain (BF) could provide such a reward signal to V1. To test its necessity, BF cholinergic innervation in V1 was lesioned -- using the selective neurotoxin 192 IgG-saporin -- prior to changing the experimental policy between cues and associated reward delays. This allowed an examination of two potential roles for BF cholinergic input: in expressing previously learned intervals and in acquiring information about new intervals. We found that neurons from saline-infused controls, but not lesioned animals, shifted as a population to report the new, behaviorally relevant intervals (Kolmogorov-Smirnov, p < 0.05). Importantly, neurons from lesioned animals continued to report the previously learned intervals, suggesting that BF cholinergic input is required to learn, but not express, reward timing. These results support the notion that acetylcholine released from BF afferents acts as a reinforcement signal that guides cortical network plasticity.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cognitive performance-associated increases in cholinergic neurotransmission also serve as a circadian signal to sustain performance-induced diurnal activity patterns.

Paolone G, Lamy D, Sarter M, Lee T (2011) Cognitive performance-associated increases in cholinergic neurotransmission also serve as a circadian signal to sustain performance-induced diurnal activity patterns. Neuroscience 2011 Abstracts 610.12. Society for Neuroscience, Washington, DC.

Summary: Daily practice of a sustained attention task (SAT) during the light phase of the light/dark cycle causes a stable, entrained, diurnal behavioral activity pattern (Gritton et al. 2009). As SAT performance is mediated by increases in cortical cholinergic neurotransmission, this experiment assessed levels of acetylcholine (ACh) release across the light and dark cycle of animals that previously performed the SAT at a fixed time. Circadian behavioral activity was recorded, and prefrontal ACh release was measured, using microdialysis, beginning on the third day following the last SAT session. SAT practice took place in either the light phase [ZT4], the dark phase [ZT16], or in a constant light condition [LL]. A control group practiced a daily fixed interval [FI-9] schedule of reinforcement at ZT4. A second control group was handled at randomly selected times but was neither water-deprived nor performed a task [NP]. Dialysates were collected, in a new environment, for 180 min total, beginning 90 min before the onset of prior task practice and again during the equivalent time period twelve hours later. For all animals, ACh release levels were higher during the dark phase. In SAT-performing animals, ACh levels increased for 45 min at ZT4 and ZT16. In addition, the ZT4 animals’ behavioral activity was robustly increased during this interval. Animals trained at ZT 4 reversed back to a nocturnal activity pattern 8-10 days after cessation of SAT practice, coinciding with the loss of the task time-synchronized cholinergic activity. In order to determine the necessity of these prior task period-synchronized release events for maintaining diurnal activity patterns, basal forerbain cholinergic neruons were lesioned by intra-basalis infusion of 192 IgG-saporin. As was expected, this lesion impaired SAT performance. Furthermore, following cessation of daily SAT practice, prior performance-period synchronized cholinergic release events were abolished in lesioned animals. Moreover, the lesion triggered a rapid post-performance return to a nocturnal acitvity pattern. Collectively, these results indicate that SAT performance-associated increases in prefrontal cholinergic activity not only support SAT performance but also contribute to cognition-induced diurnality. Furthermore, circadian control of cholinergic activation optimizes task performance as well as the generation of a cholinergic zeitgeber signal. In conclusions, the brain’s clocks and increases in cortical cholinergic neurotransmission interact bidirectionally to sustain cognitive performance and performance-evoked diurnal activity patterns.

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Cholinergic neurons of the basal forebrain and nitric oxide-mediated regulation of sleep homeostasis.

Kalinchuk AV, Porkka-Heiskanen T, Mccarley RW, Basheer R (2011) Cholinergic neurons of the basal forebrain and nitric oxide-mediated regulation of sleep homeostasis. Neuroscience 2011 Abstracts 397.15. Society for Neuroscience, Washington, DC.

Summary: The levels of adenosine (AD) and inducible nitric oxide (NO) synthase (iNOS)-mediated NO increase during sleep deprivation (SD) in the basal forebrain (BF), and, with prolongation of SD, in the frontal cortex (FC). NO donor (DETA NONOate) infusion increases AD and sleep, while iNOS/NO inhibition prevents SD-induced AD increase, suggesting that iNOS/NO stimulates AD increase (Kalinchuk et al., 2006). iNOS induction during SD occurs in wake-active neurons in the BF and FC (Kalinchuk et al., 2010, 2011), however, neurotransmitter specificity of these cells has not described. The lesion of BF cholinergic cells attenuates both SD-induced AD increase and recovery sleep response (Kalinchuk et al., 2008). Hence in this study, we tested the role of cholinergic versus non-cholinergic neurons in iNOS/NO release in BF and FC and homeostatic sleep response. Methods. We performed two types of experiments. Experiment #1. Immunohistochemical detection of neurotransmitter specificity of cells inducing iNOS during SD. The brains of SD animals and their non-SD time-of-day matched controls were subjected to double-labeling with specific markers for iNOS, acetylcholinetransferase (ChAT), vesicular glutamate transporters (VGlut) and glutamate decarboxylase (GAD67). Experiment #2. The effects of SD on iNOS/NO production and the effect of NO-donor, DETA NONOate infusion on sleep were investigated before and after destruction of BF cholinergic neurons using 192 IgG-saporin. In both experiments male rats were implanted for electrographic recording and Experiment # 2 used guide cannula for microdialysis probes targeting BF and FC. In Experiment #2, recording of sleep-waking cycle, SD for 3h and infusion of DETA NONOate for 3h were performed on the same animals before and 2 weeks after targeted saporin injections. Results. Experiment #1. SD led to significant increases in number of iNOS+ cells in the BF and FC. Preliminary data showed that in the BF, in SD group, 96% of ChAT+ cells were also iNOS+, while in the non-SD group only 4% of ChAT+ neurons had weak iNOS+ staining. Numbers of iNOS+/ChAT+ cells positively correlated with SD-induced increase in theta power. Experiment #2. Before saporin injection, both SD and infusion of DETA NONOate induced significant increases in subsequent NREM sleep/NREM delta power (by 35/47% and 39/41%, respectively). After saporin injection, both recovery NREM sleep and DETA NONOate-induced sleep were significantly attenuated (8 and 4% increase as compared with baseline) and increases in delta power were totally blocked. Conclusions. We conclude that cholinergic neurons of the BF are important for iNOS/NO-mediated homeostatic sleep control.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Role of the medial septal-diagonal band nucleus in working memory: Effects of cholinergic or GABAergic lesions on memory demand and interference

Stewart AL, Roland JJ, Servatius RJ, Pang K (2011) Role of the medial septal-diagonal band nucleus in working memory: Effects of cholinergic or GABAergic lesions on memory demand and interference. Neuroscience 2011 Abstracts 513.09. Society for Neuroscience, Washington, DC.

Summary: The medial septum and diagonal band of Broca (MSDB), a major source of afferents to the hippocampal formation, is critical for learning and memory. The primary cells comprising the septohippocampal systems are cholinergic, GABAergic and glutamatergic. Selective damage of cholinergic MSDB neurons results in mild to no impairment of spatial working memory tasks, suggesting that non-cholinergic MSDB projections are important in learning and memory. Recently, we demonstrated that GABAergic MSDB lesions impair a delayed match to position task (DNMTP) with errors suggesting enhanced proactive interference. The current study assesses the effect of manipulating the intertrial interval (ITI) and retention interval (RI) on DNMTP performance in normal rats and those with cholinergic or GABAergic MSDB damage. In addition, activation of MSDB neurons on the last day of training will be assessed. Male Sprague Dawley rats receive sham, 192-IgG saporin (192-Sap) or GAT1-saporin (GAT1-Sap) administration into the MSDB before training on a DNMTP task using a T-maze. On the sample phase of each trial, rats are forced to one arm for reinforcement. Following an RI, a choice phase allows the rats to choose from both arms. Rats are reinforced for choosing the arm not entered during the sample phase. Following the choice phase, an ITI occurs before the sample phase of the next trial. Rats are trained one session per day, 12 trials per session, and 10 sessions. In a 2 x 2 experimental design, each rat is trained on either a 0 or 60s RI and a 0 or 60s ITI. Conditions with a long RI (60 s) are designed to tax working memory, whereas conditions with a similar RI and ITI are designed to increase interference. Immunocytochemistry for c-Fos is used to assess activation of cholinergic or GABAergic MSDB neurons following the last training session. As expected, our preliminary results show that sham rats performed better on 0 s than 60 s RI (0 s = 78% correct vs 60 s = 57%, both ITI’s pooled). Analysis of the 0 s RI demonstrates that performance in conditions with different RI and ITI was better than when RI and ITI were similar (0 s RI/60 s ITI = 74% vs 0 s RI/0 s ITI = 67%). Further analysis of the 60 s RI was difficult due to the near chance performance. Rats treated with either intraseptal 192-Sap or GAT1-Sap were impaired on the 0 s RI/60s ITI condition (Sham: 85%; 192-Sap: 65%; GAT1-Sap: 72%). However, only the 192-Sap rats were impaired in the 0 s RI/0 s ITI condition (Sham: 71%; 192-Sap: 62%; GAT1-Sap: 69%). Anatomical studies are currently underway. The results of this study will further elucidate the role of MSDB neurons in two aspects of working memory: memory demand and interference.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Cholinergic modulation of cross-modal attentional orienting

Ljubojevic V, De Rosa E, Luu P (2011) Cholinergic modulation of cross-modal attentional orienting. Neuroscience 2011 Abstracts 294.07. Society for Neuroscience, Washington, DC.

Summary: We modified the classic cued target detection paradigm, using odor cues to predict a visual target, to examine cholinergic modulation of attentional control signals. It has been proposed that without ACh top-down processing will inappropriately dominate in the presence of a low validity cue, i.e., the cue will still drive attention. Thus, we reduced central cholinergic influences in rats after they acquired high validity cues to examine whether top-down processing would dominate even when these same cues changed to a lower validity. The validity effect (VE = invalid cue RT - valid cue RT) is thought to measure the ability to reorient attention, i.e., it reflects the time a subject needs to disengage from an invalidly cued location and shift attention to the actual target location. We trained 8 male Long-Evans rats until they reached the stable performance under baseline conditions: cue validity (CV) = 100%, target duration = 1s. Then we simultaneously manipulated the rats’ cholinergic system and cue validity within a testing session in a 3x3 repeated measures design. The three drug conditions were: muscarinic antagonist scopolamine (0.2mg/kg), muscarinic antagonist methylscopolamine as a peripheral nervous system control (0.2mg/kg), and saline. CV in each session was set to 100%, 75%, or 50%. In sessions with the lower cue validity of 75% and 50%, rats with scopolamine showed the predicted higher validity effect when compared to their performance with the control drugs. Based on the increased VE in scopolamine condition, we conclude that ACh plays a role in attentional orienting when cue and target are presented in a different sensory modality. We hypothesize that scopolamine may have exacerbated the top-down expectations from the cue and increased the validity effect. Thus, we are collecting data from rats that had selective cholinergic lesions of the nucleus basalis magnocellularis, which provides ACh input into the neocortex, with the cholinergic immunotoxin 192 IgG-saporin to support this pharmacological effect. We expect that NBM-ACh-lesioned rats will also have an increased validity effect as the CV decreases relative to the sham-lesioned rats. Also, we will collect the data from 8 additional rats to increase the statistical power of the experiment.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Deficits in attentional control of balance, mobility, and complex movements in a rat model of early state, multisystem Parkinson disease

Spuz CA, Paolone G, Briscoe S, Bradshaw M, Albin RL, Sarter MF (2011) Deficits in attentional control of balance, mobility, and complex movements in a rat model of early state, multisystem Parkinson disease. Neuroscience 2011 Abstracts 244.02. Society for Neuroscience, Washington, DC.

Summary: In Parkinson disease (PD), basal forebrain cholinergic loss coincides with midbrain dopaminergic neuron loss and contributes to attentional deficits in PD. We hypothesize that these attentional deficits contribute to L-DOPA-insensitive impairments of mobility and postural control in PD. To assess complex movement control, we developed a novel Complex Motor Control Test (CMCT) for rats. The CMCT consists of several 2 m long beams (plank, 13.34 cm width; round rod, 3.81 cm diameter; square rod, 2.54 cm side length), which can be placed at zero, 22.5° or 45° angles in the vertical plane. Rods can rotate at 1 rpm or 10 rpm. A separate ladder apparatus (100 cm long, 7 cm wide, 2 cm between rungs, 5 mm rung diameter) can be placed at zero, 22.5° or 45° angles in the vertical plane and tilted laterally at 15° or 30° angles. Four high-resolution cameras and mirror system record animals’ performances. Rats are habituated by learning that plank traversal allows entry of home compartments containing individual bedding and palatable food. To separately assess attentional performance, we employed our Sustained Attention Task (SAT), including a distractor condition (dSAT). Our initial experiments determined CMCT and SAT performance in three groups: (1) animals with limited (40-60%) loss of cortical cholinergic afferents following immunotoxin 192-IgG saporin basal forebrain lesions (SAP); (2) animals with dopaminergic deafferentation following 6-OHDA dorsal striatal lesions (6-OHDA); (3) animals with both types of deafferentation (DUAL). SAT performance was dramatically impaired in SAP and DUAL animals. Control animals rapidly traversed angled and rotating rods and angled and tilted ladders. Deafferented animals were able to traverse the plank at all angles as effectively as control animals. Cholinergic lesions robustly impaired animals’ ability to maintain balance on the rods, to re-adjust posture on and traverse rotating rods, and had falls (into a net) or dismounts more frequently than control animals. These data reveal unexpectedly striking impairments in complex gait and movement control resulting from loss of corticopetal cholinergic neurons. These results support the hypothesis that basal forebrain cholinergic cell loss in PD contributes to complex posture and movement control deficits.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Highly selective lesion of the cholinergic pedunculopontine neurons using a minimally-invasive angular stereotaxic surgery with the Diphteria-Urotensin-II neurotoxin in rat

Cyr, M Maclaren DA, Bédard M-A, Clark SD, Mechawar N, Rochford J, Winn P (2011) Highly selective lesion of the cholinergic pedunculopontine neurons using a minimally-invasive angular stereotaxic surgery with the Diphteria-Urotensin-II neurotoxin in rat. Neuroscience 2011 Abstracts 37.06. Society for Neuroscience, Washington, DC.

Summary: Highly selective cholinergic lesions of the basal forebrain can be achieved with the immunotoxin 192-IgG saporin. This toxin has no effect however on the cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg). For many years, most studies have used excitotoxins such as ibotenate, quisqualate, kainate, or N-methyl-D-aspartate, with a relative efficacy in targeting the PPTg cholinergic neurons, however these toxins also destroy the interdigitated glutamatergic and GABAergic neurons. More recently, selective cholinergic lesions were obtained with the Dtx-UII neurotoxin in both rats (Clark et al., 2007) and monkeys (Karachi et al., 2010). This toxin binds at the Urotensin-II receptor predominantly expressed in the pedunculopontine and the laterodorsal, but not the basal forebrain cholinergic nuclei. Because of the scattered distribution of the cholinergic neurons in the rat PPTg, infusion of the Dtx-UII requires multiple skull holes and needle lowering through areas containing critical blood vessels, increasing therefore surgery time, incidence of bleeding and mortality rate. Here, we report that these disadvantages can be avoided by doing a single Dtx-UII infusion, through an angular stereotaxic pathway. Results were contrasted with those obtained from the classical flat skull stereotaxic surgery used by Clark et al. (2007). Long Evans rats (males 250g - 300g) were operated according to three different methods. In group one, 3μl of Dtx-UII (3% concentration) was infused evenly in three unilateral stereotaxic coordinates along the PPTg (pars oralis, centralis, caudalis), using a flat skull position. In groups two and three, 2μl and 3μl of Dtx-UII were infused respectively using the angular stereotaxic method described by Wishaw et al. (1977). Incisor bar was elevated such that there was an 8º29’ angle (.147) between the latter and the interaural line. Following rat sacrifices, ChAT and NeuN immunohistochemistry were conducted in order to determine the cholinergic specificity and magnitude of the lesions. Results revealed similar PPTg cholinergic lesions between the three groups, reaching > 80% on the side of the lesions. Group 1 showed the greatest non specific lesions outside the PPTg, attributable to the needle pathways. This group of rats also showed the greatest number of surgical complications. We conclude that the cholinergic PPTg neurons can be optimally lesioned by using an angular surgical approach with the Dtx-UII toxin. Clark S.D., et al. (2007). J Neurochem., 102, 112-120. Karashi C., et al. (2010). J Clinical Investigation, 120, 2745-2754. Wishaw et al. (1977). Physiol. Behav., 19, 719-722.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation.

Savage S, Kehr J, Olson L, Mattsson A (2011) Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation. Neuroscience 195:60-69. doi: 10.1016/j.neuroscience.2011.08.027

Summary: Forebrain cholinergic dysfunction is thought to be part of the pathophysiology of schizophrenia. The authors lesioned the cholinergic corticopetal projection of rats by infusing 0.081 µg of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. The lesioned animals displayed a reduction in the duration of social interaction. When the lesioned animals were then given PCP, they were no longer able to recognize a novel object. The data suggest a role of cholinergic hypofunction in the cognitive symptoms of schizophrenia.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Decrease of GABAergic Markers and Arc Protein Expression in the Frontal Cortex by Intraventricular 192 IgG-Saporin.

Jeong DU, Chang WS, Hwang YS, Lee D, Chang JW (2011) Decrease of GABAergic Markers and Arc Protein Expression in the Frontal Cortex by Intraventricular 192 IgG-Saporin. Dement Geriatr Cogn Disord 32(1):70-78. doi: 10.1159/000330741

Summary: The authors examined the use of 192-IgG-SAP (Cat. #IT-01) to establish a standardized model for dementia. Rats received several different doses of toxin in bilateral intraventricular injections. This injection method resulted in reliable memory impairment in a behavioral test, decreased GABAergic activity in the frontal cortex affecting spatial memory, and no change in the hippocampus. Using this technique, 8 µg of 192-IgG-SAP produced the optimal memory impairment.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Acetylcholine and attention.

Klinkenberg I, Sambeth A, Blokland A (2011) Acetylcholine and attention. Behav Brain Res 221(2):430-442. doi: 10.1016/j.bbr.2010.11.033

Summary: This review article summarizes studies investigating the role of acetylcholine in attention and cognition. The roles of 192-IgG-SAP (Cat. #IT-01) and mu p75-SAP (Cat. #IT-16) in these experiments is discussed. Acetylcholine is thought to play a top-down role in the prefrontal, parietal, and somatosensory regions; playing an important role in the control of attentional orienting and stimulus discrimination.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

Cholinergic denervation disrupts temporal learning in rodent visual cortex

Roach EB, Hussain Shuler MG (2011) Cholinergic denervation disrupts temporal learning in rodent visual cortex. IBRO 2011 Abstracts International Brain Research Organization, Florence, Italy.

Summary: Local cholinergic terminals were removed using the selective neurotoxin 192 IgG-saporin between contingency reversal. This manipulation tested the necessity of cholinergic innervation in two key processes: expressing previously learned reward timing and shifting reward timing to new behaviorally relevant intervals.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The role of cholinergic cortical modulation in visual and olfactory attention using the 5-Choice serial reaction time task

Ljubojevic V, Luu P, De Rosa E (2011) The role of cholinergic cortical modulation in visual and olfactory attention using the 5-Choice serial reaction time task. IBRO 2011 Abstracts International Brain Research Organization, Florence, Italy.

Summary: After successful acquisition of both visual and olfactory task, the rats were subjected to either a cholinergic immunotoxic or sham lesion surgery of the NBM. Cholinergic deafferentation of the neocortical mantle was induced by bilaterally infusing the cholinergic immunotoxin, 192 IgG-saporin, into the NBM (0.2 μl of 0.2 μg/μl per site; two sites per hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Enhanced control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry.

St Peters M, Demeter E, Lustig C, Bruno JP, Sarter M (2011) Enhanced control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry. J Neurosci 31(26):9760-9771. doi: 10.1523/JNEUROSCI.1902-11.2011

Summary: Motivation and attention interact to preserve cognitive performance under challenging conditions. In order to better define the circuitry connecting these two processes, the authors lesioned the prefrontal cortex (200 ng of 192-IgG-SAP, Cat. #IT-01) and the posterior parietal cortex (280 ng of 192-IgG-SAP). Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data indicate that cholinergic projections to the cortex modulate detection of clues and filtering of distractors during attentional tasks, accentuating cognitive control.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Read the featured article in Targeting Trends.

BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration.

Angelucci F, Gelfo F, De Bartolo P, Caltagirone C, Petrosini L (2011) BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration. Neurochem Int 59(1):1-4. doi: 10.1016/j.neuint.2011.04.010

Summary: Brain-derived neurotrophic factor (BDNF) plays a role in neuronal function during the degeneration of neurons caused by pathological conditions such as Alzheimer’s disease. In order to investigate the relationship between brain and serum BDNF levels the authors administered 2 µg of 192-IgG-SAP (Cat. #IT-01) into each lateral ventricle of rats and measured brain and serum BDNF levels by ELISA. It was found that BDNF levels dropped in lesioned animals, but not until 15 days post surgery.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion.

Antonini V, Marrazzo A, Kleiner G, Coradazzi M, Ronsisvalle S, Prezzavento O, Ronsisvalle G, Leanza G (2011) Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. J Alzheimers Dis 24(3):569-586. doi: 10.3233/JAD-2011-101794

Summary: Sigma-1 receptor agonists such as (-)-MR22 are potential therapeutic drugs for the treatment of cognitive and affective disorders. To model a cognitive disorder, rats received 81-ng bilateral injections of 192- IgG-SAP (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of Broca, and 130-ng bilateral injections into the nucleus basalis magnocellularis. Lesioned animals also were treated with pre- aggregated amyloid peptide. Pretreatment with (-)-MR22 reversed cognitive impairments in the double-lesioned animals, indicating the potential use of sigma-1 receptor agonists as protective agents.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation.

Tai SK, Ma J, Ossenkopp KP, Leung LS (2012) Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation. Hippocampus 22(4):914-925 . doi: 10.1002/hipo.20955

Summary: The vestibular system is highly involved with spatial navigation and memory. It is thought that modulation of hippocampal function by the vestibular system is mediated by a hippocampal theta rhythm. Rats received 140 ng of 192-IgG-SAP (Cat. #IT-01) infused into the medial septum, followed by measurement of hippocampal EEG’s and evoked potentials. Theta was attenuated in rats receiving the lesion, as well as other changes that suggest the importance of septohippocampal cholinergic activity in sensorimotor processing and spatial memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Reassessment of the structural basis of the ascending arousal system.

Fuller P, Sherman D, Pedersen NP, Saper CB, Lu J (2011) Reassessment of the structural basis of the ascending arousal system. J Comp Neurol 519(5):933-956. doi: 10.1002/cne.22559

Summary: Traditional thought has been that electroencephalogram activity is mainly generated by the thalamo-cortical system. In this work the authors investigated the effects of basal forebrain lesions on various measurements of wakefulness. Rats received 4 50 ng injections of 192-IgG-SAP (Cat. #IT-01) into the basal forebrain. The effects of these lesions showed that the parabrachial nucleus/precoeruleus region projection relayed by the basal forebrain to the cerebral cortex plays a critical role in behavioral and electrocortical arousal.

Usage: Lesions of the basal forebrain were done by injecting a 0.1% solution of either 192-IgG-SAP or Orexin-SAP at four different sites.

Related Products: 192-IgG-SAP (Cat. #IT-01), Orexin-B-SAP (Cat. #IT-20)

Molsidomine modulates the cNOS activity in an experimental model of cholinergic damage induced by 192-IgG saporin.

Hernandez-Melesio MA, Gonzalez-Esquivel D, Ortiz-Plata A, Sanchez-Mendoza A, Sanchez-Garcia A, Alcaraz-Zubeldia M, Rios C, Perez-Severiano F (2011) Molsidomine modulates the cNOS activity in an experimental model of cholinergic damage induced by 192-IgG saporin. Neurosci Lett 491(2):133-137. doi: 10.1016/j.neulet.2011.01.023

Summary: Nitric oxide (NO) is required for the survival of cholinergic neurons in the basal forebrain. Delivery of nerve growth factor (NGF) is related to the modulation of NO – as excessive NO can lead to excitotoxicity. The authors administered molsidomine to rats that had previously received 220 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Molsidomine is a NO donator, and produced a significant recovery of NO activity in lesioned animals, indicating a potential therapeutic pathway.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gene regulation in the rat prefrontal cortex after learning with or without cholinergic insult.

Paban V, Chambon C, Farioli F, Alescio-Lautier B (2011) Gene regulation in the rat prefrontal cortex after learning with or without cholinergic insult. Neurobiol Learn Mem 95(4):441-452. doi: 10.1016/j.nlm.2011.02.005

Summary: Microarray technology was used to screen gene expression in a model of attention and memory deficit. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum and nucleus basalis magnocellularis (37.5 ng per side and 75 ng per side respectively). Gene expression in memory loss following the lesion was defined by one cluster related to cytoskeleton organization and proliferation, and glial and vascular remodeling. These are processes associated with brain repair after injury.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The effects of neonatal forebrain cholinergic lesion on adult hippocampal neurogenesis.

Rennie K, Frechette M, Pappas BA (2011) The effects of neonatal forebrain cholinergic lesion on adult hippocampal neurogenesis. Brain Res 1373(10):79-90. doi: 10.1016/j.brainres.2010.11.091

Summary: Intraventricular injections of 192-IgG-SAP (Cat. #IT-01) have been shown to reduce the number of cells expressing a marker for immature neuroblasts in the dentate gyrus, as well as possibly impairing the response to environmental enrichment. This study looked to expand on those observations. 300 ng of 192-IgG-SAP was infused into each ventricle of post-natal day 7 rats. The data suggest that the lesion accelerates the death of newborn cells, but does not affect survival rate or phenotypic differentiation.

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Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.

Gibbs RB, Chipman AM, Nelson D (2011) Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons. Horm Behav 59(4):503-511. doi: 10.1016/j.yhbeh.2011.01.011

Summary: Among the beneficial effects of estrogen on the brain are improved cognitive performance and prevention of age-related cognitive decline. These positive effects diminish over time following loss of ovarian function. To investigate the role of cholinergic neurons in this process, rats received 96-250 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septal nucleus followed by a cholinergic enhancer and estradiol therapy. The dual therapy had a positive effect on partially lesioned animals, but did not improve the performance of animals with severe lesions.

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Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics.

Leung LS, Petropoulos S, Shen B, Luo T, Herrick I, Rajakumar N, Ma J (2011) Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics. Exp Neurol 228(2):259-269. doi: 10.1016/j.expneurol.2011.01.019

Summary: Consciousness and response to general anesthesia have been linked to acetylcholine in the brain. The authors treated rats with 150-ng bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis to examine this connection. Lesioned animals were more affected by propofol and phenobarbitol than control animals. Some effects of halothane were also increased. The data indicate a role for acetylcholine in the brain in the response to general anesthesia.

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Molsidomine promotes the recovery of cognitive deficit induced by 192 IgG saporin in rats

Hernandez MA, Hernández-Melesio M, Gonzalez-Ezquivel D, Quevedo-Corona L, Jiménez-Cataño M, Santoyo-Pérez M, Rios-Castañeda C, Pérez-Severiano F (2010) Molsidomine promotes the recovery of cognitive deficit induced by 192 IgG saporin in rats. Neuroscience 2010 Abstracts 856.27/I33. Society for Neuroscience, San Diego, CA.

Summary: The NO donor molsidomine (MOLS) has been used as a pharmacological tool in order to antagonize the cognitive deficit associated to cholinergic hypofunction produced by scopolamine. However, the participation of NO in the recovery of cholinergic deficit due to the administration of the cholinergic immunotoxin, 192 IgG saporin (SAP) has not been analyzed. The aim of the present study was to determine the effect of MOLS to counteract the cognitive deficits induced by cholinergic denervation in the object recognition task. Male Wistar rats were divided in the follow experimental groups according to the intraseptal administration of SAP and its vehicle PBS, and the injection (i.p) of the NO donor molsidomine and its vehicle saline: SAP (0.22 µg), PBS (0.1M pH 7.4), molsidomine (4mg/kg), SAP/molsidomine. The single dose of MOLS used in this study antagonized the cognitive failure related to SAP administration and increased the exploration time of novel object. We conclude that MOLS promote the acquisition of recognition memory in the model of cholinergic denervation associated to 192 IgG SAP and further immunohistological studies are being carried out in order to demonstrate that nitric oxide could have an effect over the cholinergic functionality.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effects of basal forebrain cholinergic lesions and estradiol on relative levels of estrogen receptor mRNAs in the rat forebrain

Hammond R, Shinde A, Gibbs RB (2010) Effects of basal forebrain cholinergic lesions and estradiol on relative levels of estrogen receptor mRNAs in the rat forebrain. Neuroscience 2010 Abstracts 611.16/MMM67. Society for Neuroscience, San Diego, CA.

Summary: Beneficial effects of estradiol on cognitive performance are lost in response to cholinergic denervation of the hippocampus and frontal cortex. Effects of estradiol also decline with age and time following the loss of ovarian function, which parallels naturally-occurring declines in basal forebrain cholinergic function. We hypothesize that cholinergic impairment may alter the expression of estrogen receptors in specific regions of the brain, thereby decreasing estradiol effects. In the present study, quantitative RT-PCR was used to evaluate the effects of septal cholinergic lesions ± estradiol treatment on relative levels of three estrogen receptors, ERα, ERß, and GPR30. Young adult ovariectomized (OVX) rats received intraseptal injections of saline or 192 IgG-saporin (a selective cholinergic immunotoxin). One week later, rats received either silastic capsules containing 17ß-estradiol or a blank capsule, implanted s.c. Seven days later, rats were killed and the brains were dissected. Tissues from the hippocampus, frontal cortex, prefrontal cortex, striatum, and septum were collected. RNA was extracted and relative levels of ER mRNA determined. Levels within each sample were normalized to levels of GAPDH. Differences between treatments and controls were calculated using the ΔΔCt method. Preliminary data indicate that septal cholinergic lesions produced significant decreases in relative levels of ERα and ERß mRNA in the hippocampus, and an increase in ERß mRNA in the frontal cortex. Estradiol alone produced decreases in levels of ERα, ERß, and GPR30 mRNA in the frontal cortex, decreased levels of ERα and ERß mRNA in the septum, and increased levels of ERα mRNA in the striatum. In rats with cholinergic lesions that also received estradiol, decreased levels of ERα mRNA were detected in hippocampus and septum, and decreased levels of ERß mRNA also were detected in septum. Data suggest that some of the effects of cholinergic denervation on ER mRNA expression may be mitigated by estradiol treatment. These data show that cholinergic lesions significantly affect ER mRNA expression in the brain, and that effects are region-specific. Such effects could account for the loss of beneficial effects of estradiol on cognitive performance in association with age and time following menopause, as well as in association with specific neurodegenerative diseases such as Alzheimer’s disease.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic modulation of both visual and olfactory attention with the five-choice serial reaction time test

Ljubojevic V, Luu P, De Rosa E (2010) Cholinergic modulation of both visual and olfactory attention with the five-choice serial reaction time test. Neuroscience 2010 Abstracts 535.8. Society for Neuroscience, San Diego, CA.

Summary: The nucleus basalis magnocellularis (NBM) sends acetylcholine (ACh) to neocortical regions that are involved in attentional cognitive processes. Using the five choice serial reaction time task (5CSRTT), the rodent analog of sustained attention in the human cognitive literature, it has been shown that a loss of cholinergic cells in the NBM causes impaired visual attentional performance in rats (Lehmann et al., 2003; McGaughy et al., 2002). The present research examined the neurochemical modulation of attentional processes using both a visual and an olfactory version of the 5CSRTT. To that purpose, we trained 14 male adult Long-Evans rats to attend and react to the briefly presented visual or odor stimuli until they achieved a stable performance under the baseline task conditions, i.e., low attentional demand with stimulus duration (SD) of 1s. Following the successful acquisition of both versions of the 5CSRTT, the rats were subjected to selective cholinergic lesions of the NBM with the cholinergic immunotoxin 192 IgG-saporin to remove the cholinergic innervation from the neocortical mantle. This allowed an examination of the role of ACh in modulation of visual and olfactory attention. After the two week post-surgical recovery period, we compared the attentional performance of the saporin-lesioned (SAP) group (N=8) to that of the sham-lesioned (SHAM) group (N=6) on the two versions of the 5CSRTT task. We observed the impaired attentional performance of the SAP rats on the visual 5CSRTT under the baseline conditions (SD=1s); shortening the SD = 0.5s increased the extent of their deficits. With the olfactory 5CSRTT, the SAP impairment was only observed under the attentional challenge of SD=0.5s. However, in both modalities the difference between two groups trended toward statistical significance due to the low number of the experimental subjects in each group. We are currently performing further parametric manipulations to further challenge the rats in both modalities. We will then collect data from an additional 14 rats to increase the statistical power of our experiment. After the completion of the behavioral data collection, we will conduct acetylcholinesterase histochemistry and choline acetyltransferase immunohistochemistry in order to determine the extent of the loss of cholinergic afferents in fronto-parietal target cortical areas and the loss of cholinergic cell bodies in the NBM, respectively. In addition, parvalbumin immunohistochemistry will be carried out to quantify GABA-releasing neurons colocalized in NBM to confirm the selectivity of our lesion.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The effects of neonatal cholinergic lesion on age-related changes in behaviour, neurogenesis and CA1 pyramidal cell morphology

Rennie KE, Frechette M, Pappas BA (2010) The effects of neonatal cholinergic lesion on age-related changes in behaviour, neurogenesis and CA1 pyramidal cell morphology. Neuroscience 2010 Abstracts 349.8/J12. Society for Neuroscience, San Diego, CA.

Summary: Age-related cognitive decline is associated with dysfunction of the basal forebrain cholinergic (BFC) system, and cortico-hippocampal cholinergic denervation is a hallmark neurochemical feature of the Alzheimer’s-afflicted brain. It has been suggested that cognitive deficits that emerge with age may be rooted in early dysfunction of the BFC system and that impaired cholinergic transmission might interact with ageing-associated factors to produce cognitive decline. The purpose of this study was to examine the effects of neonatal cholinergic lesion on age-related changes in spatial working memory, neurogenesis and hippocampal CA1 pyramidal cell morphology. We have previously reported that neonatal cholinergic lesion results in only minor behavioural deficits, but impairs the birth and/or survival of new neurons and reduces CA1 dendritic complexity in the young adult rat. We hypothesized that memory impairments would become apparent in lesioned rats as they age, and that this impairment would be accompanied by more drastic reductions in neurogenesis and cytoarchitectural alterations than those that have been documented in the young adult animal after neonatal cholinergic lesion. Seven-day-old male Sprague-Dawley rats were subjected to basal forebrain cholinergic lesion by infusion of the cholinotoxin 192-IgG-Saporin into the lateral ventricles. At the age of 12 or 21 months, the rats were tested on a working memory version of the Morris water maze. While aging had only a slight effect on the memory performance of control rats, lesioned rats showed pronounced memory impairments with age. This occurred without CA1 cell loss or astrogliosis in 21-month-old lesioned rats when compared to age-matched controls. However, golgi analysis revealed that while cholinergic lesion did not alter the total dendritic length, branching, number of spines, or spine density of CA1 pyramidal cells in 21-month-old rats, the distribution of these parameters across branch orders was shifted. The lesion caused a slight reduction in apical branch length and spine density, and basal branch number, length and number of spines at low/middle branch orders, but increased these parameters at upper branch orders. Thus, perinatal cholinergic lesion precipitates spatial memory dysfunction during old age, and this seems to be associated with cytoarchitectural changes to neurons rather than neuronal loss.

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Mesolimbic-basal forebrain circuitry mediating the motivational activation of attention

St Peters MM, Bruno JP, Sarter M (2010) Mesolimbic-basal forebrain circuitry mediating the motivational activation of attention. Neuroscience 2010 Abstracts 506.12/LLL52. Society for Neuroscience, San Diego, CA.

Summary: Prefrontal circuitry mediating cue detection is modulated by the tonic component of cholinergic activity. Performance-associated increases in tonic cholinergic activity are augmented by demands on the cognitive control of attention. Highest levels of tonic cholinergic activity are observed while animals perform below baseline as a result of, for example, a distractor, but while they remain motivated to stabilize and recover attentional performance. Cortico-mesolimbic-basal forebrain circuitry is thought to mediate such motivated activation of attentional performance. We previously observed that stimulation of ionotropic glutamate receptors in the shell of the nucleus accumbens (NAs) stimulates tonic cholinergic activity in the prefrontal cortex. Here we test the hypothesis that such stimulation benefits attentional performance while distractors evoke cognitive control. Rats were trained in an operant sustained attention task (SAT) before undergoing surgery for implantation of a bilateral guide cannula targeting the NAs or, in separate animals, the core of the NA (NAc). NMDA (0.01-0.15 µg/0.5 µL/hemisphere) or vehicle (0.9% saline) was infused bilaterally into task-performing animals during SAT and the more challenging distractor version (dSAT). For the dSAT, the operant chamber ceiling lights flashed on/off at 0.5 Hz during the middle block of three blocks of trials that constituted a session. NMDA infusions in the NAs, but not into the NAc, significantly improved the animals’ attentional performance in the presence of the distractor. These findings are consistent with the hypothesis that activation of the NAs mediates attentional performance under conditions that require top-down control. The next set of experiments determined whether the effects of NAs activation require the cortical cholinergic system. We infused the immunotoxin 192 IgG saporin into prefrontal or parietal regions, in addition to implantation of guide cannula targeting the NAs. Replicating the initial finding, NAs NMDA infusions enhanced dSAT performance. Both PFC and PPC cholinergic deafferentation prevented this effect of NMDA. These findings suggest that the motivated activation of the cholinergic attention system during demands on top-down control modulates fronto-parietal attention networks to optimize attentional performance.

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Novel object recognition and social interaction in rats lacking cortical cholinergic innervation; comparing manual and digital video tracking systems

Savage ST, Olson L, Mattsson A (2010) Novel object recognition and social interaction in rats lacking cortical cholinergic innervation; comparing manual and digital video tracking systems. Neuroscience 2010 Abstracts 506.9/LLL49. Society for Neuroscience, San Diego, CA.

Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. We have shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis in adult rats leads to an enhanced locomotor sensitivity to amphetamine, as well as, a potentiated dopamine release in nucleus accumbens. We have also shown that this cortical cholinergic denervation leads to an increased locomotor response to the NMDA receptor antagonist phencyclidine (PCP), suggesting that disruption of cortical cholinergic activity can lead to disturbances of glutamatergic transmission. We hypothesize that this loss of cortical cholinergic input alters the activity of cortical glutamatergic neurons and in turn, their regulation of subcortical dopamine neurons. In current studies we are investigating memory functions using the novel object recognition task (NOR) and social interaction in adult male Lister hooded rats with cholinergic denervation of neocortex. The behavioral tasks are being conducted under normal conditions and with a PCP-challenge. The data are analyzed both manually by a trained observer, and with a nose point digital video tracking system (Clever Sys Inc.). Manually scoring behavioral data requires extensive observer training, is subject to inter-observer variability, and is time consuming. An automated tracking system could potentially improve upon these issues, however is prone to other problems, including the difficulty of accurately tracking multiple body points. Furthermore, the Lister hooded fur has two different colors which proves difficult for computerized systems to accurately determine the body points. A comparison of the manual scoring and the computerized tracking system is being conducted to determine the most reliable method for each behavioral task. Preliminary results indicate that the cholinergically denervated rats performed the NOR task under normal conditions as well as the controls, however failed to show a preference for the novel object under PCP-challenge. These results were obtained through analysis with both the manual and automated system. Despite fur color difficulties, the video tracking system was able to analyze the NOR task and accurately calculate the distance traveled, which is not easily obtained through manual scoring. These initial results indicate that cortical cholinergic deficits, in addition to a potentiation of the locomotor response to PCP, can also lead to an enhanced sensitivity to PCP-induced cognitive impairments.

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Decrease of Arc protein expression and delay of memory acquisition by immunolesion

Jeong D, Lee D, Chang J (2010) Decrease of Arc protein expression and delay of memory acquisition by immunolesion. Neuroscience 2010 Abstracts 145.5/H6. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic neuronal deficit is one of the common characteristics in both Alzheimer’s disease dementia (AD) and vascular dementia (VaD). Forebrain Cholinergic neurons in the basal forebrain project to the neocortex and the hippocampus which make an important role in memory function. We used 192 IgG-saporin to produce selective lesion of cholinergic basal forebrain neurons including the medial septum (MS) and the nucleus basalis magnocellularis (NBM). We intracerebroventricularly injected 192 IgG-saporin (0.63 µg/µl dose, 6 µl, 8 µl and 10 µl) or phosphate buffered saline (8 µl). Morris water maze and tissue perforation for immunohistochemistry and western blotting were sequentially performed 2 weeks after injection of 192 IgG-saporin. In the acquisition phase of Morris water maze, latency of 6ul group (2nd day), 8 µl group (2nd day) and 10 µl group (3rd day) was significantly delayed but it was recovered within 1week. Time in platform and the number of crossing were significantly different between 8 µl LV injection group and sham group in probe test. In immunohistological study, the extent of the cholinergic lesion was showed in the basal forebrain complex region of all 192 IgG-saporin injected rats. Expression of Arc protein is significantly decreased in the frontal cortex (8 µl and 10 µl groups) but hippocampus. Decrease of parvalbumin in the frontal cortex (8ul and 10 ul groups) and the hippocampus (10 µl) means nonselective lesion because of high dose of immunotoxin. We observed recovery after memory acquisition delay and decrease of synaptic activity in the frontal cortex except in the hippocampus. High dose of immunotoxin injured not only cholinergic neuron but also GABAergic neuron in the frontal cortex and the hippocampus. Hippocampal GABAergic cell synapse on to glutamatergic pyramidal cells. Deficit of the hippocampal inhibitory cell may facilitate hippocampal synaptic plasticity and the recovery.

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Cholinergic innervation of the hippocampus is not neccesary for episodic memory, but is required for context-place learning in rats

Easton A, Phil D, Fitchett A, Eacott MJ, Baxter MG (2010) Cholinergic innervation of the hippocampus is not neccesary for episodic memory, but is required for context-place learning in rats. Neuroscience 2010 Abstracts 99.27/KKK13. Society for Neuroscience, San Diego, CA.

Summary: Loss of cholinergic cortical input is associated with diseases in which episodic memory impairment is a prominent feature, but the degree to which this neurochemical lesion can account for memory impairment in humans with neurodegenerative diseases remains unclear. Removal of cholinergic input to hippocampus impairs some of its functions in memory, perhaps by reducing the plasticity of information representation within the hippocampus, but the role of cholinergic hippocampal input in episodic-like memories has not been investigated. To address this question we tested rats with selective lesions of basal forebrain neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), which contains hippocampal-projecting cholinergic neurons, on a task of integrated memory for objects, places, and contexts ("what-where-which" memory). This task serves as a rodent model of human episodic memory (episodic-like memory) and is sensitive to damage to the hippocampal system. Rats with lesions of cholinergic MS/VDB neurons performed as well on the what-where-which task as controls, but were impaired in a task that simply required them to associate places with contexts (“where-which” memory). Thus, episodic-like memories that rely on the hippocampus do not require cholinergic neuromodulation to be formed. Nevertheless, some more specific aspects of where-which memory, which may be more dependent on the plasticity of hippocampal spatial representations, require acetylcholine. These results suggest that cholinergic projections to hippocampus are not necessary for episodic memory, and furthermore, that hippocampal spatial representations may be to some extent dissociable from episodic memory function.

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Early post-natal cholinergic lesion impairs normal development and maturation of the motor cortex in rats

Ramanathan D, Conner JM, Anilkumar AA, Tuszynski MH (2010) Early post-natal cholinergic lesion impairs normal development and maturation of the motor cortex in rats. Neuroscience 2010 Abstracts 32.14/D20. Society for Neuroscience, San Diego, CA.

Summary: Prior studies have indicated that sensory and motor representations develop over a defined postnatal period and are dependent upon behavioral experience to achieve appropriate adult patterns. In adult animals, behaviorally driven forms of cortical map plasticity are critically dependent upon the basal forebrain cholinergic system. Based on the critical role cholinergic mechanisms play in mediating experience-dependent plasticity in adulthood, we postulated that cholinergic mechanisms may also play a critical role in shaping initial cortical map formation during development. In this study, using 25 male Fisher rats between the ages of 15 days and 60 days, we first characterized the normal motor map development in the rat. We found that motor maps underwent a significant change in overall size and refinement over time, with more mature animals having larger overall maps (p < 0.001) and an increase in the size of distal forelimb representations (p < 0.01). Following the initial characterization of normal motor map development in the rat, we used 192-IgG-saporin (SAP) to create selective cholinergic lesions early in map development (PND 24), in 5 animals (with 6 animals receiving ACSF as controls). This early cholinergic depletion impaired the normal maturation and refinement of cortical motor representations: the total caudal forelimb area (comprising elbow and wrist) was decreased by 33% in cholinergically depleted animals, from 5.1 ± 0.3 mm2 to 3.4 ± 0.3 mm2 (t-test p < 0.01). This decrease in caudal forelimb area in cholinergically-depleted animals was primarily driven by a significant 37% reduction in the size of the distal forelimb (wrist) representation, from 3.1 ± 0.1 mm2 to 2.0 ± 0.1 mm2 (p < 0.001). In a follow-up experiment with 12 additional animals (6 with cholingeric lesions and 6 controls), we found that early (PND 24) cholinergic depletions resulted in long-term impairments in skilled motor learning, with significant differences in daily motor performance beginning at day 3 of training (repeated measures ANOVA < 0.05). These results suggest a novel role for the basal forebrain cholinergic system in establishing normal cortical map formation during development.

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Subplate neurons promote the formation of barrels within rat primary somatosensory cortex

Sheikh A, Kanold PO (2010) Subplate neurons promote the formation of barrels within rat primary somatosensory cortex. Neuroscience 2010 Abstracts 33.1/E1. Society for Neuroscience, San Diego, CA.

Summary: Subplate neurons are a transient neuronal population present in the neonatal cortex. Subplate neurons receive thalamic afferents and project into the developing cortical plate. Selective removal of subplate neurons in cat visual cortex prevents the normal development of ocular dominance columns and the functional maturation of thalamocortical connections (Ghosh & Shatz 1992, Kanold et al. 2003) . A role of subplate neurons in the development of other sensory cortices is unknown. In rodents, thalamocortical afferents representing the whiskers segregate into barrels in the primary somatosensory cortex (S1). This segregation occurs postnatally and can be disrupted by manipulations of neuronal activity. We previously showed that subplate removal disrupts the development of patterned cortical activity in S1 (Tolner, Yukin, Kaila, Kanold, Abstr. SFN 2009). Thus we hypothesized that disruption of patterned activity in S1 alters the development of barrels. Thus here we investigated if subplate neurons play a role in the development of barrels in rat S1. Subplate neurons were ablated in the somatosensory cortex of rat pups at postnatal day (P) 0 by immunotoxin injections. 10-14 days later we investigated the pattern of barrels in S1 via cytochrome oxidase staining. After subplate ablation there was a disturbance in the barrel patterning when compared to the un-manipulated or control-toxin injected hemispheres. Therefore, subplate neurons are involved in the formation of barrels in S1.

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Spatial memory alterations by activation of septal 5HT(1A) receptors: no implication of cholinergic septohippocampal neurons.

Koenig J, Lecourtier L, Cosquer B, Pereira PM, Cassel J (2011) Spatial memory alterations by activation of septal 5HT(1A) receptors: no implication of cholinergic septohippocampal neurons. Psychopharmacology (Berl) 214(2):437-454. doi: 10.1007/s00213-010-2049-7

Summary: These experiments examined what effect damaged cholinergic neurons would have on memory deficits induced by the 5-HT1A/5-HT7 receptor agonist 8-OH-DPAT. Rats received 0.4 µg injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum, delivered through an infusion device. Through use of a water maze test, the authors show that several neuronal populations are involved in processing hippocampal information, and non-cholinergic neurons in this region may be more important than the cholinergic ones for memory processing.

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Septohippocampal pathways contribute to system consolidation of a spatial memory: Sequential implication of gabaergic and cholinergic neurons.

Lecourtier L, de Vasconcelos AP, Leroux E, Cosquer B, Geiger K, Lithfous S, Cassel JC (2011) Septohippocampal pathways contribute to system consolidation of a spatial memory: Sequential implication of gabaergic and cholinergic neurons. Hippocampus 21(12):1277-1289. doi: 10.1002/hipo.20837

Summary: Few studies have examined the role of GABAergic septohippocampal projections in memory consolidation. The authors administered 192-IgG-SAP (400 ng; Cat. #IT-01) and/or orexin-SAP (70 ng; Cat. #IT-20) to the medial septum/vertical limb of the diagonal band of Broca of rats. Spatial memory tests were then administered over several weeks. The data indicate that both GABAergic and cholinergic septohippocampal systems contribute to memory stabilization, possibly in a sequential manner.

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Effect of applying p75NTR saporin to a punctured intervertebral disc on calcitonin gene-related peptide expression in rat dorsal root ganglion neurons.

Sugiura A, Ohtori S, Yamashita M, Yamauchi K, Inoue G, Suzuki M, Norimoto M, Orita S, Eguchi Y, Kuniyoshi K, Ochiai N, Kishida S, Takaso M, Aoki Y, Ishikawa T, Arai G, Miyagi M, Kamoda H, Nakamura J, Takahashi K (2010) Effect of applying p75NTR saporin to a punctured intervertebral disc on calcitonin gene-related peptide expression in rat dorsal root ganglion neurons. J Orthop Sci 15(3):407-413. doi: 10.1007/s00776-010-1469-x

Summary: Lumbar intervertebral discs are suspected to be a source of low back pain, in part because of the innervation of these discs by neurons containing substance P and CGRP receptors. Rats received 2.5 µg of 192-IgG-SAP (Cat. #IT-01) into the L5/6 vertebral disc after the disc was punctured. While half of the dorsal root ganglion neurons innervating the disc were positive for CGRP post-puncture, animals receiving 192-IgG-SAP displayed reduced CGRP expression, indicating a role for the p75 receptor in discogenic pain.

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Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation.

Gil-Bea FJ, Solas M, Mateos L, Winblad B, Ramirez MJ, Cedazo-Minguez A (2011) Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation. Hippocampus 21(9):999-1009. doi: 10.1002/hipo.20812

Summary: The authors investigated the role of activity-regulated cytoskeleton associated protein (Arc) and brain-derived neurotrophic factor (BDNF) in cholinergic-induced memory formation. Rats received 67-ng bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the third ventricle after behavioral training. Lesioned animals had decreased protein and mRNA for both Arc and BDNF. Memory acquisition and recovery of acquisition were both affected. The data indicate that cholinergic denervation of the hippocampus affects the muscarinic facets of spatial memory acquisition.

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Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory.

Easton A, Fitchett AE, Eacott MJ, Baxter MG (2011) Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory. Hippocampus 21(9):1021-1027. doi: 10.1002/hipo.20814

Summary: Although it is clear that neurodegenerative diseases cause memory impairment, it is uncertain to what extent cholinergic deficits cause this loss of function. The authors administered a total of 150 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum and vertical limb of the diagonal band of Broca in rats. The lesioned animals were then tested in a rodent model for human episodic memory. The rats performed well on these tests, but struggled with tests that tested the association of places with context. The results suggest that hippocampal spatial representations might not be essential for episodic memory function.

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Gene expression profile in rat hippocampus with and without memory deficit.

Paban V, Farioli F, Romier B, Chambon C, Alescio-Lautier B (2010) Gene expression profile in rat hippocampus with and without memory deficit. Neurobiol Learn Mem 94(1):42-56. doi: 10.1016/j.nlm.2010.03.005

Summary: This work examined a wide range of gene expression in the rat hippocampus after bilateral injections of 192-IgG-SAP (Cat. #IT-01) – 37.5 ng per side in the medial septum, and 75 ng per side in the nucleus basalis magnocellularis. Memory loss following 192-IgG-SAP treatment was marked by gene expression that did not show the same cluster organization as learning processes. Genes showing differential expression were down-regulated, and one cluster associated with tissue remodeling could be identified.

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Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: Effects on proactive interference.

Pang KCH, Jiao X, Sinha S, Beck KD, Servatius RJ (2011) Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: Effects on proactive interference. Hippocampus 21(8):835-846. doi: 10.1002/hipo.20799

Summary: Recent work implicates the medial septum (MS) and diagonal band (DB) in the control of proactive interference -- forgetting older information when learning new information. Rats received GAT1-SAP (Cat. #IT-32) injections into the MS and the DB (162.5 ng and 130 ng respectively, the DB injections were bilateral). The results parallel other studies using different toxins, reinforcing the indications that GABAergic MSDB neurons are an integral part of proactive interference control.

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Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions.

De Bartolo P, Cutuli D, Ricceri L, Gelfo F, Foti F, Laricchiuta D, Scattoni ML, Calamandrei G, Petrosini L (2010) Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions. J Alzheimers Dis 20:207-227. doi: 10.3233/JAD-2010-1355

Summary: The authors characterized the differences caused by age on the effect of cholinergic lesions of the basal forebrain. Seven-day-old rats received 210 ng bilateral intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01). Eighty-day-old rats received 4 µg bilateral intracerebroventricular injections of 192-IgG-SP. Both experimental groups displayed similar behavior, indicating that development of a depleted cholinergic system yields similar results to cholinergic dysfunction in adulthood.

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Unique contributions of distinct cholinergic projections to motor cortical plasticity and learning.

Conner JM, Kulczycki M, Tuszynski MH (2010) Unique contributions of distinct cholinergic projections to motor cortical plasticity and learning. Cereb Cortex 20(11):2739-2748. doi: 10.1093/cercor/bhq022

Summary: This work mapped the basal cholinergic forebrain system associations with skilled motor learning and motor function recovery after cortical injury. Rats were lesioned with 192-IgG-SAP (Cat. #IT-01). The animals received either two rostrocaudal injections of 75-112 ng; two 19 ng injections into the “prefrontal depletion site”; or two 19 ng injections into the “motor cortex depletion site.” Loss of motor cortex cholinergic systems disrupts map plasticity and skilled motor behavior, indicating that control of these systems rests within the motor cortex.

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Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain.

Thomsen MS, Hay-Schmidt A, Hansen HH, Mikkelsen JD (2010) Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain. Cereb Cortex 20(9):2092-2102. doi: 10.1093/cercor/bhp283

Summary: a7 nicotinic acetylcholine receptor (nAChR) agonists are potential treatments for some aspect of schizophrenia. The authors examine whether cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) are a target for this treatment. Rats received 300 ng injections of 192-IgG-SAP (Cat. #IT-01) into the HDB. The results demonstrate that cholinergic neurons in the HDB are essential for a7 nAChR agonist activation of the medial prefrontal cortex.

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Estrogen therapy and cognition: a review of the cholinergic hypothesis.

Gibbs RB (2010) Estrogen therapy and cognition: a review of the cholinergic hypothesis. Endocr Rev 31(2):224-253. doi: 10.1210/er.2009-0036

Summary: This review discusses estrogen therapy for use in postmenopausal women. In this context the issues revolve around benefits vs. harm of such therapy on the brain and cognitive impairment associated with aging and Alzheimer’s disease. Use of 192-IgG-SAP (Cat. #IT-01) to investigate this paradigm is described.

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Amyloid-beta expression in retrosplenial cortex of triple transgenic mice: relationship to cholinergic axonal afferents from medial septum.

Robertson RT, Baratta J, Yu J, LaFerla FM (2009) Amyloid-beta expression in retrosplenial cortex of triple transgenic mice: relationship to cholinergic axonal afferents from medial septum. Neuroscience 164:1334-1346. doi: 10.1016/j.neuroscience.2009.09.024

Summary: In this work the authors developed a model to examine the relationship between afferent projections and the formation of amyloid-beta (Aβ) deposits. Mice received 1.86 µg unilateral injections of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricle. Lesioned animals had persistent Aβ immunoreactivity in layer III of the granular division of retrosplenial cortex (RSg). This data indicates that septal cholinergic axonal projections transport Aβ or amyloid precursor protein to layer III of the RSg.

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Effects of combined neonatal cholinergic lesion and chronic cerebral hypoperfusion on CA1 cytoarchitecture.

Rennie KE, Ward C, Fréchette M, Pappas BA (2009) Effects of combined neonatal cholinergic lesion and chronic cerebral hypoperfusion on CA1 cytoarchitecture. Neuroscience 2009 Abstracts 736.23/M38. Society for Neuroscience, Chicago, IL.

Summary: Neonatal lesioning of the basal forebrain cholinergic (BFC) system alters cytoarchitecture of pyramidal cells in both the hippocampus and neocortex of the adult rat, indicating a role for the BFC in forebrain development. In addition to altering forebrain development, neonatal cholinergic lesion may also exacerbate the brain’s response to pathological factors that emerge as the brain ages. One factor that might interact with BFC lesion is reduced cerebral blood flow (hypoperfusion). Examining this interaction is especially interesting because both BFC degeneration and reduced cerebral blood flow are characteristics of Alzheimer’s disease. In the rat, chronic cerebrovascular insufficiency by itself reportedly causes the degeneration of hippocampal CA1 pyramidal cells, alters amyloid processing and produces spatial memory impairments. We hypothesized that neonatal cholinergic lesion using the cholinotoxin 192-IgG-saporin would render the hippocampus more vulnerable to the neuropathological effects of chronic forebrain hypoperfusion induced by permanent bilateral occlusion of the carotid arteries (2VO). We previously reported that combined BFC lesion and 2VO impaired working memory in the Morris water maze and increased anxiety-like behaviours on the elevated plus apparatus, whereas neither of these treatments alone caused any of these effects. Here we report the effects of neonatal BFC lesion, 2VO, or their combined application on hippocampal CA1 cytoarchitecture using quantitative Golgi analysis. Rats subjected to 2VO showed increased apical branch length and spines, and increased basal spines. Neonatal BFC lesion on its own had only restricted effects on apical branch length at certain branch orders and no effect on spines. However, at a number of branch orders the stimulating effect of 2VO on apical spines occurred only in animals subjected to neonatal BFC lesion, indicating that this lesion modulated the response to 2VO. To our knowledge, this is the first examination of the effects of 2VO on CA1 neuron cytoarchitecture. Surprisingly, it increased rather than decreased dendritic length and spines. Furthermore, while the BFC lesion had minimal effects on its own, it was permissive to some of the effects of 2VO on dendritic spines. Taken together with our previous data, this study suggests that pre-existing cholinergic dysfunction alters aspects of both the behavioural and neural consequences of chronic hypoperfusion. These results may have implications for Alzheimer’s disease where cholinergic dysfunction and hypoperfusion are co-expressed

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Alterations in dopaminergic and glutamatergic systems following cortical cholinergic denervation.

Savage ST, Lundströmer K, Olson L, Mattsson A (2009) Alterations in dopaminergic and glutamatergic systems following cortical cholinergic denervation. Neuroscience 2009 Abstracts 839.14/M21. Society for Neuroscience, Chicago, IL.

Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. We have previously shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (nbm) in adult rats leads to an enhanced sensitivity to both amphetamine and the NMDA receptor antagonist phencyclidine (PCP). The enhanced sensitivity to amphetamine shown as a potentiated dopamine release in nucleus accumbens, along with a marked increase in locomotor activity in response to both amphetamine and PCP, suggested that the disruption of cortical cholinergic activity can lead to disturbances of glutamatergic and dopaminergic transmission. To further evaluate the consequences of cortical cholinergic denervation on the dopamine and glutamate systems, we are conducting an in depth in situ hybridization and immunohistochemistry analysis of nbm 192 IgG-saporin lesioned rats. Preliminary data from these investigations show an enhancement of expression levels of TH and DAT mRNA in the VTA and substantia nigra of the cholinergically denervated rats. The data suggests that cortical levels of NMDAR1 mRNA are not altered in the lesioned animals. However, preliminary data indicate that the induction of c-fos mRNA expression in cortex following PCP administration is reduced in denervated animals as compared to sham lesioned controls. These data may suggest hypofunction of NMDA receptors as a consequence of loss of cholinergic innervations. To evaluate the behavioral consequences of cortical cholinergic denervation, we are employing three behavioral paradigms (Locomotor and Rearing behavior, Social Interaction, and the Novel Object Recognition (NOR) task) under normal and drug challenged conditions. Preliminary social interaction studies have found that the saporin lesioned rats spend a significantly less amount of time interacting with each other as compared to control sham operated rats. We are currently investigating how this impairment is effected under drug challenge. Furthermore, we have found that the degree of lesion affects the performance to the novel object recognition task under saline and drug challenged conditions. Our results from the in situ hybridization and behavioral studies indicate that the loss of cortical acetylcholine can lead to alterations in glutamatergic and dopaminergic signaling. These observations are compatible with a possible role of cholinergic deficits in schizophrenia, and provide a possible link between different hypotheses of the disorder.

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Using visual search to examine cholinergic contributions to feature binding in the rat.

Botly LC, De Rosa E (2009) Using visual search to examine cholinergic contributions to feature binding in the rat. Neuroscience 2009 Abstracts 873.26/EE13. Society for Neuroscience, Chicago, IL.

Summary: According to the feature integration theory of attention, feature binding is an attention-dependent process whereby the different features of an object are simultaneously integrated to form a unified whole. Using a rat digging paradigm that was faithful to this theory of attention, we have previously demonstrated that acetylcholine is critical to the attention-dependent processes required for both crossmodal and intramodal feature binding. Moreover, we demonstrated that cholinergic cells in brain regions that have been implicated in human feature binding, specifically frontal and parietal cortices, supported feature binding in rats. We have now translated the gold-standard test of human feature binding, visual search (VS), for rats. In the present study, sixteen male Long-Evans rats were trained to perform VS using touchscreen-equipped operant chambers and black-and-white shapes. Testing sessions comprised Feature-Search (no feature binding required) and Conjunctive-Search (feature binding required) trials using set sizes of four, six, and eight stimuli. Following acquisition of the VS task, eight rats received bilateral 192 IgG-Saporin immunotoxic lesions of the nucleus basalis magnocellularis (NBM) of the basal forebrain to reduce cholinergic afferentation of the neocortex. Importantly, there was no significant effect of lesion on accuracy for selecting the target stimulus. As expected, relative to sham-lesioned rats, NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive-Search but not Feature-Search trials; thus reflecting a less efficient VS. These data confirm that cholinergic contributions from the NBM support feature binding using a rat analog of the VS paradigm.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effect of aging and prefrontal cholinergic deafferentation on working memory for familiar and novel odors.

Carter ES, Newman LA, Mcgaughy J (2009) Effect of aging and prefrontal cholinergic deafferentation on working memory for familiar and novel odors. Neuroscience 2009 Abstracts 879.14/EE124. Society for Neuroscience, Chicago, IL.

Summary: Aging is associated with cholinergic fiber loss in the entorhinal cortex (EC). Previous research has shown that acetylcholine (ACh) in this region mediates memory for novel information (Schon et al., 2005), and cholinergic lesions of the EC in young rats impair memory for novel, but not familiar, stimuli at an odor delayed non-match to sample task (DNMS; McGaughy et al., 2005). Currently, we tested whether age-related cholinergic fiber loss in the medial EC of male rats would be sufficient to produce impairments in memory for novel information during the DNMS task. Half of the aged animals were subjected to cholinergic depletion of medial, prefrontal cortex (pACh-lx) including both prelimbic and anterior cingulate cortex prior to the onset of testing. We hypothesized that this previous damage would result in impairments in memory for familiar items and would prevent improvements in memory shown after repeated exposure to novel items. Additionally the effects of increasing the delay between sample and choice portions of the test and memory for list of items were assessed. The pACh-lx animals were not impaired relative to sham-lx animals at memory for familiar information when there was a minimal delay between the sample and choice. However if a 15 minute delay was introduced between the sample and choice phase, pACh-lx rats performed more poorly than sham-lx rats. This suggests that ACh in the medial, prefrontal cortex is necessary for maintaining representations of familiar stimuli over a delay period. Aged rats showed accuracy impairments during sessions that required encoding of novel samples relative to their own performance at sessions requiring encoding of familiar samples. This impairment was greater on trials that required rats to discriminate the novel sample from a familiar non-match than on trials where all stimuli were novel. Though the extent of cholinergic fiber loss in EC due to aging was highly similar to that produced by infusion of the 192 IgG saporin to the EC of young rats, the severity of the cognitive impairments due to aging was not as great as that produced by lesioning. These data suggest that impact of damage to the cholinergic fibers of EC may vary based on whether the deterioration is gradual or has an acute onset.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Damage to nucleus basalis magnocellularis (nBM) cholinergic target areas produce different effects on the acquisition of learning set.

Bailey AM, Enos J, Medley V (2009) Damage to nucleus basalis magnocellularis (nBM) cholinergic target areas produce different effects on the acquisition of learning set. Neuroscience 2009 Abstracts 879.15/EE125. Society for Neuroscience, Chicago, IL.

Summary: Lesions to the nucleus basalis magnocellularis (nBM) using either quisqualic acid or 192 IgG-saporin produce differing effects on the acquisition of learning set. Specifically, quisqualic acid lesions produce severe and long lasting impairments but 192 IgG-saporin lesions produce transient effects on learning set acquisition. One possible explanation for acquisition differences involves altered neuronal activity in the cholinergic target areas of the nBM. We examined two main cholinergic targets of the nBM, namely the amygdala and the prefrontal cortex (PFC). Rats with either NMDA (20 µg/µl) lesions to the basolateral amygdala (n=10) or NMDA (20 µg/µl) lesions to the anterior cingulate PFC (n=6) were tested on an olfactory learning set formation task as well as operant delayed non-matching to-position (DNMTP) and open field activity. The rats with amygdala lesions were additionally tested on a fear conditioning task. Lesions to the PFC significantly impaired acquisition of learning set as measured by chance performance on Trial 2 (M = 56.17%, SD = 7.47). Rats with PFC lesions did not differ from sham animals on the DNMTP task (p > .05) or in activity counts in an open field (p > .05). However, rats with NMDA lesions to the amygdala were significantly higher than chance (50% correct) on Trial 2 (p .05) or percentage correct on the DNMTP task (p > .05). NMDA lesions to the amygdala did, however, significantly decrease time spent freezing to an aversive CS+ in the fear conditioning task (p < .05). In total, the results imply that learning set acquisition differences following either quisqualic acid or 192 IgG-saporin lesions to the nBM are not likely due to damage to the cholinergic projection to the amygdala but may be associated with altered PFC activity.

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Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain.

Thomsen MS, Hay-Schmidt A, Hansen HH, Mikkelsen JD (2009) Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain. Neuroscience 2009 Abstracts 646.2/V14. Society for Neuroscience, Chicago, IL.

Summary: α7 nicotinic acetylcholine receptor (nAChR) agonists are novel drugs candidates for the treatment of cognitive deficits in schizophrenia, which have shown pro-cognitive effects in clinical trials. Selective α7 nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and shell of the nucleus accumbens (ACCshell) in rats, regions which are important for cognitive function. However, the neural substrates involved in these effects remain elusive. Using retrograde tracing from the mPFC with Cholera Toxin B and immunoreactivity of the immediate-early gene c-Fos, a marker of neuronal activation, we identify the horizontal limb of the diagonal band of broca (HDB) in the basal forebrain as an important site of α7 nAChR activation. Approximately 26% of the cortically projecting neurons in the HDB are activated by acute administration of SSR180711 (10 mg/kg), and the neurons activated by SSR180711 in the HDB are cholinergic. Selective depletion of these cholinergic neurons with 192 IgG-Saporin abolishes the SSR180711-induced activation of the mPFC, but not the ACCshell, demonstrating their critical importance for α7 nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area (VTA) with 6-OHDA abolishes the SSR180711-induced activation of the ACCshell, but not the mPFC or HDB. These results indicate that two distinct neural pathways are activated by SSR180711, involving HDB-to-mPFC and VTA-to-ACCshell projections, respectively. The basal forebrain and mPFC are important for attentional function, and may subserve the pro-cognitive effects of α7 nAChR agonists, whereas activation of the ACCshell is implicated in beneficial effects on the positive symptoms of schizophrenia.

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Contributions of the medial prefrontal cortex to negative occasion setting

Macleod JE, Ackerman CM, Bucci DJ (2009) Contributions of the medial prefrontal cortex to negative occasion setting. Neuroscience 2009 Abstracts 477.2/FF61. Society for Neuroscience, Chicago, IL.

Summary: The medial prefrontal cortex of rats has a role in many aspects of cognitive function, and especially forms of inhibitory learning. Recent research has revealed heterogeneous functions of the prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex in modulating response inhibition. In a recent study, we tested the effects of separate neurotoxic lesions of the PL or IL in a serial feature negative discrimination paradigm (negative occasion setting). Rats received daily training sessions consisting of 16 trials: on 4 trials in each session, a tone was presented and followed by food reward; on the remaining trials, the tone was preceded by a visual stimulus and not reinforced. Our results indicate that PL but not IL is necessary for learning the discrimination. A second study was conducted to investigate the effects of these lesions on rats that were first extensively trained in this task. We found that rats that had been trained for 30 days prior to receiving PL or IL lesions were still able to perform the task as well as controls. Therefore, PL lesions disrupt acquisition but not performance of a serial feature negative discrimination. This same task has been used in our laboratory to investigate the effects of nicotine on learning. We have shown that nicotine-treated rats exhibit greater discrimination between the two trial types as evidenced by less frequent responding during non-reinforced trials, and learn the discrimination in fewer sessions than control rats. In addition, rats receiving nicotine showed an increase in rearing behavior during the presentation of the light, suggesting nicotine enhanced attention to the visual stimulus. One possible critical site of action for nicotine’s effects is the medial prefrontal cortex. Research in other laboratories utilizing other training procedures suggest that cholinergic activity in the medial prefrontal cortex is critical for attending to behaviorally relevant stimuli, and have implicated the rat PL in visual attention as well as inhibiting prepotent, goal oriented responses. We investigated the contribution of the cholinergic PL to learning the serial feature negative discrimination task by training rats that had received infusions of 192-IgG-saporin into PL to remove cholinergic input from the basal forebrain. No differences between control and lesion rats were observed. Taken together, the results suggest that PL is necessary for acquisition of a serial feature negative discrimination, although the basal forebrain cholinergic input into this region is not required to sufficiently learn the task.

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Role of the medial septum on navigational strategy and shifting between strategies: Effects of selective cholinergic and GABAergic lesions.

Janke KL, Fazelinik S, Roland JJ, Servatius RJ, Servatius RJ, Servatius RJ, Pang K (2009) Role of the medial septum on navigational strategy and shifting between strategies: Effects of selective cholinergic and GABAergic lesions. Neuroscience 2009 Abstracts 283.5/EE134. Society for Neuroscience, Chicago, IL.

Summary: Cholinergic and GABAergic neurons are major components of the septohippocampal pathway, and comparisons between the two neuronal populations are important for understanding the function of medial septum-vertical limb of the diagonal band (MSDB). Recently, we have been investigating the importance of MSDB neurons in cognitive flexibility. Cognitive flexibility is commonly examined in reversal of stimulus-reward associations and attention set shifting. The present studies examine whether selective lesions of cholinergic or GABAergic MSDB neurons impair shifting between egocentric and allocentric navigation strategies. Sprague Dawley rats were administered saline, GAT1-saporin or 192-IgG saporin into the MSDB to produce no damage, selective GABAergic damage or selective cholinergic damage, respectively. Lesion verification will be performed using immunocytochemistry at the end of the studies. In a plus maze, rats started in one of two arms opposite each other (i.e., north and south arms) randomized across trials. On any single trial, the arm opposite the starting arm was blocked forming a T-maze. Rats have a choice of entering one of the remaining 2 arms (east or west arms) for food reinforcement. During the acquisition phase of the first study, rats were reinforced to enter a particular arm (east or west: allocentric response) regardless of their starting location. After they reached criteria (10 consecutive correct choices), the goal location was either reversed (east to west) or shifted to an egocentric response strategy (left or right turn). Animals that received either GAT-1-saporin (.26 ug/ul) or 192-IgG saporin (.217ug/ul) lesion reached criteria faster than saline treated rats. No significant effects of either lesion were observed on spatial reversal or strategy shifts. However, qualitative assessment of the damage suggests that GAT1-saporin may have produced an incomplete lesion. Therefore, a second study using GAT1-saporin at .325 ug/ul was conducted. For this study, half of the rats were trained on an egocentric strategy and the other rats are reinforced for an allocentric response. When rats reached criteria, half of each group was trained in a reversal learning or strategy shift. Preliminary data show that rats treated with GAT1-saporin or saline learned the initial egocentric or allocentric strategy at a similar rate. However, animals were faster to reach criteria in the allocentric condition than the egocentric condition. Reversal learning and strategy shifting in the second study is currently being assessed. The results of this study will provide important insight into the role of the MSDB in learning and cognitive flexibility.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Selective cholinergic and GABAergic lesions of the medial septum slows acquisition of the classically conditioned eyeblink response in rats.

Roland JJ, Janke KL, Gluck MA, Beck KD, Pang KCH, Servatius RJ (2009) Selective cholinergic and GABAergic lesions of the medial septum slows acquisition of the classically conditioned eyeblink response in rats. Neuroscience 2009 Abstracts 283.6/EE135. Society for Neuroscience, Chicago, IL.

Summary: Both human and animal studies have demonstrated that the hippocampus is not essential for the acquisition of delay eyeblink conditioning. However, nonselective medial septal damage, in both rabbits and humans, impaired acquisition of delayed eyeblink conditioning, as well as latent inhibition of eyeblink conditioning. The medial septum provides a major cholinergic and GABAergic afferent projection to the hippocampus, and the effects of medial septal damage is widely believed to occur through its connections to the hippocampus. Cholinergic muscarinic antagonists impaired delay eyeblink conditioning when administered systemically or directly into the hippocampus. Computational models also predicted the lack of effects on delay conditioning or latent inhibition of eyeblink conditioning caused by interference of the cholinergic septohippocampal system Recent studies have suggested that the GABAergic septohippocampal system may be a major site of action for scopolamine. Therefore, the current study examined the effect of selective cholinergic or GABAergic medial septal lesions on the classically conditioned eyeblink response. Adult male Sprague-Dawley rats received either a sham, cholinergic (192-IgG saporin) or GABAergic (GAT1-saporin) lesion in the MS/DB. Two weeks later, all animals were implanted with stimulating and recording electrodes in the periorbital muscle. Following recovery, all animals received three consecutive days of delay eyeblink conditioning. Each daily session consisted of 100 paired CS-US (conditional stimulus - unconditioned stimulus) trials with an average intertrial interval (ITI) of 30 seconds. The CS was a 500ms tone which co-terminated with the US, a 10ms, 10V periorbital stimulation. Our preliminary results shows that both cholinergic and GABAergic lesions impaired acquisition of delayed eyeblink conditioning, as compared to the sham-lesioned group. However, after three days of training all three treatment groups reached the same asymptotic performance. Future studies will assess the effects of combined cholinergic and GABAergic lesions and the effects of these septal lesions on latent inhibition of the conditioned eyeblink response.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment.

Lima T-Z, Blanco MM, Bueno MA, Dos Santos Junior JG, Bargieri DY, Mello LE (2009) The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment. Neuroscience 2009 Abstracts 139.26/D36. Society for Neuroscience, Chicago, IL.

Summary: A substantial loss of cholinergic innervation in the hippocampus and cerebral cortex is universally accepted as a typical feature of Alzheimer's disease (AD). Cholinergic deafferentation is an often, but not a constant phenomenon in AD and its contribution to the progression of disease is not completely understood. The present work was aimed to evaluate the effect of cholinergic deafferentation on cognitive decline and on Amyloid-b (A_) metabolism and how this outcome is modulated by lithium. To this end rats were subjected to neonatal intracerebroventricular injection of 192 IgG-saporin (an immunotoxin selective to cholinergic neurons). Three months after surgery animals were evaluated in Morris Water Maze (MWM) and then entered a three months long lithium (LiCl) or control treatment. At the end of treatment, animals were once again tested in MWM and their cerebral cortical A_ levels were measured. We found that working memory impairment arises earlier and it is also more severe than reference memory related deficits. The cognitive performance was only slightly influenced by LiCl treatment. Furthermore we found that the cholinergic denervation produced by neonatal IgG-sap infusion did not modify A_ levels or its aggregation state. Moreover lithium increased the levels of A_1-42 despite decreasing the amount of A_1-40, an effect that is dependent of cholinergic integrity. These data suggest that the contribution of cholinergic deafferentation, which occurs over the progression of disease, to the amyloigenesis is likely to be modest in AD brain. In addition the effects of lithium treatment presented here imply in avoiding its use as prophylactic propose for AD and in AD cases without marked cholinergic degeneration.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Role of cholinergic NBM neurons in timing and divided attention.

Mcauley J, Stewart AL, Pang KCH (2009) Role of cholinergic NBM neurons in timing and divided attention. Neuroscience 2009 Abstracts 95.12/EE81. Society for Neuroscience, Chicago, IL.

Summary: The nucleus basalis magnocellularis (NBM) provides cholinergic and GABAergic innervation to the neocortex. In previous studies, non-selective lesions of the NBM using ibotenic acid impaired interval timing and divided attention. Rats with NBM damage produced rightward shifts in peak times, demonstrating overproduction (underestimation) of time. Additionally, NBM damage impaired the ability to divide attention when timing two intervals simultaneously. Damage of the frontal cortex produced similar impairments in timing and divided attention as NBM damage, suggesting the NBM projections to frontal cortex were critical. Currently, the NBM neurons responsible for modulating timing and attention are unknown. The present study will determine the importance of cholinergic NBM neurons in timing and attention using the selective immunotoxin 192-IgG saporin (192-SAP). Sixteen Sprague Dawley rats were first trained on a peak-interval (PI) procedure using fixed-intervals of 12 s and 24 s paired with light and tone stimuli, respectively. During this phase, only one stimulus was presented during a trial (focused attention). Following the initial phase of training, rats were trained on a divided attention version of the peak-interval procedure, in which 2 stimuli were presented simultaneously in a trial and rats timed both intervals in parallel. Rats were administered 192-SAP into the NBM (n = 10) or given SHAM surgeries (n = 6). Following surgery, 192-SAP rats produced a leftward shift in timing with increased variability compared to SHAM rats. These changes in timing were observed in both focused and divided attention conditions, but the effects were larger in divided attention conditions than in focused attention conditions. Results implicate the cholinergic NBM neurons in the modulation of interval timing and divided attention. Current work is verifying the selectivity and efficacy of the 192-SAP administration. Additional studies will examine the role of GABAergic NBM neurons in interval timing and divided attention.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Spatial memory following selective cholinergic lesion of the nucleus basalis magnocellularis.

Dashniani M, Burjanadze M, Beselia G, Maglakelidze G, Naneishvili T (2009) Spatial memory following selective cholinergic lesion of the nucleus basalis magnocellularis. Georgian Med News 174:77-81.

Summary: This study investigated the role of cholinergic nucleus basalis magnocellularis (NBM) cells in learning and memory. Rats received bilateral 200 ng injections of 192 IgG-SAP (Cat. IT-01) into the NBM. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The results indicate that the NBM is important in accurate spatial learning and the processing of information about the spatial environment. Deficits in rats with the cholinergic lesion may be due to lowered attentional function.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

NGF is essential for hippocampal plasticity and learning.

Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR, Sejnowski TJ, Tuszynski MH (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29:10883-10889. doi: 10.1523/JNEUROSCI.2594-09.2009

Summary: This work aimed to define NGF modulation of plasticity and function in adults. Rats received 50 ng injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Lesioned animals exhibited impaired retention of spatial memory and significantly reduced hippocampal long term potentiation. These results indicate that NGF modulates neuronal plasticity and behavior by exerting effects on cholinergic projections to hippocampal and cortical targets.

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Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs.

Ma J, Tai SK, Leung LS (2009) Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs. Psychopharmacology (Berl) 206:457-467. doi: 10.1007/s00213-009-1623-3

Summary: Schizophrenic patients do not experience the usual diminished response to repeated stimuli, otherwise known as gating. Gating loss can be caused by the administration of some psychotomimetic drugs. This study used 170 ng injections of 192-IgG-SAP (Cat. #IT-01) to examine the effect of ketamine on sensory gating loss. Elimination of septohippocampal cholinergic neurons alleviated the disruption of auditory gating caused by ketamine.

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A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning.

Esclassan F, Coutureau E, Di Scala G, Marchand AR (2009) A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning. J Neurosci 29:8087-8093. doi: 10.1523/JNEUROSCI.0543-09.2009

Summary: Higher cognitive involvement can be modeled through the use of trace conditioning in simple associative tasks. Rats received several 20-80 ng injections of 192-IgG-SAP (Cat. #IT-01) into the entorhinal cortex (EC) in order to clarify the mechanisms that allow learning through the association of events that occur at different times. Cholinergic depletion of the EC did not result in a training deficit, indicating that these cells are not necessary for trace conditioning.

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Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: Involvement of the HPA axis.

Aisa B, Gil-Bea FJ, Marcos B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ (2009) Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: Involvement of the HPA axis. Psychoneuroendocrinology 34(10):1495-1505. doi: 10.1016/j.psyneuen.2009.05.003

Summary: Early adverse life events such as maternal separation (MS) can increase vulnerability to psychopathology as an adult. The authors administered bilateral intracerebroventricular 1 µg injections of 192-IgG-SAP (Cat. #IT-01) to MS rats then analyzed choline acetyltransferase and acetylcholinesterase activity. Lesioned animals displayed reduced activity of both of these enzymes, as well as decreased glucocorticoid receptor density. The results suggest that vulnerability of basal forebrain cholinergic cells may be affected by the hypothalamic-pituitary-adrenal axis.

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Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology.

De Bartolo P, Gelfo F, Mandolesi L, Foti F, Cutuli D, Petrosini L (2009) Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology. J Alzheimers Dis 17:177-191. doi: 10.3233/JAD-2009-1035

Summary: Donepezil has been shown to enhance cognitive functioning in both healthy patients and those suffering from dementia. This study examined whether donepezil treatment changes neocortical morphology in healthy or diseased brains. Rats received 4 µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricles. Various morphological parameters were analyzed demonstrating that in the absence of cholinergic neurons donepezil prevented the compensatory response rather than enhanced function.

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The basal forebrain cholinergic system is required specifically for behaviorally mediated cortical map plasticity.

Ramanathan D, Tuszynski MH, Conner JM (2009) The basal forebrain cholinergic system is required specifically for behaviorally mediated cortical map plasticity. J Neurosci 29:5992-6000. doi: 10.1523/JNEUROSCI.0230-09.2009

Summary: In this work the authors examined what types of neuronal plasticity require the cholinergic system. Selective depletion of the basal forebrain cholinergic system was accomplished by bilateral 112-ng and 75-ng injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis/substantia inominata. The results indicate a linkage between cholinergic mechanisms and distinct forms of cortical plasticity, supporting the role of the forebrain cholinergic system in modulating plasticity associated with behavioral experience.

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Cholinergic depletion of the medial septum followed by phase shifting does not impair memory or rest-activity rhythms measured under standard light/dark conditions in rats.

Craig LA, Hong NS, Kopp J, McDonald RJ (2009) Cholinergic depletion of the medial septum followed by phase shifting does not impair memory or rest-activity rhythms measured under standard light/dark conditions in rats. Brain Res Bull 79(1):53-62. doi: 10.1016/j.brainresbull.2008.10.013

Summary: It has been theorized that cognitive decline observed in Alzheimer’s disease is in part due to disruption of the circadian rhythm (CR) in these patients. Some basal forebrain cholinergic neurons project to the suprachiasmatic nucleus, which is responsible for maintenance of CR. Rats received two injections totaling 7.5 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum/diagonal band of Broca. Lesioned animals did not show any evidence of CR disruption.

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Cholinergic deafferentation of the neocortex using 192 IgG-saporin impairs feature binding in rats.

Botly LC, De Rosa E (2009) Cholinergic deafferentation of the neocortex using 192 IgG-saporin impairs feature binding in rats. J Neurosci 29:4120-4130. doi: 10.1523/JNEUROSCI.0654-09.2009

Summary: It has been hypothesized that the nucleus basalis magnocellularis (NBM) is the source of cholinergic input to the neocortex that is responsible for incorporating different features of an object into a unified neural representation of said object. Rats received 0.04-µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the NBM. In lesioned animals modes of learning requiring feature binding were impaired, while processes not using feature binding were left intact.

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Neurotrophic signaling molecules associated with cholinergic damage in young and aged rats: environmental enrichment as potential therapeutic agent.

Paban V, Chambon C, Manrique C, Touzet C, Alescio-Lautier B (2011) Neurotrophic signaling molecules associated with cholinergic damage in young and aged rats: environmental enrichment as potential therapeutic agent. Neurobiol Aging 32(3):470-485. doi: 10.1016/j.neurobiolaging.2009.03.010

Summary: This study examined the potential of long-term environmental enrichment as a therapeutic agent for cholinergic damage. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum (37.5 ng per side) and nucleus basalis magnocellularis (75 ng per side). Through the use of cDNA macroarrays the authors associated the therapeutic effects of environmental enrichment with downregulation of gene expression associated with certain cell processes, and upregulation of gene expression associated with signal transduction.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Anti-amnesic properties of (+/-)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats.

Antonini V, Prezzavento O, Coradazzi M, Marrazzo A, Ronsisvalle S, Arena E, Leanza G (2009) Anti-amnesic properties of (+/-)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats. J Neurochem 109:744-754. doi: 10.1111/j.1471-4159.2009.06000.x

Summary: Sigma-1 receptors are found throughout the central nervous system, and are thought to be a target for regenerative therapy in Alzheimer’s disease. Rats received 3.0 µg or 5.0 µg of 192-IgG-SAP (Cat. #IT-01) injected intracerebroventricularly. The lesioned animals displayed dose-dependent deficits in water maze performance. Treatment with the sigma-1 receptor agonist (±)-PPCC significantly improved both reference and working memory performance in treated animals, indicating that (±)-PPCC-mediated positive effects are probably a function of the sigma-1 receptor.

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Cognitive performances of cholinergically depleted rats following chronic donepezil administration.

Cutuli D, Foti F, Mandolesi L, De Bartolo P, Gelfo F, Federico F, Petrosini L (2009) Cognitive performances of cholinergically depleted rats following chronic donepezil administration. J Alzheimers Dis 17(1):161-176. doi: 10.3233/JAD-2009-1040

Summary: The authors examined whether donepezil could improve cognitive functions in rats with lesions of the cholinergic cells in the forebrain. Treated animals received 4 µg bilateral intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01), followed by treatment with donepezil or a control. Donepezil-treated animals performed significantly better than control animals.

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Recent progress in research on ribosome inactivating proteins.

Ng TB, Wong JH, Wang H (2009) Recent progress in research on ribosome inactivating proteins. Curr Protein Pept Sci 1323:94-108. doi: 10.2174/138920310790274662

Summary: This review discusses recent literature on ribosome inactivating proteins including the use of saporin-based conjugates in neuroscience and cancer research. Brief descriptions of research done using 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02), dermorphin-SAP (Cat. #IT-12), anti-SERT-SAP (Cat. #IT-23), SSP-SAP (Cat. #IT-11), anti-DBH-SAP (Cat. #IT-03), CTB-SAP (Cat. #IT-14), and other conjugates are provided along with basic information about ribosome inactivating proteins.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Anti-SERT-SAP (Cat. #IT-23), SSP-SAP (Cat. #IT-11), CTB-SAP (Cat. #IT-14), Anti-DBH-SAP (Cat. #IT-03)

Developmental forebrain cholinergic lesion and environmental enrichment: behaviour, CA1 cytoarchitecture and neurogenesis.

Frechette M, Rennie K, Pappas BA (2009) Developmental forebrain cholinergic lesion and environmental enrichment: behaviour, CA1 cytoarchitecture and neurogenesis. Brain Res 1252:172-182. doi: 10.1016/j.brainres.2008.11.082

Summary: The authors investigated the effect of neonatal cholinergic lesions on plasticity in the presence or absence of enrichment. Each lateral ventricle of 7 day-old rats received 300 ng of 192-IgG-SAP (Cat. #IT-01). Although the lesions did not attenuate neurobehavioral plasticity, there were several physiological changes that occurred despite the environmental enrichment.

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Effects of the selective lesions of cholinergic septohippocampal neurons on different forms of memory and learning process.

Dashniani MG, Beseliia GV, Maglakelidze GA, Burdzhanadze MA, Chkhikvishvili N (2009) Effects of the selective lesions of cholinergic septohippocampal neurons on different forms of memory and learning process. Georgian Med News 166:81-85.

Summary: The hippocampus is crucial for the ability to recollect everyday events and factual knowledge. Here the authors looked at the role of the septo-hippocampal cholinergic system of the medial septum in learning and memory. Rats received 200 ng injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data suggest that although the septo-hippocampal region is essential for spatial learning, hippocampal acetyl cholinesterase may not be essential for all types of hippocampal-dependent memory.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Attentional demands for demonstrating deficits following intrabasalis infusions of 192 IgG-saporin.

Burk JA, Lowder MW, Altemose KE (2008) Attentional demands for demonstrating deficits following intrabasalis infusions of 192 IgG-saporin. Behav Brain Res 195:231-238. doi: 10.1016/j.bbr.2008.09.006

Summary: Attentional processing has been shown to be dependent on basal forebrain cholinergic inputs to the cerebral cortex. In this work the authors wished to specify which components should be used to demonstrate deficits following the loss of these neurons. Rats received 200 ng intrabasalis infusions of 192-IgG-SAP (Cat. #IT-01). Testing of lesioned animals indicated that attentional deficits are due to increase of overall attentional task demands as opposed to any single task parameter.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Selective lesion of septal cholinergic neurons in rats impairs acquisition of a delayed matching to position T-maze task by delaying the shift from a response to a place strategy.

Fitz NF, Gibbs RB, Johnson DA (2008) Selective lesion of septal cholinergic neurons in rats impairs acquisition of a delayed matching to position T-maze task by delaying the shift from a response to a place strategy. Brain Res Bull 77:356-360. doi: 10.1016/j.brainresbull.2008.08.016

Summary: It has been theorized that the effect of cholinergic lesions of the medial septum on learning depend on the stressful nature of the task being learned. The authors injected 0.2 µg of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats then examined the strategies used by these animals to learn a delayed matching to position T-maze task. Lesioned animals were less able to switch from one strategy to another, indicating that this mechanism is the primary one affected by septal cholinergic lesions.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Organization of food protection behavior is differentially influenced by 192 IgG-saporin lesions of either the medial septum or the nucleus basalis magnocellularis.

Martin MM, Winter SS, Cheatwood JL, Carter LA, Jones JL, Weathered SL, Wagner SJ, Wallace DG (2008) Organization of food protection behavior is differentially influenced by 192 IgG-saporin lesions of either the medial septum or the nucleus basalis magnocellularis. Brain Res 1241:122-135. doi: 10.1016/j.brainres.2008.09.018

Summary: In this work the authors used a food-protection model to investigate the role of cholinergic neurons in the processing of information from internal and external sources. Rats received the following amounts of 192-IgG-SAP (Cat. #IT-01): 15 ng or 20 ng into the medial septum (MS), or 20 ng into the nucleus basalis magnocellularis (NB). While the NB lesions reduced the number of successful food protection behaviors, lesions in the MS disrupted the temporal organization of this behavior.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Enhanced sensitivity to phencyclidine following cortical cholinergic denervation

Savage ST, Oberg J, Pernold K, Mattsson A (2008) Enhanced sensitivity to phencyclidine following cortical cholinergic denervation. Neuroscience 2008 Abstracts 842.7/X2. Society for Neuroscience, Washington, DC.

Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. We have recently shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis in adult rats, leads to an enhanced sensitivity to amphetamine. Thus, saporin lesioned rats show a marked increase in locomotor activity, as well as a potentiated dopamine release in nucleus accumbens when challenged with amphetamine. We hypothesize that the loss of cortical cholinergic input alters the activity of cortical glutamatergic neurons and in turn, their regulation of subcortical dopamine neurons. We have previously shown that this cortical cholinergic denervation leads to an increased locomotor response to the NMDA receptor antagonist phencyclidine (PCP), suggesting that disruption of cortical cholinergic activity can lead to disturbances of glutamatergic transmission. In current studies we are investigating attention and memory functions of rats with cholinergic denervation of neocortex using the novel object recognition task. Preliminary data from these investigations shows impairment in performance under PCP-challenge in saporin lesioned rats as compared to sham lesioned controls. These results indicate that cortical cholinergic deficits, in addition to leading to a dramatic potentiation of the locomotor response to PCP, can also lead to an enhanced sensitivity to PCP-induced cognitive impairments. Using pharmacological magnetic resonance imaging (MRI) we are investigating possible spatiotemporal differences in brain activation in rats with cortical cholinergic deficits following administration of PCP. Preliminary data have provided indications of a greater activation in cortical areas in saporin lesioned rats as compared to sham lesioned controls following PCP-challenge. Evaluations of possible alterations in social behavior following cortical cholinergic denervation are ongoing. Social interaction will be investigated under normal conditions, as well as after PCP-challenge. Preliminary results from these studies together with our previous results indicate that loss of cortical acetylcholine can lead to alterations in glutamatergic signaling. These observations are compatible with a possible role of cholinergic deficits in schizophrenia, and provide a possible link between different hypotheses of the disorder.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Involvement of the habenula in cognition through its regulatory role upon monoamine and acetylcholine transmissions

Lecourtier L (2008) Involvement of the habenula in cognition through its regulatory role upon monoamine and acetylcholine transmissions. Neuroscience 2008 Abstracts 698.4. Society for Neuroscience, Washington, DC.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effects of cholinergic deafferentation of medial, prefrontal cortex on a cross-modal divided attention task

Carter ES, Newman LA, Galler JR, Mcgaughy J (2008) Effects of cholinergic deafferentation of medial, prefrontal cortex on a cross-modal divided attention task. Neuroscience 2008 Abstracts 590.6/TT58. Society for Neuroscience, Washington, DC.

Summary: Previous research has shown that cholinergic lesions of the nucleus basalis magnocellularis impair cross-modal divided attention (Turchi and Sarter 1997). Cholinergically lesioned rats showed increased response latencies relative to sham-lesioned rats if required to divide attention but did not differ from sham-lesioned rats when tested in a focused attention condition. In the present study, the effects of selective cholinergic depletion of the medial, prefrontal cortex were assessed in the same cross-modal divided attention task (CMDAT). Male, Long-Evans rats were trained on one set of conditional response rules for visual stimuli and another for auditory stimuli. In the CMDAT, rats received 20 trials of either auditory or visual stimuli followed by twenty trials of the alternate modality (focused attention). Within the same session rats received 60 trials of a randomized sequence of all possible stimuli (divided attention). These trials were followed by two additional blocks of focused attention (20 trials/block) so the trial block sequence was Focused Attention 1 (FA1): Divided Attention (DA) : Focused attention 2 (FA2). Subjects received infusions of 192 IgG saporin (pACh-LX) or its vehicle (SHAM-LX) to the prelimbic cortex. Response latencies for all subjects were longer under conditions of divided attention when performance was compared to the first block of focused attention trials. However in pACh-LX rats response latencies in the second block of focused attention trials were longer than in the divided attention trials. The slowed performance in the FA2 block may suggest cognitive fatigue after performing the divided attention trials or may be due to the effects of prolonged time on task. To address this question, a novel sequence of trials DA : FA1 : FA2 was tested. This session showed no difference in response latencies across blocks in either group. The lack of increased response latencies in FA2 suggests the effect in the standard task is related to cognitive fatigue after completion of the DA block and prolonged time on task. The accuracy of pACh-LX rats was decreased in the divided attention block relative to SHAM-LX rats in this block and relative to pACh-LX rats’ own performance in the DA block of the standard task. This loss of accuracy with decreased latency suggests that lesioned rats show a cost of divided attention if no focused attention blocks precede divided attention testing. These data support the hypothesis that cholinergic afferents to the prefrontal cortex mediate divided attention and a loss of these afferents exacerbates cognitive fatigue.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Selective cholinergic lesions of the nucleus basalis magnocellularis disrupt attention in appetitive trace conditioning

Butt AE, Kinney-Hurd BL, Flesher MM, Amodeo DA, Horn LR, Greenfield V, Lladones R, Hernandez G, Loson L (2008) Selective cholinergic lesions of the nucleus basalis magnocellularis disrupt attention in appetitive trace conditioning. Neuroscience 2008 Abstracts 686.14/SS65. Society for Neuroscience, Washington, DC.

Summary: Pavlovian trace conditioning, but not delay conditioning, is a form of declarative memory that requires attention and depends on the medial prefrontal cortex and hippocampus. We have previously shown that selective lesions of the cholinergic basal forebrain projections to the neocortex and to hippocampus disrupt trace conditioning but not delay conditioning. The current experiment examines the contribution of the cortical cholinergic projections of the nucleus basalis magnocellularis (NBM) to the behavioral impairments previously observed following complete basal forebrain lesions involving both the NBM and the hippocampally-projecting medial septum (MS). We hypothesized that selective lesions of the cholinergic NBM neurons would disrupt trace conditioning in a manner similar to that observed following basal forebrain lesions. Additionally, because cholinergic modulation of prefrontal cortex mediates attention in other tasks, we hypothesized that increasing demands on attention in trace conditioning would exacerbate NBM lesion-induced impairments. Rats with bilateral 192 IgG-saporin lesions of the NBM and sham lesion control animals were tested in the trace conditioning paradigm either in the presence or absence of an attention-demanding visual distractor (intermittent, unpredictable flashing light). Rats received 60 trials per day for 10 days, where each trial consisted of a 10 s white noise CS, followed 10 s later by the delivery of a sucrose pellet unconditioned stimulus (US). Conditioned responding was assessed by measuring approach to the food cup. Approach during the CS itself was considered to be non-adaptive, while approach during the trace interval was classified as adaptive responding. Contrary to our hypothesis, results showed that NBM lesions failed to impair acquisition of trace conditioning in the absence of additional attentional demands. These findings suggest that the trace conditioning impairment previously observed following complete basal forebrain lesions were due either to damage to the hippocampally-projecting MS or to a cumulative effect of combined NBM and MS damage. The presence of the visual distractor, however, disrupted acquisition performance in the current experiment as hypothesized. The NBM lesion group in the distracted condition showed excessive non-adaptive responding during CS presentation as compared to controls. The increased attentional load caused by the visual distractor appears to have caused a disinhibition of non-adaptive responding in the NBM lesion group. These results suggest that cholinergic modulation of neocortex is involved in mediating attention during trace conditioning.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Learning strategy selection in the water maze in medial septal electrolytic and selective cholinergic neurons lesioned rats

Burjanadze M, Beselia G, Chkhikvishvili N, Kotaria N (2008) Learning strategy selection in the water maze in medial septal electrolytic and selective cholinergic neurons lesioned rats. Neuroscience 2008 Abstracts 389.5/TT33. Society for Neuroscience, Washington, DC.

Summary: In this experiment the ability of medial septal electrolytic, selective ACh lesioned (by immunotoxin 192 IgG-saporin) and sham-operated rats, to learn the location of a visible, as well as submerged platform in a water maze was investigated. A total of 36 male outbred albino rats were used in the study. All experiments were approved by the Animal Care and Use Committee of the Institute and were in accordance with the principles of laboratory animal care. The rats’ responses in the competition test were classified as either cue or place directed, based on the swim path for those trials. Sham-operated rats acquired both the visible and hidden platform versions of the task, but when required to choose between the spatial location they had learned and the visible platform in a new location, majority of them swam first to the old spatial location. The medial septal electrolytic lesioned rats acquired the visible platform version of the water maze task but failed to learn the platform location in space. When the visible platform was moved to a new location they often swam directly to it. The medial septal selective ACh lesioned rats, as well as sham-operated, acquired the platform location in space. Sham-operated and selective ACh lesioned rats identified as place responders, had significantly more accurate searches during hidden platform training, providing additional evidence of their effective use of a place learning strategy rather than medial septal electrolytic lesioned rats. These findings suggest that the septo-hippocampal system is essential for accurate spatial learning and suggest its role in processing information about the spatial environment, but deficits observed after septal electrolytic lesions cannot be accounted solely to the loss of hippocampal ACh and raised the unexpected possibility that hippocampal ACh is not essential for all types of hippocampal-dependent memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Galanthamine does not attenuate attentional or temporal impairments subsequent to cholinergic deafferentation of the cortex or hippocampus

Martin MM, Weathered SL, Wagner SJ, Wallace DG (2008) Galanthamine does not attenuate attentional or temporal impairments subsequent to cholinergic deafferentation of the cortex or hippocampus. Neuroscience 2008 Abstracts 441.12/T4. Society for Neuroscience, Washington, DC.

Summary: The role of the basal forebrain cholinergic system in early symptomology of dementia of the Alzheimer’s type (DAT) remains an area of intense debate. Although involvement of the basalocortical cholinergic system in attentional processing has been established, function of the septohippocampal cholinergic system remains to be determined. A recent study demonstrated a double dissociation between these systems in the organization of rat food protection behavior that may parallel the attentional impairments and temporal disorientation observed during the early stages of DAT. The current study sought to examine whether an acetylcholinesterase inhibitor currently used for the treatment of DAT (i.e., galanthamine) could attenuate these deficits. Consistent with previous research, intraparenchymal injections of 192 IgG-Saporin into the nucleus basalis or medial septum area in female Long Evans rats produced dissociable effects on the organization of food protection behavior. Specifically, nucleus basalis lesions selectively reduced the number of successful food protection behaviors; whereas, medial septum lesions selectively disrupted the temporal organization of food protection behavior. These impairments were not attenuated by the administration of 3 mg/kg s.c. galanthamine twice daily. Results of this study suggest that the modest benefits afforded by galanthamine administration in DAT patients may not reflect improved attention or temporal orientation. Continued studies aimed at understanding the neural dysfunction underlying these deficits may lead to the development of novel therapeutic agents for DAT.

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The effect of electrical stimulation in the rats for dementia animal model.

Jeong D, Hwang Y, Chang J (2008) The effect of electrical stimulation in the rats for dementia animal model. Neuroscience 2008 Abstracts 340.11/M2. Society for Neuroscience, Washington, DC.

Summary: Forebrain Cholinergic neurons in the nucleus basalis meynert (NBM) project primarily to the neocortex, and those in the medial septum project to the hippocampus and make a role in memory function. A case study was reported that electrical stimulation of the hypothalamus improves hippocampus dependent memory function. The hypothesis of this study is that electrical stimulation of NBM would induce memory enhancement by effect on neocortex and/or hippocampus. Animal models were induced by selective immunolesion of cholinergic neurons. The cholinergic immunotoxin 192 IgG-saporin was injected in lateral ventricle. 192 IgG-saporin injected rats were compared with Dulbecco’s phosphate bufferd saline (DPBS) injected rats. Neurological deficit and functional outcome were determined by immuohistochemistry using anti-choline acetyl transferase antibody and Morris water maze behavioral test. DBS electrode was implanted in NBM and Stimulation parameters are selected from animal stimulation test. Extent of the cholinergic lesion was showed in the basal forebrain complex region at 192 IgG-saporin injected rats. 192 IgG-saporin injected rats were severely impaired in the probe test of the water maze test. We observe that NBM stimulation induced memory enhancement in dementia models through the behavioral test. Therefore, our animal DBS system could be a useful instrument for investigation of dementia.

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Cholinergic deafferentation of the neocortex with 192 IgG-Saporin impairs feature binding in rats

Botly LC, De Rosa E (2008) Cholinergic deafferentation of the neocortex with 192 IgG-Saporin impairs feature binding in rats. Neuroscience 2008 Abstracts 418.2. Society for Neuroscience, Washington, DC.

Summary: The binding problem refers to the fundamental challenge of the central nervous system to integrate sensory information registered by distinct brain regions to form a unified neural representation of a stimulus. While the cognitive mechanisms and functional neuroanatomy of feature binding have been well examined by the human cognitive literature, the neurochemistry of feature binding remains unknown. We contend that acetylcholine (ACh) is critical for feature binding given this neuromodulator’s presumed role in modulating attention, and the well-established importance of attention to feature binding. Using systemic pharmacology in rats, we have previously established a critical role for ACh in feature binding at encoding, but have yet to identify the target brain regions cholinergic input must reach for successful feature binding to occur. Given the recognized importance of the frontal and parietal cortices to attentional processing, we hypothesized that cholinergic deafferentation of the neocortex would impair feature binding in a similar manner to that of systemic cholinergic blockade. To test this hypothesis, rats received bilateral 192 IgG-Saporin lesions of the nucleus basalis magnocellularis (NBM) of the basal forebrain. Relative to sham-lesioned rats, NBM-lesioned rats were significantly impaired at acquiring a crossmodal Feature-Conjunction (FC) task, while their ability to retrieve the FC task and to acquire a crossmodal Feature-Singleton (FS) task remained intact. These findings provide further support for our cholinergic attentional hypothesis of feature binding and reveal the importance of neocortical cholinergic input from the basal forebrain to the feature binding encoding process.

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A synergistic role for GABAergic and cholinergic neurons of the medial septum in spatial reference memory processing: assessment with the Morris water-maze and a novel double-H maze in rats

Lecourtier L, Leroux E, Cosquer B, Cassel JC (2008) A synergistic role for GABAergic and cholinergic neurons of the medial septum in spatial reference memory processing: assessment with the Morris water-maze and a novel double-H maze in rats. Neuroscience 2008 Abstracts 389.10/TT38. Society for Neuroscience, Washington, DC.

Summary: The medial septum - from which GABAergic and cholinergic neurons project to the hippocampus - might be one of the key structures involved in hippocampal-dependent spatial memory processing. Indeed, lidocaine-induced septal inactivation disrupts encoding and retrieval, but not consolidation of a spatial memory in the water maze. Furthermore, the activation of septal 5-HT1A receptors prevents encoding but neither immediate consolidation nor retrieval of such a memory. As i) 5-HT1A receptors are located on most GABAergic and a significant part of cholinergic neurons of the medial septum, and ii) highly selective cholinergic lesions in the medial septum weakly affect spatial learning, it is possible that normal spatial memory processing depends on a cooperation between cholinergic and GABAergic neurons of this region. To address this possibility using selective lesions, 192 IgG-Saporine (IgG group) or Orexine-Saporine (OREX group) was infused into the septum to damage cholinergic or GABAergic neurons, respectively. In a third group (IgG/OREX group), both lesions were combined. Sham-operated rats were used as controls. The lesion effects were assessed on locomotor activity and on acquisition/retrieval of two water-maze tasks, the Morris maze and the double-H maze. In separate groups, retrieval was tested at three post-acquisition intervals in the Morris maze, namely 1, 5 and 25 days, and two post-acquisition periods in the double H maze, namely 5 and 25 days. Only the combined lesion resulted in nocturnal hyperactivity. In the Morris water-maze, at 25 days, there was no retrieval, whatever the group; whereas at the 1-day delay all groups retrieved the platform, at the 5-day delay, IgG and OREX rats showed normal performance while IgG/OREX rats were impaired. In the double-H maze, at the 5-day delay all groups remembered the platform location. These effects will be compared to those found at the 25-day delay (experiment currently running). Our data show that the GABAergic and cholinergic neurons of the septum synergistically contribute to the regulation of hippocampal-dependent (declarative-like) spatial memory processing.

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Role of medial septum-diagonal band of Broca neurons in cognitive flexibility

Pang K, Janke K, Servatius RJ (2008) Role of medial septum-diagonal band of Broca neurons in cognitive flexibility. Neuroscience 2008 Abstracts 89.20/SS37. Society for Neuroscience, Washington, DC.

Summary: Cholinergic and GABAergic neurons are major components of the septohippocampal pathway, and comparisons between the two neuronal populations are important for understanding the function of medial septum and vertical limb of the diagonal band (MSDB). Recently, we have been investigating the importance of MSDB neurons in cognitive flexibility. Cognitive flexibility is commonly examined in procedures that require reversal of stimulus-reward associations and those that require shifts in attention set, involving switching attention to different stimulus dimensions. Our recent studies demonstrated that selective damage of GABAergic but not cholinergic MSDB neurons impaired spatial reversal. The present study will determine whether selective lesions of cholinergic or GABAergic MSDB neurons impairs shifting of attentional set. Sprague Dawley rats will be administered saline, GAT1-saporin or 192-IgG saporin into the MSDB to produce no damage, selective GABAergic damage or selective cholinergic damage, respectively. Verification of the lesions will be performed using immunocytochemistry at the end of the study. The behavioral procedure will occur in a plus maze. Rats will start in one of two arms opposite each other (i.e., north and south arms) randomized across trials. On any single trial, the arm opposite the starting arm will be blocked forming a T-maze. Rats will have a choice of entering one of the remaining 2 arms (east or west arms) for food reinforcement. Half of the rats will be reinforced to make an egocentric response (left or right turn) and the other rats will be reinforced to go to a particular arm (east or west; allocentric response) regardless of starting location. After reaching criterion (10 consecutive correct choices), the goal location will be reversed (i.e., left turn to right turn or east to west arm) or shifted to a different dimension (i.e., left turn to east arm or west arm to right turn). It is expected that rats treated with GAT1-saporin, but not 192-saporin, will be impaired on the reversal procedure, similar to previous studies. Impairments in shifting attention set would suggest a global impairment in cognitive flexibility. However, an impairment in the reversal procedure but not shifting of attention set would be similar to recently described deficits in the nucleus basalis magnocellularis using ibotenic acid and 192-IgG saporin lesions (Tait and Brown, Behav Brain Res. 187:100, 2008). The results of this study will provide important insight into the role of the MSDB in learning, attention and cognitive flexibility.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

192-IgG Saporin lesions of the medial septum or nucleus basalis magnocellularis disrupt exploratory trip organization

Wallace DG, Winter SS, Martin MM, Mcmillin JL (2008) 192-IgG Saporin lesions of the medial septum or nucleus basalis magnocellularis disrupt exploratory trip organization. Neuroscience 2008 Abstracts 90.15/SS57. Society for Neuroscience, Washington, DC.

Summary: Previous work has demonstrated that rats use self-movement cues to organize their exploratory behavior. The hippocampus and several cortical areas have been implicated in processing self-movement cues. The current study investigated whether selective cholinergic deafferentation of the hippocampus or cortex differentially influenced the organization of exploratory behavior. Long Evans female rats received injections of 192 IgG-Saporin or saline into the medial septum (MS) or nucleus basalis magnocellularis (NB). Subsequent to recovery, rats were placed on a large circular table that provided access to a refuge under complete dark conditions (infrared cameras and goggles were used to visualize the rat). All rats established a home base in the refuge; however, impairments in exploratory trip organization specific to the homeward segment were observed in MS and NB rats. Both groups displayed increased variability in the temporal pacing of speeds on the homeward return, consistent with impaired distance estimation. Only the NB group displayed a significant reduction in stop duration after short, medium, and long searching progressions. These observations are consistent with different roles for hippocampal and cortical cholinergic function in processing self-movement cues.

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The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions.

Kalinchuk AV, McCarley RW, Stenberg D, Porkka-Heiskanen T, Basheer R (2008) The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions. Neuroscience 157:238-253. doi: 10.1016/j.neuroscience.2008.08.040

Summary: The level of adenosine in the basal forebrain increases during sleep deprivation (SD). The cholinergic system of the basal forebrain is thought to be involved in the control of this process. 0.23 µg of 192-IgG-SAP (Cat. #IT-01) was injected into the horizontal diagonal band/ substantia innominata/ magnocellular preoptic nucleus, or 6 µg into the lateral ventricle of rats. The time course was dependent on the injection site, but eventually the SD-induced increase in adenosine was virtually eliminated.

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Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats.

Craig LA, Hong NS, Kopp J, McDonald RJ (2009) Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats. Exp Brain Res 193(1):29-42. doi: 10.1007/s00221-008-1592-5

Summary: Recent work has suggested that reduced levels of acetylcholine, seen in Alzheimer’s disease patients, increases the susceptibility of hippocampal neurons to future challenges. Rats received two injections totaling 7.5 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of Broca. The vasoconstrictor endothelin-1 was used to create small localized strokes in the hippocampus of lesioned animals. The data suggest that loss of these hippocampal neurons compromises functional recovery from stroke.

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Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion.

Mandolesi L, De Bartolo P, Foti F, Gelfo F, Federico F, Leggio MG, Petrosini L (2008) Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion. J Alzheimers Dis 15:11-28. doi: 10.3233/jad-2008-15102

Summary: The cognitive reserve model suggests individuals can develop resources that reduce the risk of later cognitive impairment. This theory was tested by raising rats in standard vs. enriched environments then lesioning the animals with 192-IgG-SAP (Cat. #IT-01). A total of 0.8 µg of 192-IgG-SAP was administered in bilateral injections, followed by various behavioral tests. It was found that animals raised in an enriched environment had reduced cognitive impairment following forebrain lesions.

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Functional convergence of dopaminergic and cholinergic input is critical for hippocampus-dependent working memory.

Wisman L, Sahin G, Maingay M, Leanza G, Kirik D (2008) Functional convergence of dopaminergic and cholinergic input is critical for hippocampus-dependent working memory. J Neurosci 28:7797-7807. doi: 10.1523/JNEUROSCI.1885-08.2008

Summary: Analysis of cholinergic alterations in PD patients may help to understand and treat the nonmotor symptoms of the disease.

Usage: Cholinergic neurons in theNBMand the MS/vDBB were lesioned by bilateral injection of the immunotoxin 192 IgG-SAP (0.85 µl of dissolved at a concentration of 0.142 µg/µl in PBS).

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Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures.

Craig LA, Hong NS, Kopp J, McDonald RJ (2008) Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures. Hippocampus 18(11):1112-1121. doi: 10.1002/hipo.20471

Summary: The loss of cholinergic neurons in the medial septum and seizures are both associated with Alzheimer’s disease. The authors investigated links between these factors using 192-IgG-SAP (Cat. #IT-01) and kainic acid. Rats received 0.15 µg of 192-IgG-SAP delivered to the medial septum and vertical limb of the diagonal band of Broca in four injections. Animals receiving both 192-IgG-SAP and kainic acid performed significantly worse in water maze tests than control animals, indicating that loss of cholinergic neurons and seizures interact in Alzheimer’s disease.

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Neuromodulatory role of acetylcholine in visually-induced cortical activation: Behavioral and neuroanatomical correlates.

Dotigny F, Ben Amor AY, Burke M, Vaucher E (2008) Neuromodulatory role of acetylcholine in visually-induced cortical activation: Behavioral and neuroanatomical correlates. Neuroscience 154(4):1607-1618. doi: 10.1016/j.neuroscience.2008.04.030

Summary: Acetylcholine is thought to have a neuromodulatory role in visual processing. After rats were treated with 192-IgG-SAP (Cat. #IT-01, 2 µl of 2.4 µg/µl into the lateral ventricle) visual acuity and performance in a visual water maze task were analyzed. Lesioned animals displayed no loss in acuity, but were less able to learn a new orientation discrimination task. These data suggest that the cholinergic system in the basal forebrain plays an important role in post-synaptic visual processing.

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Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility.

De Bartolo P, Leggio MG, Mandolesi L, Foti F, Gelfo F, Ferlazzo F, Petrosini L (2008) Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility. Neuroscience 154(2):444-453. doi: 10.1016/j.neuroscience.2008.03.069

Summary: The basal forebrain cholinergic system is a crucial participant in various facets of learning and memory. This work examines whether environmental enrichment can reduce the effect of cholinergic lesions on learning and memory tasks. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the cholinergic projection to the neocortex. Deficits caused by the lesion were attenuated in rats experiencing an enriched environment.

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Involvement of the basal cholinergic forebrain in the mediation of general (propofol) anesthesia.

Laalou FZ, de Vasconcelos AP, Oberling P, Jeltsch H, Cassel JC, Pain L (2008) Involvement of the basal cholinergic forebrain in the mediation of general (propofol) anesthesia. Anesthesiology 108:888-896. doi: 10.1097/ALN.0b013e31816d919b

Summary: The authors examined whether the basal forebrain cholinergic system is involved in mediating the effects of general anesthesia. Three different forms of 192-IgG-SAP (Cat. #IT-01) administration were used: intracerebroventricular injection of 2 µg, 0.4 µg injected into the nucleus basalis magnocellularis, and 0.8 µg into the medial septum/vertical diagonal band of Broca. The results suggest that loss of cholinergic neurons in the cortex and hippocampus leads to potentiation of the anesthetic effects of Propofol.

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Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress.

Craig LA, Hong NS, Kopp J, McDonald RJ (2008) Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress. Eur J Neurosci 27:2262-2271. doi: 10.1111/j.1460-9568.2008.06179.x

Summary: Although it is clear that loss of cholinergic neurons in the basal forebrain is intrinsic to Alzheimer’s disease, interaction of this loss with other factors in causing the disease symptoms has not been completely elucidated. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum and vertical limb of the diagonal band of Broca totaling 0.075 µg. Lesioned animals were not impaired in a water maze task, but lesioning combined with stress caused a significant reduction in performance.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting.

McGaughy J, Ross RS, Eichenbaum H (2008) Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 153:63-71. doi: 10.1016/j.neuroscience.2008.01.064

Summary: Norepinephrine and acetylcholine are involved in the mediation of attention, however, it is not yet clear whether the roles of these molecules are unique. This work utilizes a specific task shown to dissociate the roles played by the dorsolateral prefrontal cortex and the orbitofrontal cortex in primates. Rats received 5-ng infusions of anti-DBH-SAP (Cat. #IT-03) or 192-IgG-SAP (Cat. #IT-01) into each hemisphere. The type of lesion had an effect on attentional shifts and reaction to irrelevant stimuli.

Related Products: Anti-DBH-SAP (Cat. #IT-03), 192-IgG-SAP (Cat. #IT-01)

Selective cholinergic lesions in the rat nucleus basalis magnocellularis with limited damage in the medial septum specifically alter attention performance in the five-choice serial reaction time task.

Harati H, Barbelivien A, Cosquer B, Majchrzak M, Cassel JC (2008) Selective cholinergic lesions in the rat nucleus basalis magnocellularis with limited damage in the medial septum specifically alter attention performance in the five-choice serial reaction time task. Neuroscience 153:72-83. doi: 10.1016/j.neuroscience.2008.01.031

Summary: The cognitive deficits reported in rats on use of 192-IgG-SAP (Cat. #IT-01) are varied. Here the authors examined the effect of lesions in the nucleus basalis magnocellularis (NBM) when septal damage was kept to a minimum. The NBM received bilateral 0.2-µg injections of 192-IgG-SAP, and the animals were then tested in a 5-choice serial reaction time task. The disruption of sustained visual attention remained, but other variables such as motivational, locomotion, and impulsivity-related biases were close to normal.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic deafferentation of prefrontal cortex increases sensitivity to cross-modal distractors during a sustained attention task.

Newman LA, McGaughy J (2008) Cholinergic deafferentation of prefrontal cortex increases sensitivity to cross-modal distractors during a sustained attention task. J Neurosci 28:2642-2650. doi: 10.1523/JNEUROSCI.5112-07.2008

Summary: The authors injected 5 ng of 192-IgG-SAP (Cat. #IT-01) into the prefrontal cortex of rats to investigate the effect of cholinergic loss on distractors to attentional demand. Where all animals experienced impaired performance in the presence of visual distractions, lesioned animals were more sensitive to auditory distractions. While these results indicate compromised top-down processing, lesioned animals showed improved performance in bottom-up processing, possibly caused by a shift in circuit dynamics after the lesion.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice.

Moreau PH, Cosquer B, Jeltsch H, Cassel JC, Mathis C (2008) Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice. Hippocampus 18(6):610-622. doi: 10.1002/hipo.20422

Summary: 192-IgG-SAP (Cat. #IT-01) has been used for over a decade to examine the cholinergic system in the basal forebrain of rats. Establishing the same reagent for mice has been problematic. Here the authors describe the use of a mouse-specific lesioning agent, mu p75-SAP (Cat. #IT-16). After deciding on a dosage of 0.4 µg administered in the form of bilateral intracerebroventricular injections, mice were lesioned and tested. Lesioned animals displayed increased locomotor activity, and spatial learning and memory deficits, with minimal side effects.

Related Products: mu p75-SAP (Cat. #IT-16), 192-IgG-SAP (Cat. #IT-01)

Read the featured article in Targeting Trends.

Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats.

Tait DS, Brown VJ (2008) Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats. Behav Brain Res 187:100-108. doi: 10.1016/j.bbr.2007.08.035

Summary: The authors compared specific lesions of the basal forebrain using 192-IgG-SAP (Cat. #IT-01) with non-specific lesions generated by ibotenic acid. Rats were given 0.12 µg per 0.5 µl bilateral injections of 192-IgG-SAP. The treated animals were then tested in food reward tasks involving two-choice discriminations and reversal of stimulus-reward. Animals with specific lesions did not show impairment with any of the tasks suggesting that non-cholinergic neurons are involved in reversal learning. This work also demonstrates the similarities between monkey and rodent basal forebrain function.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Septal grafts restore cognitive abilities and amyloid precursor protein metabolism.

Aztiria E, Cataudella T, Spampinato S, Leanza G (2009) Septal grafts restore cognitive abilities and amyloid precursor protein metabolism. Neurobiol Aging 30(10):1614-1625. doi: 10.1016/j.neurobiolaging.2007.12.018

Summary: Although cholinergic loss and the presence of ß-amyloid plaques are well documented in Alzheimer’s disease, it is unknown whether restoration of regulatory cholinergic inputs affects in vivo b-amyloid precursor protein (APP). 5 µg of 192-IgG-SAP (Cat. #IT-01) was split between the lateral ventricles of rats. 6 months post-surgery the animals were implanted with cholinergic-rich septal tissue grafts. Grafted animals exhibited normal or near-normal levels of APP. APP levels, as well as improved spatial navigation performance, correlated strongly with graft-induced cholinergic changes.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The pedunculopontine tegmental nucleus and the nucleus basalis magnocellularis: do both have a role in sustained attention?

Rostron CL, Farquhar MJ, Latimer MP, Winn P (2008) The pedunculopontine tegmental nucleus and the nucleus basalis magnocellularis: do both have a role in sustained attention?. BMC Neurosci 9:16. doi: 10.1186/1471-2202-9-16

Summary: This study provided further investigation into the role of the pedunculopontine tegmental nucleus (PPTg) in control of sustained attention. Rats were given 0.13 µg injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. The immunotoxin-treated animals were compared to animals receiving ibotenate injections into the PPTg. Results suggest that ibotenate lesions cause impaired selection of conditioned response as shown by an increase in unconditioned behaviors. 192-IgG-SAP treated animals exhibited difficulty obtaining successful lever presses linked to attention.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effects of ibotenate and 192IgG-saporin lesions of the nucleus basalis magnocellularis/substantia innominata on spontaneous sleep and wake states and on recovery sleep after sleep deprivation in rats.

Kaur S, Junek A, Black MA, Semba K (2008) Effects of ibotenate and 192IgG-saporin lesions of the nucleus basalis magnocellularis/substantia innominata on spontaneous sleep and wake states and on recovery sleep after sleep deprivation in rats. J Neurosci 28:491-504. doi: 10.1523/JNEUROSCI.1585-07.2008

Objective: To examine the role of this area of the brain in several facets of sleep behavior.

Summary: The results suggest that cholinergic neurons and non-cholinergic neurons in the basal forebrain play different, but important roles in non-rapid eye movement sleep and EEG delta power after sleep loss. Non-cholinergic basal forebrain neurons inhibit delta waves, whereas cholinergic neurons promote wakefulness.

Usage: The caudal basal forebrain of rats was lesioned with 0.26-µg bilateral injections of 192-IgG-SAP.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake.

Blanco-Centurion C, Gerashchenko D, Shiromani PJ (2007) Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 27:14041-14048. doi: 10.1523/JNEUROSCI.3217-07.2007

Summary: Orexin neurons in the basal forebrain, tuberomammillary nucleus (TMN), and locus ceruleus (LC) are thought to regulate arousal. Rats were injected with two or three of the following targeted conjugates: anti-DBH-SAP (Cat. #IT-03), 0.25 µl bilateral injections of 1 µg/µl into the LC; orexin-SAP (Cat. #IT-20), 0.25 µl injection of 0.25 µg/µl into the TMN; 192-IgG-SAP (Cat. #IT-01), 3 µl injection of 2 µg/µl into the lateral ventricle. Small differences were observed in sleep architecture, but the data do not support the traditional hypothesis that these three areas of the brain are essential links in the control of wake levels.

Related Products: Anti-DBH-SAP (Cat. #IT-03), Orexin-B-SAP (Cat. #IT-20), 192-IgG-SAP (Cat. #IT-01)

The role of the nucleus basalis of Meynert and reticular thalamic nucleus in pathogenesis of genetically determined absence epilepsy in rats: A lesion study.

Berdiev RK, Chepurnov SA, Veening JG, Chepurnova NE, van Luijtelaar G (2007) The role of the nucleus basalis of Meynert and reticular thalamic nucleus in pathogenesis of genetically determined absence epilepsy in rats: A lesion study. Brain Res 1185:266-274. doi: 10.1016/j.brainres.2007.09.010

Summary: Absence seizures due to epilepsy usually occur during passive behavior. This work investigated the role of the cholinergic nucleus basalis of Meynert (NB) and the reticular thalamic nucleus (RT) in these seizures. Rats received either 75 ng of 192-IgG-SAP (Cat. #IT-01) or the control, mouse IgG-SAP (Cat. #IT-18), into the NB and the RT. Loss of cholinergic neurons in the NB resulted in an increased number of spike-and-wave discharges, a marker for absence seizures.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Survival, integration and differentiation of human neural stem cells transplanted into an animal model of cholinergic degeneration

Cusulin C, Aztiria E, Cacci E, Battaglini PP, Kokaia Z, Leanza G (2007) Survival, integration and differentiation of human neural stem cells transplanted into an animal model of cholinergic degeneration. Neuroscience 2007 Abstracts 779.5/E7. Society for Neuroscience, San Diego, CA.

Summary: The recently characterized F7B cell line, derived from human fetal cortex (Cacci et al, 2007) has been observed able to differentiate in vitro into different glial and neuronal subtypes. However, no much data is available about its capacity for differentiation in vivo. In the present work, F7B cells were grafted to the medial septum of newborn (P8) intact rats and to littermates that had been subjected to selective cholinergic deafferentation at P4 using the 192 IgG-saporin immunotoxin. The animals were sacrificed 1 or 3 months after grafting and the dissected brains were processed for immunocytochemistry, using cell-specific (HuNu and GFP) and differentiation markers (Dcx, GFAP, NeuN, and HuD). Overall, grafted F7B cells exhibited an excellent ability to survive and differentiate into the host tissue environment. Survival rate varied among the groups, being consistently higher when the cells were grafted into lesioned, as opposed to intact, animal. Moreover, a better survival was seen at 1 month, compared to 3 months post-grafting, regardless the lesion condition. Interestingly, the presence of a cholinergic depletion in the recipient appeared to affect differentiation of grafted F7B cells. In fact, higher numbers of Dcx+ and HuD+ cells were scattered within the grafts placed in lesioned animals, as compared to controls. In lesioned, but not intact animals, at 3 months post-grafting, sparse F7B cells were found to express the mature neuronal marker NeuN. On the other hand, grafted F7B immunoreactive for GFAP were similarly detected in all transplanted animals. F7B cells appear to be feasible for transplantation, being able to survive and differentiate into a developing brain, and to positively respond to the new environment created by a lesion. Further studies are warranted to test their actual capacity for functional integration.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Immunotoxin lesion of cholinergic nucleus basalis magnocellularis neurons in Lister hooded rats impair performance in a delayed matching-to-place task

Savage S, Ogren S, Olson L, Mattsson A (2007) Immunotoxin lesion of cholinergic nucleus basalis magnocellularis neurons in Lister hooded rats impair performance in a delayed matching-to-place task. Neuroscience 2007 Abstracts 840.1/TT24. Society for Neuroscience, San Diego, CA.

Summary: Central cholinergic systems play an important role in various aspects of cognition, and deficits in cortical cholinergic function have been implicated in the cognitive impairments associated with normal aging and dementia. Cholinergic dysfunctions have also been implicated in several neuropsychiatric disorders, including schizophrenia. Though cognitive dysfunctions, such as impaired working memory, are observed in Alzheimer, as well as schizophrenic patients, the cholinergic mechanisms behind these dysfunctions are not well characterized in animal models. To investigate whether specific cortical cholinergic deficits will affect spatial learning and memory functions, we lesioned the basalo-cortical cholinergic system by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (NBM) of adult male Lister hooded rats. Learning and memory was assessed using a delayed matching-to-place (DMP) paradigm in the water maze. We found that animals with cholinergic denervation of neocortex were impaired in the DMP-task. Thus, while the sham-operated animals rapidly learned the task without prior training, saporin-treated rats showed impairment during the initial three days of testing. By the end of the testing period, the lesioned animals had acquired the task. However, the cholinergically denervated animals showed a performance deficit throughout the duration of the experiment with higher trial latencies and longer distance traveled to find the platform as compared to the controls. They also seemed to employ a different strategy to find the hidden platform as compared to control animals. Whether the deficits after cholinergic lesions to the NBM seen in the present experiment are mnemonic and/or attentional in nature remains to be elucidated.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Selective hippocampal cholinergic deafferentation disrupts exploratory trip organization

Wallace DG, Knapp SK, Silver JA, Martin MM, Winter SS (2007) Selective hippocampal cholinergic deafferentation disrupts exploratory trip organization. Neuroscience 2007 Abstracts 743.17/BBB11. Society for Neuroscience, San Diego, CA.

Summary: Rats organize their exploration of an environment around a central location or home base. Movements away from the home base are characterized as a series of slow progressions punctuated by stops. Subsequent to the last stop, the homeward segment is a single, rapid progression associated with a consistent temporal pacing of linear speeds. Observing these characteristics of exploratory behavior independent of environmental cue availability or familiarity has supported rats’ use of self-movement cues generated after departing the home base to estimate the distance and direction back to the home base. The current study investigated the effects of selective hippocampal cholinergic deafferentation on home base establishment and exploratory trip organization. Long Evans female rats either received injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum. Subsequent to recovery, rats were placed on a large circular table with access to a refuge under complete dark conditions (infrared cameras and goggles were used to visualize the rat). Although all rats established a home base in the refuge, impairments in exploratory trip organization specific to the homeward segment were observed in SAP rats. Specifically, SAP rats displayed inconsistent temporal pacing of homeward segment linear speeds. These observations are consistent with a role for hippocampal cholinergic function in processing self-movement cues.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Neuronal mechanisms underlying the cognitive symptoms in a model of schizophrenia: prefrontal cholinergic inputs are necessary for attentional performance following repeated exposure to amphetamine

Young D, Howe WM, Martinez V, Bruno JP, Sarter M (2007) Neuronal mechanisms underlying the cognitive symptoms in a model of schizophrenia: prefrontal cholinergic inputs are necessary for attentional performance following repeated exposure to amphetamine. Neuroscience 2007 Abstracts 606.9/GG1. Society for Neuroscience, San Diego, CA.

Summary: The neuronal and cognitive effects of repeated exposure to amphetamine (AMPH) model important aspects of schizophrenia. Our prior results indicated that the attentional performance of AMPH-pretreated animals was maintained by abnormally high levels of prefrontal acetylcholine (ACh) release, and that the disruption of attentional performance by AMPH challenges was associated with a failure of the prefrontal cholinergic input system to respond to task onset (Kozak et al. 2007). The present experiment was designed to demonstrate that prefrontal cholinergic inputs are necessary for the (residual) attentional performance following repeated AMPH exposure. As removal of cortical cholinergic inputs per se disrupts attentional performance, we tested the hypothesis that limited prefrontal cholinergic deafferentation, which does not affect baseline attentional performance, prevents the establishment of normal performance following AMPH pretreatment. Rats were trained to perform a sustained attention task requiring the detection of visual signals and the discrimination between signal and non-signal events. Bilateral infusions of small concentrations and volumes of the immunotoxin 192 IgG-saporin into the medial prefrontal cortex did not affect the animals’ baseline performance. After re-establishing stable baseline performance, animals were pretreated with either saline or AMPH in accordance with an established, non-neurotoxic, escalating dosing regimen (1-10 mg/kg, twice daily over 40 days; Robinson et al. 1988). Animals were tested daily throughout the experiment. Following completion of the pretreatment regimen, the attentional performance of sham-lesioned controls recovered slowly over three weeks of continued training/testing. In contrast, performance recovery of deafferented, AMPH-pretreated animals was robustly attenuated and failed to reach pre-treatment levels. Collectively, these results indicate the necessary role of the prefrontal cholinergic input system in mediating the residual attentional performance of repeated AMPH. Therefore, pro-cholinergic treatments are predicted to benefit the attentional performance of schizophrenics. Repeated AMPH serves as a useful model to investigate the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Walking the Plank: Role of the medial septum in distance estimation

Winter SS, Martin MM, Wallace DG (2007) Walking the Plank: Role of the medial septum in distance estimation. Neuroscience 2007 Abstracts 743.21/BBB15. Society for Neuroscience, San Diego, CA.

Summary: Controversy surrounds the role of the septohippocampal system in spatial orientation. Recent work has demonstrated that selective cholinergic deafferentation of the hippocampus impairs use of self-movement cues while sparing environmental cue use. Self-movement cues are generated from changes in position or direction. The current study examines the role of the septohippocampal cholinergic system in processing of self-movement cues related to changes in position or distance estimation in a food hoarding task. The probability of food hoarding has been shown to be influenced by travel distance and time to consume the food item. Long Evans female rats received either injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum. Subsequent to recovery, rats were placed in a refuge on a 15 cm wide plank and allowed to traverse the plank to collect food pellets located at the end. Both the distance to the food pellet (2.4 vs. 4.8 m) and size of the food pellet (190, 500, 1000 mg) were varied across days. Differences in food hoarding probability were observed between groups. SAP rats were less likely to modify their food hoarding probability in response to changes in plank length relative to SHAM rats. These results are consistent with selective hippocampal cholinergic deafferentation producing deficits in processing self-movement cues related to distance estimation.

Related Products: 192-IgG-SAP (Cat. #IT-01)

On the survival of nestin-expressing neurons in the cholinergic basal forebrain after an immunolesion with 192-IgG-saporin

Nguyen WT, Buhalog A, Hendrickson M, Kalil RE (2007) On the survival of nestin-expressing neurons in the cholinergic basal forebrain after an immunolesion with 192-IgG-saporin. Neuroscience 2007 Abstracts 674.5/D24. Society for Neuroscience, San Diego, CA.

Summary: Nestin is a class VI intermediate filament protein that is widely accepted as a marker for uncommitted neural progenitor cells. However, we have described a class of cells in the cholinergic basal forebrain of the adult rat and human that express markers associated exclusively with neurons, e.g., NeuN, β-III tubulin, and choline acetyl transferase (ChAT) and also express nestin. We have termed these cells nestin-expressing neurons (NENs). To explore the possibility that the expression of nestin by NENs might provide a neuroprotective effect, we administered the immunotoxin 192-IgG-saporin (192-saporin). The toxin consists of a ribosome-inactivating protein coupled to a monoclonal antibody directed against the p75 nerve growth factor receptor (p75 NGFr). As a result, 192-saporin selectively destroys cells expressing this receptor, such as most of the cholinergic neurons in the basal forebrain. Two micrograms of 192-saporin in 6 µL of saline were injected unilaterally into the lateral ventricle of the brain in each of four adult Sprague-Dawley rats. Following a six day survival period, the rats were deeply anesthetized, perfused with 4% paraformaldehyde, and the brains were sectioned and immunostained for nestin and ChAT. After confirming that NENs, which were identified by the co-expression of nestin and ChAT, express the p75 NGFr, we determined the number of NENs in the medial septum and in the nucleus of the diagonal band as a percentage of all ChAT-positive neurons in these nuclei in rats treated with 192-saporin and in controls. We found no statistically significant difference in the proportion of NENs between rats that had received 192-saporin and controls. This result indicates that for the dose of 192-saporin and survival period used in these experiments, the expression of nestin does not confer a neuroprotective effect. Experiments using lower doses of 192-saporin and shorter survival times are underway.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Neonatal cholinergic lesion and environmental enrichment:behavior, neurogenesis and CA1 cytoarchitecture

Frachette M, Rennie K, Pappas BA (2007) Neonatal cholinergic lesion and environmental enrichment:behavior, neurogenesis and CA1 cytoarchitecture. Neuroscience 2007 Abstracts 691.9/M9. Society for Neuroscience, San Diego, CA.

Summary: The effects of neonatal cholinergic lesion and environmental enrichment on rat behaviour and hippocampal morphology were determined. Rats were injected with the immunotoxin 192 IgG- saporin (192S) on postnatal day 7, selectively lesioning forebrain cholinergic neurons as shown by their loss of acetylcholinesterase staining and p75NTR immunoreactive (IR) neurons. After weaning, the rats were placed in enriched or standard housing for 42 days. Enriched rats, regardless of whether or not they had received 192S, subsequently showed significantly enhanced performance on the working memory version of the Morris water maze. The lesion had no effect on spatial learning. However, the lesion significantly reduced doublecortin (DCX) IR cells in the dentate gyrus, indicating reduced hippocampal neurogenesis. Enrichment did not affect the number of DCX IR cells in lesioned rats whereas there was an apparent trend towards increased cells in non-lesioned rats. The number of DCX IR neurons in the enriched and impoverished lesion groups were identical and both were significantly less than the average for the enriched non-lesioned mean, suggesting that the lesioned rats were resistant to the effects of enrichment on neurogenesis. As shown by quantitative analysis of Golgi stained CA1 neurons, the cholinergic lesion affected CA1 cell morphology, reducing apical branches and total basal branch length. This was not prevented by enrichment. There were also a number of other effects selective for certain branches but these effects tended to be observed equally often in impoverished and enriched rats. In other words, the consequences of the cholinergic lesion were immune to the housing condition. Enrichment had several effects on hippocampal cytoarchitecture but these were selective for certain branch orders rather than global alterations. The most interesting consequence of enrichment, in terms of its implication for synapse density and information processing capability, was the increased spine density and spine number observed on some branches of the apical tree. This was evident only in the non-lesioned rats. Thus, neonatal cholinergic forebrain lesion reduces dentate gyrus neurogenesis, alters CA1 dendritic morphology but has no effect on spatial learning/memory. It also renders rats unresponsive to the effects of enrichment on dentate gyrus neurogenesis, CA1 dendritic spine morphology but not spatial learning/memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Behavioural consequences of combined cholinergic lesion and chronic cerebral hypoperfusion in rats

Rennie KE, Frechette M, Pappas BA (2007) Behavioural consequences of combined cholinergic lesion and chronic cerebral hypoperfusion in rats. Neuroscience 2007 Abstracts 698.16/R26. Society for Neuroscience, San Diego, CA.

Summary: Chronic cerebral hypoperfusion compromises the health of hippocampal neurons, leading to a slowly emerging loss of pyramidal cells accompanied by spatial memory impairments in rats. Recent research suggests that vascular abnormalities resulting in insufficient cerebral blood flow or impaired nutrient delivery to the brain represent a significant risk factor for Alzheimer’s disease (AD) and may contribute to its pathogenesis. AD is also characterized by dysfunction of the forebrain cholinergic system. Since there is evidence that this system is involved in the control of local cerebral blood flow, we hypothesized that there would be synergistic effects of chronic cerebral hypoperfusion and cholinergic dysfunction. Hence, the aim of this study was to determine whether cholinergic dysfunction exacerbates the effects of cerebral hypoperfusion. Female rats were subjected to forebrain cholinergic lesion or control surgery by intraventricular infusion of the immunotoxin 192-IgG-saporin (192S) or phosphate buffered saline (PBS) on postnatal day 7. Six months later the rats underwent permanent bilateral occlusion of the carotid arteries (2VO), which causes moderate, chronic cerebral hypoperfusion, or sham surgery. When exposed to an open field 48, 72 and 96 hours after 2VO or sham surgery, the groups did not differ on measures of overall activity. However, the cholinergic lesion increased the latency to enter the centre area, and reduced both the number of centre entries and the percentage of total distance that was traveled in the inner squares. The lesion effects were mainly seen in the combined 192S/2VO group while 192S or 2VO alone produced only minor behavioural changes. Elevated plus testing 2 weeks after surgery revealed a reduction in open but not closed arm entries due to the cholinergic lesion. Interestingly, the effects of 2VO were dependent on the status of the cholinergic system. 2VO increased open arm entries in the PBS group, but decreased this behaviour in the 192S group. Thus on both the open field and elevated plus maze, the cholinergic lesioned rats displayed more anxious behaviour, particularly after 2VO. Finally, cholinergic lesion produced impairments on the working memory version of the Morris water maze. Again, this effect was most pronounced in the combined 192S/2VO group. This effect is unlikely to be due to motivational or sensorimotor deficits as all groups performed similarly on a cued platform version of the maze. Cholinergic lesion and 2VO appear to act synergistically to produce behavioural alterations, even at relatively early time points after 2VO. Their combined effects on CA1 pyramidal cell viability are currently under examination.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Progressive decrease in sleep deprivation-induced extracellular adenosine release and recovery NREM sleep following intracerebroventricular injection of 192 IgG-saporin

Kalinchuk AV, Porkka-Heiskanen T, McCarley RW, Basheer R (2007) Progressive decrease in sleep deprivation-induced extracellular adenosine release and recovery NREM sleep following intracerebroventricular injection of 192 IgG-saporin. Neuroscience 2007 Abstracts 735.10/TT29. Society for Neuroscience, San Diego, CA.

Summary: The basal forebrain (BF) is an important site in the homeostatic regulation of sleep mediated by adenosine (AD) release (Porkka-Heiskanen et al., 1997). The BF comprises different neuronal populations, including cholinergic, GABAergic and glutamatergic cells. Immunotoxin 192 IgG-saporin has been used in several studies to investigate the role of the BF cholinergic vs. non-cholinergic cells in the regulation of spontaneous sleep and homeostatic sleep response after sleep deprivation (SD) but results of these studies are controversial. 2 weeks after local saporin injection into the caudal BF (horizontal diagonal band/magnocellular preoptic area/substantia innominata, HDB/MCPO/SI), recovery sleep is reduced; however, 2 weeks after ICV saporin injection, no changes in recovery sleep occur. We hypothesized that this difference in ICV vs. local effects might be explained by a delayed lesion of the cholinergic cells in the HDB/MCPO/SI area after ICV injection. Consequently, in the same rats, we examined the time course of the effects of ICV-injected saporin on SD-induced BF AD levels and the homeostatic sleep response at both 2 and 3 weeks post-injection. Male rats were ICV injected with saporin (6μg, n=9) or saline (n=5) and implanted with EEG/EMG electrodes and guide cannulae for microdialysis probes targeting the HDB/MCPO/SI. Experimental schedule, performed for each rat at 2 and 3 weeks post-injection, included spontaneous sleep-wake recording for 24h beginning at 8am (7am:7pm L:D) and SD for 6h beginning at 10am followed by recovery sleep at 4pm-8am. AD samples were collected at 30min intervals on SD day from 8am to 8pm. Histology evaluated the extent of cholinergic cell loss and probe locations. 2 weeks after ICV saporin injection, SD induced significant increases in BF AD levels (+126%), NREM recovery sleep duration (+41%) and NREM delta power (+91%). All values were similar to saline-treated animals. However, 3 weeks after ICV saporin injection, SD did not increase BF AD nor NREM recovery sleep, while delta power in NREM sleep had a modest increase (+21%). The changes observed 3 weeks after ICV injection were quantitatively similar to those observed 2 weeks after local BF saporin administration (Kalinchuk et al., 2005). We conclude that the effect of ICV saporin-induced cholinergic lesions follows a slower time course (3 weeks or longer) compared to local BF injections in reducing the SD-induced AD increase and the homeostatic sleep response. Taken together, our present and previous observations imply that cholinergic neurons in the BF play an important role in the regulation of SD-induced AD release and NREM recovery sleep.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Organization of food protection behavior is differentially influenced by hippocampal and cortical cholinergic deafferentation

Martin MM, Carter LA, Jones JL, Winter SS, Wallace DG (2007) Organization of food protection behavior is differentially influenced by hippocampal and cortical cholinergic deafferentation. Neuroscience 2007 Abstracts 742.6/AAA9. Society for Neuroscience, San Diego, CA.

Summary: Previous work has suggested that rats use temporal information to organize their food protection behaviors. Studies have demonstrated different roles for hippocampal and cortical cholinergic function in processing of temporal information in standard interval timing procedures. The present study examined the role of hippocampal and cortical cholinergic function on the organization of food protection behavior. Long Evans female rats received either injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum (MS) or nucleus basalis (NB). Subsequent to recovery, rats were placed into an enclosure and provided a hazelnut in the presence of an unoperated conspecific. All rats engaged in dodging or bracing behaviors to prevent the theft of the hazelnut. During a dodge, the rat places the food item in its mouth to use both fore- and hind-limbs to escape the approaching conspecific. In contrast, during a brace, the rat’s forelimbs maintain contact with the food item, and only the hind limbs are used to make shorter lateral movements. Only rats receiving sham lesions displayed a consistent transition from primarily engaging in dodging behavior to primarily engaging in bracing behavior during the consumption of the hazelnut. The MS SAP group displayed a disruption in their temporal organization of food protection behaviors. Although the NB SAP animals displayed impaired responding to the approaching conspecific (resulting in frequent thefts), their food protection behaviors tended to exhibit temporal organization. These results provide further evidence as to the role of the basal forebrain cholinergic system in temporal organization of behavior.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Vestibular activation stimulates cholinergic system in the hippocampus

Tai S, Ma J, Leung L (2007) Vestibular activation stimulates cholinergic system in the hippocampus. Neuroscience 2007 Abstracts 399.21/OO13. Society for Neuroscience, San Diego, CA.

Summary: The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. We examined the mechanisms that induced hippocampal theta, a 4-10 Hz rhythm in the electroencephalogram (EEG), during vestibular activation in rats. Freely behaving rats were rotated at various speeds, on a vertical axis, in the light or dark. Hippocampal EEGs were recorded by implanted electrodes in hippocampal CA1, and analyzed by spectral analysis. A clear hippocampal theta rhythm was induced during immobility by rotations at different speeds (20-70 rpm). The rotation-induced theta was abolished, in light and dark settings, by muscarinic cholinergic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood-brain barrier. Rotation-induced theta was attenuated in rats in which the cholinergic neurons in the medial septum (MS) were lesioned by 192 IgG-saporin (0.14 µg/0.4 µl infused bilaterally into the MS 10-20 days prior to the experiments). Cholinergic lesion in the MS was confirmed by a depletion of MS neurons that stained positively for choline acetyltransferase and an absence of acetylcholinesterase histochemical staining in the hippocampus. Bilateral lesion of the vestibular receptors (by 0.1 ml intratympanic injection of 300 mg/ml sodium arsanilate) also attenuated the rotation-induced theta rhythm. Vestibular lesion was confirmed by the contact righting test where lesioned rats will “walk” upside down on a Plexiglas sheet placed in contact with the soles of the feet while intact rats will right themselves immediately. In summary, an atropine-sensitive hippocampal theta is activated by septohippocampal cholinergic neurons which are in turn activated by vestibular stimulation. Vestibular-activated septohippocampal cholinergic activity is likely an important component of spatial navigation.

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Effects of spatial cueing on visual discrimination performance of rats following loss of basal forebrain corticopetal cholinergic neurons

Burk JA, Altemose KE, Lowder MW (2007) Effects of spatial cueing on visual discrimination performance of rats following loss of basal forebrain corticopetal cholinergic neurons. Neuroscience 2007 Abstracts 424.4/HHH3. Society for Neuroscience, San Diego, CA.

Summary: Basal forebrain corticopetal cholinergic neurons are necessary for normal attentional performance. However, the exact attentional task parameters that are sufficient for inducing deficits following loss of basal forebrain corticopetal cholinergic neurons remain unclear. In Experiment 1, rats were trained to perform a spatially cued visual discrimination task (press a lever under an illuminated panel light) with explicit attentional demands removed. Animals then received infusions of the cholinergic immunotoxin, 192IgG-saporin, or saline into the basal forebrain. All animals were then tested in the same task trained before surgery and then task parameters, including the duration of visual signals and the inter-trial interval, were manipulated in order to tax attentional processing. Lesioned animals exhibited an initial increase in response latencies immediately following surgery but this deficit was not observed when task demands were increased. When the task was modified to remove spatial cueing, by presenting visual signals or no signal from a centrally-located panel light, lesioned animals exhibited an increase in lever press latencies compared to sham-lesioned animals. In Experiment 2, rats were trained in a visual discrimination task that, within each session, had blocks of trials with or without spatial cueing, using procedures similar to Experiment 1. After receiving intra-basalis infusions of 192IgG-saporin or saline, animals were tested for 12 sessions in the same task trained before surgery followed by one session in which the inter-trial interval was decreased. Lesioned animals did not exhibit deficits immediately following surgery, but did show elevated lever press latencies compared to sham-lesioned animals when the inter-trial interval was decreased. There was a trend for this lesioned-induced deficit to be more pronounced when spatial cues were not present. These experiments indicate that cortical acetylcholine is critical for maintaining normal visual discrimination performance when spatial cueing is not available. We speculate that, under conditions in which spatial cueing is unavailable, the lesion-induced increased lever press latencies reflect a disruption in recalling rules for an appropriate response.

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192 IgG-saporin lesions of the cholinergic basal forebrain disrupt selective attention and trace conditioning but spare delay and long-delay conditioning

Butt AE, Amodeo D, Flesher M, Marsa K, Holt R, Lladones R, Olney R, Haynes J, Kinney-Hurd BL, Dach N (2007) 192 IgG-saporin lesions of the cholinergic basal forebrain disrupt selective attention and trace conditioning but spare delay and long-delay conditioning. Neuroscience 2007 Abstracts 424.9/HHH8. Society for Neuroscience, San Diego, CA.

Summary: Recent research suggests that Pavlovian trace conditioning, but not delay conditioning, is a form of declarative memory that requires attention, where both of these processes depend on specific brain systems. For example, past research has shown that although amnesiac humans with damage to the hippocampus (HPC) acquire a normal conditioned response (CR) in delay conditioning paradigms, where the conditioned stimulus (CS) and unconditioned stimulus (US) partly overlap, they fail to acquire the CR in trace conditioning paradigms, where the CS and US are separated in time. Others have shown that the anterior cingulate cortex (ACC) in rats and the medial prefrontal cortex (mPFC) in rabbits are similarly necessary for trace but not delay conditioning. The basal forebrain cholinergic system (BFCS) has projections to the mPFC, ACC, and HPC. Given that each of these regions is critical for trace but not delay conditioning, we hypothesized that lesions of the BFCS using 192 IgG-saporin (SAP) would selectively impair trace but not delay or long-delay appetitive conditioning in rats. Additionally, given evidence suggesting BFCS involvement in attention, it was hypothesized that the addition of varying levels of distraction during the trace conditioning task would cause progressively greater degrees of impairment in the BFCS lesion groups compared to controls. In contrast, neither the control groups nor the BFCS lesion groups were expected be negatively affected by the addition of a distracting stimulus in the delay and long-delay conditioning tasks. Rats received bilateral SAP lesions or sham lesions of the BFCS prior to conditioning with a white noise CS and sucrose pellet US in either a delay, long-delay, or 10 s trace conditioning paradigm. Separate groups of BFCS lesion and control rats were subjected to varying levels of visual distraction (flashing house light) in each paradigm; no distraction, low distraction (continuously blinking light), and high distraction (intermittent, unpredictable flashing light). Results supported our hypotheses, with the BFCS lesion groups showing normal delay and long-delay conditioning regardless of level of distraction. In contrast, trace conditioning was impaired in the BFCS lesion groups, with progressively greater degrees of impairment occurring with greater levels of distraction, and complete disruption of learning in the high distraction condition. Together, these experiments suggest that the BFCS is necessary for normal trace conditioning, and that the BFCS is critically involved in selective attention tasks where animals must discriminate relevant stimuli from distracting background stimuli.

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Ketamine-induced gating deficit of hippocampal auditory evoked potentials in rats is alleviated by medial septum inactivation and antipsychotic drugs

Ma J, Tai S, Leung LWS (2007) Ketamine-induced gating deficit of hippocampal auditory evoked potentials in rats is alleviated by medial septum inactivation and antipsychotic drugs. Neuroscience 2007 Abstracts 498.12/GG19. Society for Neuroscience, San Diego, CA.

Summary: Gating of sensory responses is impaired in schizophrenic patients and animal models of schizophrenia. Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to induce schizophrenic-like symptoms in humans. In this study, we investigated some conditions underlying ketamine’s effect on the gating of auditory responses in the hippocampus of freely moving rats. Gating was measured by the ratio of the second-click response (P2) to the first-click response (P1), or P2/P1, with P1 and P2 measured as peak amplitudes. Ketamine (1, 3 or 6 mg/kg s.c.) dose- dependently increased P2/P1 ratio as compared to saline (s.c.). P2/P1 ratio in saline injected rats was 0.48 + 0.05 and was 0.73 + 0.17 in ketamine (3mg/kg) treated rats. Pre-inactivation of the medial septum with GABAA receptor agonist muscimol (0.25 μg/0.6 μL) or systemic administration of antipsychotic drugs, including chlorpromazine (5 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or clozapine (7.5 mg/kg i.p.), decreased P2/P1 to values comparable to normal rats without drug injection. Infusion of muscimol in the medial septum or injection of antipsychotic drug alone did not affect the P2/P1 ratio. However, rats with selective lesion of the septohippocampal cholinergic neurons (by 192-IgG saporin) showed significant higher P2/P1 (0.86 + 0.10) than that of sham lesioned rats (0.26 + 0.07), but ketamine’s effect in increasing P2/P1 ratio was preserved. It is suggested that the septohippocampal cholinergic inputs participate in normal auditory gating in the hippocampus whereas the entire medial septum mediates ketamine-induced deficit of hippocampal auditory gating. In addition, the effectiveness of various antipsychotic drugs in antagonizing ketamine-induced impairment of auditory gating confirms the validity of this animal model of schizophrenia. (Supported by NSERC grant and CIHR grant 15685).

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Poster: Recognition of novel objects and their location in rats with selective cholinergic lesion of the medial septum

Cai L, Johnson DA (2007) Poster: Recognition of novel objects and their location in rats with selective cholinergic lesion of the medial septum. Neuroscience 2007 Abstracts 92.21/TT2. Society for Neuroscience, San Diego, CA.

Summary: The goal of this project was to determine whether cholinergic neurons projecting from the medial septum (MS) to the hippocampus play a role in novel object recognition or location. The specific aim was to determine whether lesion of cholinergic neurons in MS by the selective cholinergic neurotoxin 192IgG-saporin (SAP) would induce retrograde amnesia and/or anterograde amnesia for a novel object and/or its location. Male SD rats were tested in an object recognition paradigm. The time the rats spent examining old and novel objects was measured. Infusion of SAP into medial septum was performed 2 days after a one week pre-surgery training. Fourteen days after surgery post-surgery retention testing for retrograde object memory was carried out. Then 3 days later, a new acquisition training and retention testing for anterograde memory was started. One-way ANOVA and Fisher’s exact test were used for statistical analysis. There were no significant differences in the exploration ratios between the control group without surgery and the CSF surgical group. The mean exploration ratios for both groups demonstrated retention of memory for the novel object and its placement. SAP infusion into the MS failed to induce a deficit in retrograde amnesia 2 days after training, but did show a strong trend for anterograde amnesia for novel object recognition and a significant association with anterograde amnesia for object location. Conclusions were that cholinergic neurons of MS were not involved in retrograde object memory 2 days before the infusion of SAP and may or may not be necessary for anterograde object memory formation, but cholinergic neurons of the MS were involved in anterograde spatial memory formation for novel objects.

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Sensory experience determines enrichment-induced plasticity in rat auditory cortex.

Percaccio CR, Pruette AL, Mistry ST, Chen YH, Kilgard MP (2007) Sensory experience determines enrichment-induced plasticity in rat auditory cortex. Brain Res 1174:76-91. doi: 10.1016/j.brainres.2007.07.062

Summary: Animals housed in enriched environments display numerous signs of good neural health. In this work the authors examined the role acetylcholine plays in this plasticity. 2.6 µg of 192-IgG-SAP (Cat. #IT-01) was injected into the left lateral ventricle of rats. Auditory evoked responses were used to assess the effect of lesioning cholinergic neurons. Response strength was not reduced in lesioned animals, indicating that cholinergic deficits do not affect this system.

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Neonatal basal forebrain cholinergic hypofunction affects ultrasonic vocalizations and fear conditioning responses in preweaning rats.

Ricceri L, Cutuli D, Venerosi A, Scattoni ML, Calamandrei G (2007) Neonatal basal forebrain cholinergic hypofunction affects ultrasonic vocalizations and fear conditioning responses in preweaning rats. Behav Brain Res 183:111-117. doi: 10.1016/j.bbr.2007.05.035

Summary: In order to expand on previous work investigating the effect of early cholinergic lesions on processing of aversive stimuli the authors administered 0.21 µg of 192-IgG-SAP (Cat. #IT-01) into the third ventricle of 7 day-old rat pups. One unexpected result in lesioned animals was the enhancement of fear-conditioned responses that are dependent on the hippocampus. The authors discuss several theories addressing the implications of these data. NOTE: material from Chemicon, CA

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Selective hippocampal cholinergic deafferentation impairs self-movement cue use during a food hoarding task.

Martin MM, Wallace DG (2007) Selective hippocampal cholinergic deafferentation impairs self-movement cue use during a food hoarding task. Behav Brain Res 183:78-86. doi: 10.1016/j.bbr.2007.05.026

Summary: There are conflicting data surrounding the role of the septohippocampal system in spatial orientation. The authors suggest that the presence of spatial clues during some of these tests may skew those results. Rats were injected with a total of 0.35 µg of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Lesioned animals had more difficulty navigating by self-movement cues, but the ability to use of environmental cues was left intact. These experiments demonstrate that rats can use environmental information to compensate for loss of circuits that analyze self-movement.

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Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex.

Severino M, Pedersen AF, Trajkovska V, Christensen E, Lohals R, Veng LM, Knudsen GM, Aznar S (2007) Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex. Neurosci Lett 428:47-51. doi: 10.1016/j.neulet.2007.09.026

Summary: Changes in several neurotransmitter systems, including serotonin and 5HT2A receptors, are associated with early Alzheimer’s disease (AD). The authors gave rats intracerebroventricular injections of either 2.5 or 5 µg of 192-IgG-SAP (Cat. #IT-01) then examined both of these systems. 5HT2A receptor levels were markedly decreased in the frontal cortex and markedly increased in the hippocampus of animals lesioned with 5 µg of 192-IgG-SAP. The change in 5HT2A receptor number suggests that the AD effect stems from interaction with the cholinergic system.

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Induction and survival of binucleated Purkinje neurons by selective damage and aging.

Magrassi L, Grimaldi P, Ibatici A, Corselli M, Ciardelli L, Castello S, Podesta M, Frassoni F, Rossi F (2007) Induction and survival of binucleated Purkinje neurons by selective damage and aging. J Neurosci 27:9885-9892. doi: 10.1523/JNEUROSCI.2539-07.2007

Summary: Donor bone marrow derived cells are thought to fuse with host Purkinje cells in small numbers to create binucleated cells. These fusions have been found to persist within the recipient for long periods of time. The authors injected 2.2 µg of 192-IgG-SAP (Cat. #IT-01) into the right lateral ventricle of rats; to examine whether the damage of host Purkinje cells is a method to increase the numbers of binucleated cells. The data suggest an alternate method is present for the creation of these cells. NOTE: material from Millipore, Billerica MA

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Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: Alteration of c-Fos and polysialylated neural cell adhesion molecule expression.

Chambon C, Paban V, Manrique C, Alescio-Lautier B (2007) Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: Alteration of c-Fos and polysialylated neural cell adhesion molecule expression. Neuroscience 147:893-905. doi: 10.1016/j.neuroscience.2007.05.022

Summary: In this work the authors looked to expand the knowledge of molecular events and brain structure changes following cholinergic immunolesion. Rats were treated with bilateral injections of 192-IgG-SAP (Cat. #IT-01); 37.5 ng per side into the medial septum, and 75 ng per side into the nucleus basalis magnocellularis. 1 month after treatment behavioral deficits were drastic and cholinergic neurons had completely disappeared. Elevated levels of polysialylated neural cell adhesion molecule were temporarily able to compensate for the loss of cholinergic neurons. NOTE: material from Chemicon, Paris.

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Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not in the striatum.

Mattsson A, Olson L, Svensson TH, Schilstrom B (2007) Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not in the striatum. Exp Neurol 208(1):73-79. doi: 10.1016/j.expneurol.2007.07.012

Summary: Previous data has implicated cholinergic dysfunction in the pathogenesis of schizophrenia. Here the authors investigated whether increased amphetamine-induced release of dopamine was a response to cortical cholinergic denervation. Rats received bilateral 0.067 µg injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis, and dopamine release was monitored in the nucleus accumbens and striatum. Surprisingly, the increased dopamine release was not linked to loss of cholinergic neurons, but to blocking of muscarinic receptors.

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Estradiol enhances DMP acquisition via a mechanism not mediated by turning strategy but which requires intact basal forebrain cholinergic projections.

Gibbs RB (2007) Estradiol enhances DMP acquisition via a mechanism not mediated by turning strategy but which requires intact basal forebrain cholinergic projections. Horm Behav 52:352-359. doi: 10.1016/j.yhbeh.2007.05.011

Summary: Estradiol appears to enhance cholinergic projections to the hippocampus and frontal cortex as shown by tests of response patterns and strategy in rats. The author tested whether this affect was involved with turning strategy, defined as which arm was chosen first in a T-maze. 0.22 µg injections of 192-IgG-SAP (Cat. #IT-01) were made into the medial septum of rats. Lesioned animals utilized a persistent turning strategy; they always chose the same arm of the maze first, even after the administration of estradiol. These data suggest that although the effects of estradiol are not linked to turning strategy, estradiol does interact with the cholinergic system.

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Cholinergic modulation of spindle bursts in the neonatal rat visual cortex in vivo.

Hanganu IL, Staiger JF, Ben-Ari Y, Khazipov R (2007) Cholinergic modulation of spindle bursts in the neonatal rat visual cortex in vivo. J Neurosci 27:5694-5705. doi: 10.1523/JNEUROSCI.5233-06.2007

Summary: The authors investigated the relationship between cholinergic drive and spindle burst oscillation driven by retinal waves. 0.5 µl of 0.2-µg/µl 192-IgG-SAP (Cat. #IT-01) was injected into both ventricles of rat pups. The lesioned animals displayed markedly decreased oscillatory activity. Since this activity may be used as a functional template for cortical networks and architecture, the results suggest a link between cholinergic activity and cortical development.

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Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman.

Myhrer T, Enger S, Aas P (2007) Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman. Neurotoxicology 28(4):819-828. doi: 10.1016/j.neuro.2007.03.010

Summary: Soman is a nerve agent that irreversibly inhibits acetylcholinesterase, resulting in respiratory dysfunction, seizures, convulsions, coma, and death. In this work the authors investigated whether elimination of cholinergic pathways in the medial septum (MS) or diagonal band nucleus (DBN) would affect the onset of convulsions. 0.3 µl of 0.5-µg/µl 192-IgG-SAP (Cat. #IT-01) was infused into the MS and/or DBN. Lesioned animals still experienced convulsions, suggesting that cholinergic MS systems are not the only ones involved.

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Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy.

Gibbs RB, Johnson DA (2007) Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy. Neurobiol Learn Mem 88:19-32. doi: 10.1016/j.nlm.2007.03.007

Summary: It has been well established that the cholinergic system of the basal forebrain plays a critical role in many cognitive processes. This work utilized injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum, the nucleus basalis magnocellularis, or both to examine the lesioning effect on two cognitive tasks in rats. The data indicate that cholinergic lesions of the basal forebrain produce learning deficits that are task specific, and that learning is affected without corresponding deficits in memory.

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Extensive training in a maze task reduces neurogenesis in the adult rat dentate gyrus probably as a result of stress.

Aztiria E, Capodieci G, Arancio L, Leanza G (2007) Extensive training in a maze task reduces neurogenesis in the adult rat dentate gyrus probably as a result of stress. Neurosci Lett 416(2):133-137. doi: 10.1016/j.neulet.2007.01.069

Summary: Ascending cholinergic inputs from the basal forebrain modulate hippocampal neurogenesis, although it is not clear if the modulation is direct or indirect. In this study rats experienced extended training in a spatial navigation task following 192-IgG-SAP (Cat. #IT-01) lesions. 192-IgG-SAP was injected into the basal forebrain nuclei and the cerebellar cortex. Although the lesioned animals displayed an 80% reduction in neuron proliferation in the dentate gyrus, extended training and learning did not affect proliferation.

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Astrocytic reaction to a lesion, under hormonal deprivation.

Martinez L, de Lacalle S (2007) Astrocytic reaction to a lesion, under hormonal deprivation. Neurosci Lett 415(2):190-193. doi: 10.1016/j.neulet.2007.01.020

Summary: One effect of estradiol on astrocytes is the mediation of neuronal sprouting. Astrocytes express glial fibrillary acidic protein (GFAP) in response to injury, but estradiol has been shown to repress GFAP expression. Ovariectomized female rats received 15 ng of 192-IgG-SAP (Cat. #IT-01) into the horizontal limb of the diagonal band of Broca, followed by long-term estrogen treatment. The results suggest that estradiol deprivation may exacerbate the effects of a cholinergic lesion, and administration of estradiol may aid the recovery of lesioned cholinergic neurons by blocking GFAP expression.

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Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning.

Quinlivan M, Chalon S, Vergote J, Henderson J, Katsifis A, Kassiou M, Guilloteau D (2007) Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning. Neurosci Lett 415(2):97-101. doi: 10.1016/j.neulet.2006.08.065

Summary: The vesicular acetylcholine transporter (VAChT) is a useful imaging target to assess Alzheimer’s disease, since this transporter is expressed on cholinergic cells that are lost as the disease progresses. Through the use of 192-IgG-SAP (Cat. #IT-01) the authors demonstrate the use of two radioligands, one that binds VAChTs, the other which binds nicotinic acetylcholine receptors (nAChRs). The results show the efficacy of each radioligand, as well as the loss of nAChRs on cholinergic neurons after treatment with 192-IgG-SAP.

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Immunotoxic cholinergic lesions in the basal forebrain reverse the effects of entorhinal cortex lesions on conditioned odor aversion in the rat.

Ferry B, Herbeaux K, Cosquer B, Traissard N, Galani R, Cassel JC (2007) Immunotoxic cholinergic lesions in the basal forebrain reverse the effects of entorhinal cortex lesions on conditioned odor aversion in the rat. Neurobiol Learn Mem 88:114-126. doi: 10.1016/j.nlm.2007.01.007

Summary: The entorhinal cortex (EC) is intimately involved in olfactory learning. Lesioning of this structure produces septo-cholinergic sprouting. Rats that had previously received EC lesions were treated with 5-µg intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01). The results point to a role for hippocampal cholinergic neurons in the modulation of memory processes involved with conditioned odor aversion.

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Lesions to the nucleus basalis magnocellularis lower performance but do not block the retention of a previously acquired learning set.

Bailey AM, Lee JM (2007) Lesions to the nucleus basalis magnocellularis lower performance but do not block the retention of a previously acquired learning set. Brain Res 1136:110-121. doi: 10.1016/j.brainres.2006.12.028

Summary: A major source of cholinergic innervation to several cortices is the nucleus basalis magnocellularis (NBM). Rats were trained to acquire an olfactory discrimination learning set, then were lesioned with 192-IgG-SAP (Cat. #IT-01) or quisqualic acid. 0.075 µg of 192-IgG-SAP was administered in 2 sets of bilateral infusions. While treated animals performed poorly following the surgery, performance improved to better than expected by chance during the second trial. The authors discuss the role of the NBM in cognitive flexibility.

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Cholinergic modulation of sensory interference in rat primary somatosensory cortical neurons.

Alenda A, Nunez A (2007) Cholinergic modulation of sensory interference in rat primary somatosensory cortical neurons. Brain Res 1133:158-167. doi: 10.1016/j.brainres.2006.11.092

Summary: One critical feature of cognition is the ability to focus on selected sensory inputs while ignoring irrelevant inputs. In this work the authors examine basal forebrain participation in sensory interference effects. Following 0.15 µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the basal forebrain of rats, the ability of primary somatosensory cortical neurons to respond in the presence of sensory interference was assessed. A decrease in the number of neurons showed sensory interference in lesioned animals.

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Selective cholinergic depletion of the hippocampus spares both behaviorally induced Arc transcription and spatial learning and memory.

Fletcher BR, Baxter MG, Guzowski JF, Shapiro ML, Rapp PR (2007) Selective cholinergic depletion of the hippocampus spares both behaviorally induced Arc transcription and spatial learning and memory. Hippocampus 17:227-234. doi: 10.1002/hipo.20261

Summary: The immediate early gene Arc is required for long-term synaptic changes and memory consolidation. The authors lesioned the fornix to examine cholinergic contributions of the medial septum and the vertical diagonal band to spatial learning impairments and behavioral induction of Arc transcription. 0.24-0.36 µg of 192-IgG-SAP (Cat. #IT-01) was delivered to the fornix of rats. Results from various water-maze tasks indicate that spatial learning deficits and impaired Arc transcription associated with lesions of the fornix are not caused by cholinergic deafferentation.

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Dissociation of attention in learning and action: effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex

Maddux JM, Kerfoot EC, Chatterjee S, Holland PC (2007) Dissociation of attention in learning and action: effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex. Behav Neurosci 121(1):63-79. doi: 10.1037/0735-7044.121.1.63

Objective: To study the effect of the amygdala central nucleus (CEA) on aspects of attention.

Summary: Lesions of the cholinergic afferents of the medial prefrontal cortex interfered with five-choice serial reaction time (5CSRT) performance but not with surprise-induced enhancement of learning, whereas lesions of cholinergic afferents of posterior parietal cortex impaired the latter effects but did not affect 5CSRT performance. CEA lesions impaired performance in both tasks.

Usage: Rats received bilateral infusions of 192IgG-saporin (0.25 μg/μl) into the posterior parietal cortex.

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Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations.

Dwyer TA, Servatius RJ, Pang KC (2007) Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations. J Neurosci 27:299-303. doi: 10.1523/JNEUROSCI.4189-06.2007

Summary: The medial septum and the vertical limb of the diagonal band of Broca (MSDB) have extensive connections to the hippocampus. In general, impairments due to loss of cholinergic neurons in this area have been smaller than those due to the loss of noncholinergic neurons. The authors treated rats with either 192-IgG-SAP (Cat. #IT-01) or kainic acid into each hemisphere of the medial septum. Behavioral testing following surgery demonstrated that the animals with noncholinergic lesions had impaired performance, even when compared to the animals with cholinergic lesions.

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Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism.

Walker BR, Diefenbach KS, Parikh TN (2007) Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism. Behav Brain Res 176(1):109-120. doi: 10.1016/j.bbr.2006.08.008

Summary: In this work the authors use environmental exploration deficits in rats as a model for autism. Animals received 2 µg of either OX7-SAP (Cat. #IT-02) or 192-Saporin (Cat. #IT-01) into each ventricle. Only the OX7-SAP treated rats displayed a reduction in exploration behavior, and the anticonvulsant muscimol restored exploration behavior to control levels. This system may have use in controlling behavior deficits seen in autism.

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Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from alpha2-adrenoceptor stimulation.

Ma W, Eisenach JC (2007) Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from alpha2-adrenoceptor stimulation. Brain Res 1127(1):52-58. doi: 10.1016/j.brainres.2006.10.008

Summary: Peripheral nerve injury resulting in neuropathic pain often responds poorly to opioid treatment. alpha2-adrenoreceptor (AR) agonists, however, perform better after this type of injury. After a spinal nerve ligation, rats were treated with a 0.6 µg-intrathecal injection of 192-saporin (Cat. #IT-01). The increase of neuronal nitric oxide synthase (nNOS) caused by spinal ligation was abolished in the lesioned animals. The data indicate that AR agonists may reduce sensitization by activating nNOS fibers in the superficial dorsal horn.

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Selective lesions of the nucleus basalis magnocellularis impair cognitive flexibility.

Cabrera SM, Chavez CM, Corley SR, Kitto MR, Butt AE (2006) Selective lesions of the nucleus basalis magnocellularis impair cognitive flexibility. Behav Neurosci 120:298-306. doi: 10.1037/0735-7044.120.2.298

Summary: In humans, one aspect of cognitive flexibility is being able to shift attention under a variety of pressures. Here the authors suggest that lesions to the cholinergic nucleus basalis magnocellularis (NBM) will impair cognitive flexibility. The NBM of rats was lesioned with 0.08 µg of 192-IgG-SAP (Cat. #IT-01). Both lesioned and controlled animals displayed a similar ability to learn a discrimination task, but lesioned animals displayed perseveration - the uncontrollable repetition of a previously correct response - indicating a loss of cognitive flexibility.

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Basal forebrain and saporin cholinergic lesions: the devil dwells in delivery details.

Kalinchuk AV, Porkka-Heiskanen T, McCarley RW (2006) Basal forebrain and saporin cholinergic lesions: the devil dwells in delivery details. Sleep 29:1385-1389. doi: 10.1093/sleep/29.11.1385

Summary: The authors of this commentary discuss results presented by Blanco-Centurion et al. The topic is the role of adenosine in the basal forebrain in the control of sleep homeostasis. Discussion covers the potential differences found when 192-IgG-SAP (Cat. #IT-01) is administered locally as compared to an intracerebroventricular injection.

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See Also:

Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory.

Garcia-Alloza M, Zaldua N, Diez-Ariza M, Marcos B, Lasheras B, Javier Gil-Bea F, Ramirez MJ (2006) Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory. J Neuropathol Exp Neurol 65(11):1074-1081. doi: 10.1097/01.jnen.0000240469.20167.89

Summary: The authors compared two lesioning methods using 192-Saporin (Cat. #IT-01) to examine the role of the serotonergic system in learning and memory. 0.067 µg of conjugate administered to each hemisphere of the nucleus basalis of Meynert reduced cholinergic markers in the frontal cortex. 1 µg of conjugate administered to the ventricle of each hemisphere reduced cholinergic markers in the frontal cortex and hippocampus. Both models reduced serotonin levels in the frontal cortex, but only the ICV injections modified learning.

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Basal forebrain cholinergic lesions reduce heat shock protein 72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex.

Willis CL, Ray DE, Marshall H, Elliot G, Evans JG, Kind CN (2006) Basal forebrain cholinergic lesions reduce heat shock protein 72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex. Neurosci Lett 407(2):112-117. doi: 10.1016/j.neulet.2006.08.020

Summary: The NMDA receptor antagonist MK-801 may have use in establishing a model for schizophrenia. The mechanism by which cortical neurons are damaged by these antagonists is unknown. The authors tested the theory that cholinergic hyperstimulation of cingulate neurons is involved by administering 80 ng of 192-Saporin (Cat. #IT-01) unilaterally to rats. The results indicate that although cholinergic neurons are involved in the heat shock response to MK-801, the pathological effects follow a different pathway.

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The role of septo-hippocampal cholinergic lesion, place versus response strategy, and acquisition of a delayed matching to position T-maze task

Fitz NF, Gibbs RB, Johnson DA (2006) The role of septo-hippocampal cholinergic lesion, place versus response strategy, and acquisition of a delayed matching to position T-maze task. Neuroscience 2006 Abstracts 751.20. Society for Neuroscience, Atlanta, GA.

Summary: Previously we showed that loss of cholinergic input to the hippocampus results in a significant impairment in acquisition of a delayed matching-to-position T-maze task. Further studies suggest that rats adopt different strategies during different stages of acquisition, initially using a response-type strategy or side preference strategy (independent of external cues) and then switching to a more efficient place strategy (reliant on external cues). We hypothesized that animals with lesions of hippocampal cholinergic inputs would have difficulty shifting to a place strategy, resulting in more days using a response-type strategy, and resulting in the deficit in acquisition. Male Sprague-Dawley rats received intraseptal infusions of either artificial cerebrospinal fluid (CSF) or the selective cholinergic immunotoxin, 192 IgG-saporin (SAP; 0.2 μg in 1.0 μl) into the medial septum (MS). Following recovery from surgery, animals were trained in a DMP T-maze task that consisted of learning to return to an arm of the maze that had been explored during a previous trial. Typically, in both treatment groups, rats would initially adopt a strategy of selecting an arm that resulted in a consistent turn (left or right), which was independent of external cues (response-type strategy). Later in training, the animals adopted a strategy that required a turn that was dependent on external cues (place strategy). Compared to controls, SAP animals had a loss of hippocampal cholinergic innervation and an increase in the number of days to reach criterion (21.7 ± 1.6 days vs. 15.9±0.5 days, p < 0.05). For the SAP group, the increased days to criterion was due to a significant increase in the number of days animals used the response-type strategy (14.8 ± 1.8 days vs. 8.1 ± 1.7 days, p < 0.05). There was no significant difference between groups in the number of days animals utilized the place strategy. These data are consistent with the hypothesis that the cause of the learning impairment on the DMP task observed following cholinergic deafferentation of the hippocampus is due to an impairment in the ability to shift from a response-type strategy to a place strategy.

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Rodent models: Autism and fragile x syndrome

Walker BR, Klueger K (2006) Rodent models: Autism and fragile x syndrome. Neuroscience 2006 Abstracts 764.6. Society for Neuroscience, Atlanta, GA.

Summary: While the exact etiology of autism is not known, autism spectrum disorders (ASD) are most commonly characterized by behavioral deficits in social interaction and communication, obsessional mannerisms, behavioral inflexibility, impairments in planning, attention, hyperactivity and a lack of environmental awareness. These behavioral characteristics have been theorized to be the result of altered forebrain and/or cerebellar circuitry and neurotransmitter transmission. There is some evidence to suggest that treatments effective against seizure and mood disorders that alter these specific neuronal populations are also effective against some core behavioral characteristics of persons with ASD. Therefore, in the present study we tested the hypothesis that electrical stimulation of the rat vagus nerve, as it enters the nucleus tractus solitarius (NTS), will ameliorate social behavior deficits caused by forebrain ACh lesions. To this end, we measured social interaction behavior in rats following bilateral i.c.v. injection of 192-IgG saporin (192-sap; 2 µg/side) or saline, and again following electrical stimulation of the vagus nerve/NTS (100-900 microA). As shown by us previously, bilateral 192-sap injections created a significant decrease in social behavior, as compared to controls. Electrical stimulation of the vagus/NTS, however, reduced these social deficits in 192-sap rats, while having no effect on the social interaction of sham controls. These findings suggest that the circuitry mediating the behavioral deficits seen in autism and ASD may functionally overlap with circuitry of seizure and mood disorders. In addition, our results suggest that vagal nerve stimulation (VNS) may be effective in reducing some of these core behavioral features seen in autism and ASD.

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Cell type specificity of the c-Fos immunoreactive neurons of cortical layer IV after patterned visual stimulation

Vaucher EJ, Dotigny F (2006) Cell type specificity of the c-Fos immunoreactive neurons of cortical layer IV after patterned visual stimulation. Neuroscience 2006 Abstracts 545.28. Society for Neuroscience, Atlanta, GA.

Summary: The cortical processing of specific visual stimuli may be enhanced or suppressed by neuromodulators, such as acetylcholine or norepinephrine as early as in the primary visual area. We have recently shown using c-Fos immunoreactivity that the specific lesion of basal forebrain cholinergic projections abolished the visually-induced neuronal activity of the layer IV of the primary visual cortex. The present study investigated further which cell types immunoreactive for c-Fos were modulated by the cholinergic afferents. Twenty male Long Evans Rats (275-300g) were anaesthetized with urethane (1.3g/kg). C-Fos immunocytochemistry was used as a single cell resolution marker of functional activity induced by sinusoidal grating in the visual cortex in control condition, specific lesion of the cholinergic fibers using 192-IgG saporin, muscarinic inhibition by scopolamine (1mg/kg) or NMDA receptors inhibition by CPP (10mg/kg). c-Fos/Parvalbumin and c-Fos/rat-brain-pyramidal-cells-marker double immunocytochemistry was performed to determine the localization of the visually-induced c-Fos immunoreactivity within the GABAergic interneurons or pyramidal cells of the layer IV of the rat cortex. The results demonstrated that the c-Fos immunoreactivity evoked by patterned stimulation in layer IV was rarely (less than 5%) co-localized with either parvalbumin or rat-brain-pyramidal-cells-marker. In addition, this functional activity was blocked by a cholinergic deficit but was independent of NMDA receptors transmission, since their inhibition by CPP did not affect the activity-dependent c-Fos immunoreactivity. These results suggest an effect of the patterned visual stimulation and the cholinergic fibers on the excitatory spiny stellate cells rather than the GABAergic or pyramidal cells. It suggests a role of the basal forebrain cholinergic neurons in the modulation of the thalamo-cortical transmission rather than local cortical microcircuitry in the rat visual cortex.

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Effects of selective cholinergic NBM lesions on short-interval timing

Miller JP, McAuley JD, Pang KC (2006) Effects of selective cholinergic NBM lesions on short-interval timing. Neuroscience 2006 Abstracts 572.24. Society for Neuroscience, Atlanta, GA.

Summary: The nucleus basalis magnocellularis (NBM) and its connection to the frontal cortex are important for timing short durations and divided attention. Although the NBM provides the major cholinergic input to the frontal cortex, GABAergic and other neurons are also located in the NBM and project to neocortex. To examine the role of the NBM in timing and attention, previous investigators used non-selective lesions of the NBM using ibotenic acid (IBO). In the present study, we examined the importance of cholinergic NBM neurons in timing using the selective immunotoxin 192-IgG saporin (SAP). Fisher 344 rats were trained on a peak-interval (PI) procedure using fixed-intervals of 12 s and 24 s. Once trained, stereotaxic surgeries where conducted on the rats and either SAP or nothing (SHAM) was administered into the NBM to create selective cholinergic or control lesions respectively. Preliminary results show that SAP did not alter peak times (SHAM: 11.82 s & 22.59 s versus SAP: 11.98 s & 22.88 s) or coefficient of variability (CV, SHAM: 0.41 & 0.45 versus SAP: 0.44 & 0.47). However, upon inspection of the brains, SAP lesions did not reduce the number of cholinergic neurons in the NBM. In a separate study using the PI procedure with a single fixed-interval of 18 s, IBO altered timing accuracy as measured by the absolute difference in peak times (pre-op versus post-op: SHAM = 0.60 s; IBO = 1.94 s) and altered variability as measured by the change in CV (pre-op versus post-op: SHAM = 0.02; IBO = 0.20). Preliminary results with IBO showing a non-directional reduction in accuracy are different from previous studies that have reported systematic overestimation of duration, although in our study the damage caused by IBO was restricted to the anterior NBM. Current studies are further evaluating the role of NBM neurons in timing with more selective and complete cholinergic lesions using SAP and more complete non-selective lesions using IBO.

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Astrocytic reaction to a lesion, under hormonal deprivation

Miller A, Martinez L, De LaCalle S (2006) Astrocytic reaction to a lesion, under hormonal deprivation. Neuroscience 2006 Abstracts 660.1. Society for Neuroscience, Atlanta, GA.

Summary: The basal forebrain cholinergic system plays an essential role in cortical plasticity and functional recovery following brain injury, although the precise mechanism is not known. Earlier studies from our laboratory have suggested that estrogen may have a protective effect on the basal forebrain cholinergic system, particularly in the maintenance of neuronal architecture. Although there is evidence for direct actions of estrogen on cholinergic neurons in vitro, the contribution of local glial cells to neuronal repair in this cell group, in vivo, has not been documented. We hypothesized that estrogen could also mediate neuronal repair through a modulatory effect on the activation of reactive astrocytes. Young adult female rats (n=28) were used in these studies, 14 were ovariectomized and the rest were left intact. All animals received a unilateral injection of 200 nl of the immunotoxin 192 IgG-saporin into the nucleus of the horizontal limb of the diagonal band of Broca (HDB). One month after the lesion, half of the animals in each group were implanted subcutaneously with a pellet releasing estrogen or placebo (n=7 per group) for 60 days. Using immunocytochemistry with an antibody against glial fibrillary acidic protein (GFAP), a specific marker for astrocytes, we studied changes in the expression of GFAP in the basal forebrain at the end of the treatment. Image analysis of histological sections revealed that GFAP levels in the side of the lesion were slightly higher that in the corresponding contralateral intact side. Overall change in GFAP expression in the ovariectomized animals treated with estrogen was not significantly different from the non-ovariectomized controls. In the ovariectomized animals treated with placebo (therefore undergoing a 3 month estrogen deprivation), levels of GFAP on the lesioned side were 20% higher than in controls. These results suggest that estrogen may prevent activation of astrocytes after a lesion, and perhaps allow a regenerative remodeling process to occur.

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192 IgG-saporin lesions of the cholinergic basal forebrain disrupt attention and awareness in Pavlovian trace but not delay conditioning in rats

Torner EK, Flesher MM, Chavez CM, Linton KD, Herbert MS, Butt AE (2006) 192 IgG-saporin lesions of the cholinergic basal forebrain disrupt attention and awareness in Pavlovian trace but not delay conditioning in rats. Neuroscience 2006 Abstracts 667.19. Society for Neuroscience, Atlanta, GA.

Summary: Recent research suggests that Pavlovian trace conditioning, but not delay conditioning, requires awareness or attention, where these processes appear to depend on specific brain systems. For example, past research has shown that although amnesiac humans with damage to the hippocampus (HPC) acquire a normal conditioned response (CR) in delay conditioning paradigms where the conditioned stimulus (CS) and unconditioned stimulus (US) partly overlap, they fail to acquire the CR in trace conditioning paradigms where the CS and US are separated in time. Others have shown that the anterior cingulate cortex (ACC) is similarly necessary for trace but not delay conditioning in rats. Another study in rabbits also suggests medial prefrontal cortex (mPFC) involvement in trace but not delay conditioning. The basal forebrain cholinergic system (BFCS) has projections to mPFC, ACC, and HPC. Given that each of these regions is critical for trace but not delay conditioning, we hypothesized that lesions of the BFCS using 192 IgG-saporin (SAP) would selectively impair trace but not delay appetitive conditioning in rats. Rats received bilateral injections of SAP or saline only (sham lesion control group) into BFCS prior to conditioning with a white noise CS and sucrose pellet US in either a delay or 10 s trace conditioning paradigm. Results supported our hypotheses, with the BFCS lesion group showing normal delay conditioning but impaired trace conditioning. In order to assess the potential for distraction to exacerbate the observed BFCS lesion-induced impairments in trace conditioning, a visual distracter (continuously flashing light) was added to the trace conditioning paradigm in a second experiment. Given evidence suggesting BFCS involvement in attention, it was hypothesized that the addition of a visual distracter to the trace conditioning task would cause a greater degree of impairment in the BFCS lesion group than in the control group tested in that task. Preliminary data support this hypothesis. Together, these experiments suggest that the BFCS is necessary for normal trace conditioning, which is argued to require both awareness and working memory. The additional impairment in trace conditioning caused by the visual distracter further suggests a role for the BFCS in mediating attention.

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Cholinergic agonists restore deficits in hippocampal neurogenesis after basal forebrain lesions in the adult rat brain

Van Kampen JM, Eckman CB (2006) Cholinergic agonists restore deficits in hippocampal neurogenesis after basal forebrain lesions in the adult rat brain. Neuroscience 2006 Abstracts 674.13. Society for Neuroscience, Atlanta, GA.

Summary: Discrete regions of the adult CNS, including the dentate gyrus of the hippocampus, retain the capacity for neurogenesis. Progenitor cells in these regions may represent a potential source of endogenous cells for replacement therapies in neurodegenerative diseases. In order to facilitate the development of such therapeutic approaches, an understanding of the microenvironmental signals regulating neurogenesis in the adult brain is essential. Small molecule neurotransmitters, such as acetylcholine, have been shown to regulate neurogenesis both during development and in the adult brain. In the studies presented here, we examine the effects of various cholinergic agonists on hippocampal neurogenesis in the adult rat brain. Intraventricular administration of a nicotinic agonist significantly attenuated proliferation, while muscarinic agonists triggered a dose-dependent increase in neurogenesis within the dentate gyrus and CA1 regions of the hippocampus. This effect was blocked by the M1 receptor-selective antagonist, pirenzepine. The basal forebrain provides an abundant source of cholinergic input to the hippocampus, thought to play an important role in learning and memory and Alzheimer’s disease (AD) pathophysiology. Loss of this cholinergic innervation, as occurs in AD, was achieved by a selective immunotoxin and resulted in a significant reduction in hippocampal neurogenesis. This loss of neurogenesis was reversed by intraventricular administration of a muscarinic receptor agonist. The loss of basal forebrain cholinergic inputs observed in AD may contribute to deficits in learning and memory through reductions in hippocampal neurogenesis. The results reported here suggest that pharmacological manipulation of the cholinergic system may represent a means of stimulating hippocampal neurogenesis as a potential treatment strategy.

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Effects of hypocretin-1 in 192-IgG-saporin-lesioned rats.

Blanco-Centurion CA, Shiromani A, Winston E, Shiromani PJ (2006) Effects of hypocretin-1 in 192-IgG-saporin-lesioned rats. Eur J Neurosci 24(7):2084-2088. doi: 10.1111/j.1460-9568.2006.05074.x

Summary: The basal forebrain is a major arousal center. Using 6 µg of 192-Saporin (Cat. #IT-01) injected into the lateral ventricle of rats, the role of non-cholinergic neurons in the basal forebrain was investigated. Administration of orexin, also known as hypocretin, to lesioned animals produced sleep/wake patterns identical to non-lesioned animals. The results indicate that non-cholinergic neurons in the basal forebrain are sufficient to promote arousal in response to orexin.

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Anatomical and neurochemical mediators of nicotine-induced activation of orexin neurons

Pasumarthi RK, Fadel J (2006) Anatomical and neurochemical mediators of nicotine-induced activation of orexin neurons. Neuroscience 2006 Abstracts 369.22. Society for Neuroscience, Atlanta, GA.

Summary: Orexin/hypocretin neurons of the lateral hypothalamus and contiguous perifornical area (LH/PFA) are important for state-dependent behavior and metabolic regulation. These neurons are activated-as indicated by Fos expression-by a variety of psychostimulant drugs including nicotine. Previously, we have shown that acute nicotine-induced activation of orexin neurons can be blocked by either the non-selective nicotinic antagonist mecamylamine or the selective α4β2 antagonist dihydro-beta-erythroidine (DHβE). However, the hypothalamic afferents and neurotransmitters mediating nicotine-elicited activation of orexin neurons remain to be established. Since the LH/PFA is rich in glutamatergic and cholinergic inputs, we performed in vivo microdialysis to determine the effect of both systemic and local nicotine on release of glutamate and acetylcholine (ACh) in this region of the hypothalamus. Local nicotine administration (100 μM; 2.0 mM) increased ACh and glutamate release in the LH/PFA. Furthermore, in a separate experiment, nicotine-elicited Fos expression in orexin neurons was reduced by either ibotenic acid lesions of the prefrontal cortex (PFC), which provides a substantial glutamatergic input to the hypothalamus, or by cholino-selective (192 IgG saporin) lesions of the basal forebrain. Collectively, these data suggest that glutamatergic inputs from the PFC and cholinergic inputs from the basal forebrain may act cooperatively to mediate the effect of acute nicotine on orexin neurons. Neural circuitry linking orexin neurons with the basal forebrain, PFC and PVT is likely to contribute to the effects of nicotine on wakefulness and attention.

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Cholinergic modulation of posterior parietal neuronal activity associated with the detection of signals in attentional task-performing rats

Broussard JI, Venugopal S, Sarter M, Givens B (2006) Cholinergic modulation of posterior parietal neuronal activity associated with the detection of signals in attentional task-performing rats. Neuroscience 2006 Abstracts 369.7. Society for Neuroscience, Atlanta, GA.

Summary: The posterior parietal cortex (PPC) is considered a major component of the brains’ attention systems, specifically of the orientation control network. This network controls the selection of stimuli, especially if stimuli are presented at unpredictable or multiple locations. Thus, mechanisms optimizing stimulus detection are hypothesized to represent fundamental components of the processes mediated via neuronal circuitry involving the PPC. Previous studies indicated the role of basal forebrain cholinergic projections to the cortex in the detection of signals. Furthermore, we demonstrated that performance of an attentional task involving signal detection activates PPC neurons in rat, specifically if signals are followed by a behavioral response indicating successful detection. The present experiment was designed to test the hypothesis that signal detection-related activation of PPC neurons depends on the integrity of cholinergic inputs to the PPC. Animals were trained to perform an operant sustained attention task involving signal detection as well as responding to non-signal events. Animals were equipped with a drivable headstage to insert stereotrodes into the PPC. After recording PPC neuronal activity during several baseline sessions, including the effects of a distractor, cholinergic projections to the PPC were lesioned by infusing 192 IgG-saporin into the recording region. Recordings from control animals prior to and after saline infusions (599 neurons total) indicate that PPC neurons (56 %) display increases in single unit activity evoked by detected visual signals. Presentation of a visual distractor reduced the number of signal detections but did not alter the detection-associated firing characteristics of PPC neurons, and relatively few neurons were modulated by the onset or offset of the distractor (8%). Unilateral, restricted removal of cholinergic inputs to the PPC did not affect the animals’ detection rate but reduced the proportion of neurons showing detection-related increases in neuronal activity (27 %). These data support the hypothesis that cholinergic inputs to the PPC mediates the detection of signals and thus contributes to the fundamental attentional processing mediated via PPC circuitry.

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Detailed analysis of ultrasound vocalizations emitted by 12-d-old rats during homing test: effects of a brief reunion with littermates in neonatal basal forebrain cholinergic lesioned pups

Iacobucci P, Colonnello V, Ricceri L (2006) Detailed analysis of ultrasound vocalizations emitted by 12-d-old rats during homing test: effects of a brief reunion with littermates in neonatal basal forebrain cholinergic lesioned pups. Neuroscience 2006 Abstracts 374.17. Society for Neuroscience, Atlanta, GA.

Summary: To evaluate the role of the developing cholinergic basal forebrain system on neonatal behavioural repertoire, seven day-old rats received lesions using intraventricular injections of 192 IgG-saporin or saline; on postnatal day (pnd) 12 we recorded ultrasonic vocalizations (USVs) emitted during a homing test (an olfactory based test carried out in a T-shaped arena to measure discrimination of home- versus non familiar- nest odors). USVs emitted by isolated 12-day-old pups were recorded during a first exposure to the homing test (4 min) and during a second exposure in the same setting (4 min), after a 1 min reunion with littermates. In all pups (control and 192 IgG-saporin) number of USVs (ranging between 30 and 60 kHz) significantly increased after reunion with littermates. Analysis of the sonographic structure of the pup calls identified 15 different classes of signals and revealed that the increase in USVs after reunion with littermates was due to a selective increase in 4-5 of the 15 classes [namely, constant frequency signals, brief calls (dot-shape), multiple sweeps calls (e.g. M- or W-shape), rising sweeps (/)]. Also time spent over the home-scented area increased during the second exposure to the homing test in all pups, but such increase was more evident in control than in cholinergic lesioned pups. Even if effects of the neonatal cholinergic lesions were limited, from a methodological point of view these results suggest that USV emission can be measured not only in standard neonatal isolation settings, but also while the subject is performing another neonatal behavioral task. Interestingly, the USV emission during the homing test is modulated by the rat pup after a brief reunion with littermates (a phenomenon resembling the “maternal potentiation”). Such modulation affects both quantitative and qualitative USV features, as well as the time spent by the pups over the home-scented area.

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Adenosine and sleep debt in the basal forebrain

Shiromani PJ, Blanco-Centurion C, Xu M, Murillo-Rodriguez E, Gerashchenko D, Hof PR (2006) Adenosine and sleep debt in the basal forebrain. Neuroscience 2006 Abstracts 458.13. Society for Neuroscience, Atlanta, GA.

Summary: The waxing and waning of the sleep drive is hypothesized to be regulated by endogenous sleep factors acting on specific neurons in the brain. One such factor, adenosine (AD), accumulates during wake and begins to inhibit neural activity in wake-promoting brain regions. The current version of the AD hypothesis (Strecker et al., Sleep, 2006) postulates that the adenosine A1 receptor activation on cholinergic neurons in the basal forebrain (BF) is key to sleep debt. Here we directly test this by administering 192-IgG-saporin to lesion the BF cholinergic neurons and then measuring AD levels in the BF via microdialysis. 46 Sprague-Dawley rats were administered either saline (n=21) or 192-IgG-SAP (n=25) (under anesthesia) and two weeks later when it is known that the cholinergic neurons have died, experiments were started. Rats were maintained on 12:12 light-dark schedule and given food and water ad-libitum. In rats with 95% lesion of the BF cholinergic neurons (n=7) AD levels in the BF did not increase with 6 h of prolonged waking but consistent with established findings it increased in non-lesioned rats (n=6). The lesioned rats had intact sleep drive after 6 and 12 h of prolonged waking, including a robust increase in delta power, indicating that the AD accumulation in the BF is not necessary for sleep drive. Next we determined that in the absence of the BF cholinergic neurons the selective adenosine A1 receptor agonist, CHA, administered to the BF continued to be effective in inducing sleep in a concentration-dependent manner, indicating that the BF cholinergic neurons are not essential to sleep induction. Basal sleep-wake levels and the amplitude of the diurnal rhythm of sleep-wake were not different between lesioned and non-lesioned rats. Thus, the hypothesis that basal forebrain cholinergic neurons are central to the AD regulation of sleep debt is rejected since neither the activity of the BF cholinergic neurons nor the accumulation of AD in the BF during wake is necessary for accumulating sleep debt.

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Hypocretin-1 stimulates wake and decreases sleep in the basal forebrain of rats with 192-IgG-sap induced lesion of the cholinergic neurons

Blanco-Centurion CA, Shiromani PJ (2006) Hypocretin-1 stimulates wake and decreases sleep in the basal forebrain of rats with 192-IgG-sap induced lesion of the cholinergic neurons. Neuroscience 2006 Abstracts 458.7. Society for Neuroscience, Atlanta, GA.

Summary: Hypocretin (orexin) containing neurons are located in the lateral hypothalamus (LH) from where they project to major arousal centers in the brain including the basal forebrain (BF). Waking, in part, may be driven by the action of HCRT on BF neurons. However, the BF contains various phenotypes of neurons and to test whether HCRT stimulates wake via the cholinergic neurons we utilize 192-IgG-saporin (192-IgG-SAP) to lesion the BF cholinergic neurons and then determine the potency of HCRT-1 in stimulating wake. Sprague-Dawley rats were administered (under anesthesia) saline (n=5) or 192IgG-SAP (4-6 ug/6ul, n=7). Three weeks later microinjections of aCSF or HCRT (0.06, 0.125, 0.25 nmol/250ul) were administered to the BF via a cannula in a random order. Sleep was recorded for 6h. In lesioned rats 95% of the BF cholinergic neurons were destroyed. However, in these rats, HCRT-1 in a dose-dependent manner significantly increased the time to onset of NREM and REM sleep and this was not different compared to non-lesioned rats. Percent wake was also not different compared to non-lesioned rats. Four hours after microinjection, wake-sleep levels were back to normal. Two studies (Espana et al., 2001) (Thakkar et al., 2001) have infused HCRT-1 into the BF and monitored changes in sleep-wake. However, because the BF contains a heterogenous population of neurons, HCRT-1 is likely to act on all of the BF neurons that contain the HCRT receptor. Here, we found that in the absence of the BF cholinergic neurons HCRT-1 increased wake and decreased sleep to the same degree as in non-lesioned rats, suggesting that non-cholinergic BF neurons are able to mediate unabated HCRT’s arousal signal.

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Prefrontal cholinergic modulation of attentional performance-associated increases in posterior parietal acetylcholine release

Kozak R, Brown HD, Bruno JP, Sarter M (2006) Prefrontal cholinergic modulation of attentional performance-associated increases in posterior parietal acetylcholine release. Neuroscience 2006 Abstracts 369.15. Society for Neuroscience, Atlanta, GA.

Summary: Increases in medial prefrontal cortex (mPFC) cholinergic activity were demonstrated to mediate attentional performance, particularly under conditions that require increases in attentional effort such as coping with the detrimental performance effects of distractors. Activation of the mPFC, in part as a result of cholinergic activity, is thought to orchestrate top-down effects for optimization of input processing elsewhere in the cortex. The cholinergic inputs to posterior cortical regions have been conceptualized as a branch of the PFC efferent circuitry mediating such top-down effects. Therefore, cholinergic inputs to the mPFC are expected to modulate performance-associated activation of cholinergic projections to the posterior parietal cortex (PPC). Furthermore, the mPFC modulatory influence should be particularly robust in response to performance challenges. This hypothesis was tested by assessing attentional performance-associated ACh release in the PPC in rats after removal of cholinergic inputs to the mPFC. Attentional task-performing animals were equipped with a guide cannula for insertion of a microdialysis probe into the PPC. Cholinergic projections to the mPFC and medial cingulate region were lesioned bilaterally by infusing 192-IgG saporin into the mPFC. Standard task performance of intact rats increased PPC ACh release by ~100% (over baseline).While lesioned animals’ standard task performance was mildly but significantly impaired, performance-associated increases in PPC ACh release in lesioned animals were higher than those observed in intact rats (150-200% over baseline). Presentation of the distractor impaired the performance of intact animals; the lesion exaggerated the detrimental effects of the distractor. In both intact and lesion animals, distractor performance-associated increases in PPC ACh release were higher than the increases observed during standard task performance. However, while peak ACh levels were observed immediately after distractor onset in intact rats, PPC ACh release in lesioned animals increased toward the end of the session, peaking 16 min after distractor termination. These data support the hypotheses that mPFC cholinergic inputs contribute to the regulation of PPC cholinergic activity, particularly following performance challenges.

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Nucleus basalis magnocellularis cholinergic lesions attenuate approach and approach-avoidance conflict

Norman GJ, Knox DK, Brothers H, Berntson GG (2006) Nucleus basalis magnocellularis cholinergic lesions attenuate approach and approach-avoidance conflict. Neuroscience 2006 Abstracts 369.17. Society for Neuroscience, Atlanta, GA.

Summary: Approach-avoidance conflict is a construct that underlies many behavioral tests that model anxiety. These tests include the elevated plus maze, shock-probe avoidance, and operant suppression. Previous reports have demonstrated that nucleus basalis magnocellularis (NBM) cholinergic lesions attenuate operant suppression induced by aversive stimuli. Furthermore, NBM cholinergic lesions attenuate avoidance behavior induced by predator odor. This suggests that NBM cholinergic lesions impact avoidance behavior during approach-avoidance conflict but the effect of NBM cholinergic lesions on approach behavior has not been evaluated extensively. In this study we attempted to separately evaluate the effect of NBM cholinergic lesions on approach and approach-avoidance conflict. NBM cholinergic lesions were induced using the selective cholinergic immunotoxin 192 IgG saporin. Time required to start consumption of a food reward was used as an index of approach. Time required to start consumption of a food reward in the presence of predator odor (trimethylthiazoline) was used as an index of approach-avoidance conflict. NBM cholinergic lesions attenuated the time required to consume a food reward in the presence and absence of trimethylthiazoline. The methods in the study describe a novel way of indexing approach-avoidance conflict. Furthermore, the results suggest that NBM cholinergic neurons may separately modulate neurobehavioral systems that mediate approach and avoidance.

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Effects of cholinotoxic and excitotoxic posterior parietal cortical lesions on attention in rats

Howe WM, Burk JA (2006) Effects of cholinotoxic and excitotoxic posterior parietal cortical lesions on attention in rats. Neuroscience 2006 Abstracts 369.18. Society for Neuroscience, Atlanta, GA.

Summary: Basal forebrain corticopetal cholinergic neurons are necessary for normal attentional processing. However, the interactions of acetylcholine with processing mediated by particular cortical regions remain unclear. The posterior parietal cortex has been implicated in models of attention, including the ability to attend selectively to target stimuli when distracting stimuli are presented. In the present experiment, rats were trained to perform a two-lever attention task that required discrimination of visual signals and trials when no signal was presented. Animals then received infusions of the cholinotoxin, 192IgG-saporin, the excitotoxin, n-methyl-D-aspartate, or vehicle into the posterior parietal cortex (n=9/group). Postsurgically, rats were tested for 30 sessions in the same task trained before surgery followed by 30 sessions with the houselight flashed one sec prior to a signal or non-signal. Lesions did not differentially affect performance in the task tested immediately following surgery. However, when the houselight was flashed prior to the signal or non-signal, both lesion groups were differentially affected compared to sham-lesioned animals. Sham-lesioned animals showed a decrease in the latency to press a lever following lever extension when the houselight was flashed compared to sessions when it was not flashed. However, cholinotoxic lesioned animals did not show this effect. Furthermore, planned comparisons revealed an elevated omission rate for excitotoxic lesioned animals compared to sham-lesioned animals during sessions when the houselight was flashed. The present data support the idea that the posterior parietal cortex and its cholinergic afferents from the basal forebrain are necessary for maintaining attentional performance when task irrelevant stimuli are presented.

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Basal forebrain cholinergic lesions impair endogenous covert orienting of attention in the rat

Farovik A, Brown VJ (2006) Basal forebrain cholinergic lesions impair endogenous covert orienting of attention in the rat. Neuroscience 2006 Abstracts 369.19. Society for Neuroscience, Atlanta, GA.

Summary: The cholinergic system plays an important role in attention, including covert orienting of spatial attention. Covert orienting of attention results in faster reaction times and also fewer errors if attention is directed towards target location by a preceding cue compared to when a cue misdirects attention away from the upcoming target location. This differential effect of the cue on performance is called the ‘validity effect’ (Posner, 1980 Q J E P 32:3-25) and it reflects the benefit of directed attention and the cost of needing to redirect attention from one location to another. Covert orienting can be exogenously cued (e.g., a visual event) or endogenously cued (e.g., a ‘cognitive’ cue indicating the probable target location). In the rat, covert orienting has been demonstrated using exogenous cues, but not, to date, endogenous cues. We used a reaction time task to examine the effects of basal forebrain cholinergic lesions on endogenously cued covert attention. Rats made a directional (left or right) response according to the spatial location (left or right) of target. The probable location of the target varied as a function time, such at shorter foreperiods, there was a greater probability of a left target while at longer foreperiods, right targets were more probable. Reaction time was linearly related to the a priori target probability, reflecting directed attention. Eleven rats received bilateral injections of the selective immunotoxin 192-IgG saporin (0.25µg/µl) into the basal forebrain at coordinates AP - 0.7 ML ± 2.9 DV - 6.7 (from dura). Eleven control rats received injections of vehicle. Overall, the lesion did not impair accuracy of performance, however, the reaction times no longer reflected attentional orienting in lesioned animals. Lesioned animals continued to show delay-dependent speeding prior to the target similar to controls, suggesting that changes in reaction times were not due to effects on motor readiness. We conclude that endogenous attentional orienting reflects a different, and independent, process from that of response preparation and that normal cholinergic function is required for the former but not the latter.

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Bilateral removal of cholinergic inputs to the medial prefrontal cortex disrupts the ability of rats to cope with challenges on attentional performance

Brown HD, Kozak R, Sarter M (2006) Bilateral removal of cholinergic inputs to the medial prefrontal cortex disrupts the ability of rats to cope with challenges on attentional performance. Neuroscience 2006 Abstracts 369.20. Society for Neuroscience, Atlanta, GA.

Summary: Studies using microdialysis for the measurement of the release of neurotransmitters in task-performing animals demonstrated attentional performance-associated increases in acetylcholine (ACh) release in the medial prefrontal cortex (mPFC). Moreover, these studies indicated that challenges on attentional performance are associated with augmented increases in mPFC ACh release. Such increases in ACh release were observed while the animals’ performance remained impaired in response to pharmacological or behavioral challenges, and while performance recovered from such challenges. These findings support the general hypothesis that increases in prefrontal cholinergic neurotransmission mediate increases in attentional effort, including the recruitment of prefrontal efferent projections to optimize top-down input processing in sensory and sensory-associational cortical regions. This hypothesis further suggests that cholinergic inputs to these regions directly amplify input processing, and that this more posterior branch of the cortical cholinergic input system is regulated in part by prefrontal outputs (Sarter et al. 2005, 2006). We have previously demonstrated that cortex-wide removal of cholinergic inputs results in persistent impairments in attentional performance. The present experiment was designed to demonstrate that restricted removal of mPFC cholinergic inputs selectively disrupts the animals’ ability to increase their attentional effort in order to maintain and recover from impairments produced by a visual distractor. Animals were trained in a sustained attention task and familiarized with the distractor. Cholinergic inputs to the prelimbic and anterior cingulate cortex were removed by infusions of 192 IgG-saporin into the mPFC. Results indicate that this lesion primarily exaggerated the detrimental performance effects of the distractor. Specifically, the ability of lesioned animals to stabilize their residual hit rate was impaired following distractor presentation. These results indicate that the integrity of cholinergic inputs to the mPFC is necessary for the recruitment of the cognitive mechanisms mediating stabilization and recovery of cognitive performance following attentional challenges.

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Comparison of the effects of selective cholinergic or noradrenergic deafferentation in the medial, prefrontal cortex on sustained attention

Newman LA (2006) Comparison of the effects of selective cholinergic or noradrenergic deafferentation in the medial, prefrontal cortex on sustained attention. Neuroscience 2006 Abstracts 369.21. Society for Neuroscience, Atlanta, GA.

Summary: Acetylcholine (ACH) and norepinephrine (NE) have been shown to be critically important in controlling the activity of cortical neurons during attention demanding tasks. ACH efflux increases during performance of a sustained attention task and the introduction of distracting stimuli augment this efflux (Himmelheber, Sarter and Bruno 2000). Electrophysiological recordings in NE cell bodies in the locus coeruleus show an increase in tonic firing when distracting stimuli are presented during an attentional task (Aston-Jones and Cohen 2005). The current study assesses the effects of neuroanatomically discrete depletions of these neurotransmitters in the prefrontal cortex (PFC) on a sustained attention task. Male, Long Evans rats received either sham (SHAM), cholinergic (ACH LX) or noradrenergic (NE LX) lesions of the medial wall of the PFC by injections of vehicle, 192 IgG saporin or dopamine beta-hydroxylase saporin respectively. Rats were trained to detect brief, temporally unpredictable, visual cues of varying duration (500, 100, 25 msec) and discriminate these events from non-signal trials. Several manipulations were run to vary the attentional load of the task. These manipulations include a tone with a predictable on-off pattern or a tone with an unpredictable on-off pattern. Preliminary results suggest that NE LX rats were more vulnerable than SHAM or ACH LX rats to the detrimental effects of the unpredictable but not predictable tone. These data suggest that NE is critical to filtering unpredictable distractor stimuli. Additionally we tested the effects of disrupting the temporal contiguity between correct responses and reinforcement as this has previously been shown to increase NE efflux in the frontal cortex. All animals were impaired by the introduction of a variable delay between a correct response and the delivery of a food reinforcer, however NE and ACH lesions of the PFC augmented this impairment. This suggests that both neuromodulators are critical in maintaining performance when reinforcer predictability changes. Manipulations of event rate, event asynchrony, signal probability and the dynamic stimulus range will also be discussed.

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Selective 192 IgG-saporin lesions of the cholinergic basal forebrain impair negative patterning discrimination learning in rats

Cortez AM, Amodeo D, Chavez C, Flesher M, Balbous M, Butt AE (2006) Selective 192 IgG-saporin lesions of the cholinergic basal forebrain impair negative patterning discrimination learning in rats. Neuroscience 2006 Abstracts 162.7. Society for Neuroscience, Atlanta, GA.

Summary: We have previously argued that the cholinergic nucleus basalis magnocellularis (NBM) is necessary for complex or “configural” association learning, but is not necessary for simple association learning. The current experiment further tests the hypothesis that the cholinergic basal forebrain is involved in configural association learning by examining the respective contributions of the NBM projections to neocortex and the medial septal (MS) projections to hippocampus in separate groups of rats. Rats with bilateral 192 IgG-saporin lesions of either the NBM or MS were tested in a negative patterning operant discrimination task. Rats were food-reinforced (+) for responding in the presence of a light (L+) or a tone (T+), but were not reinforced (-) for responding in the presence of the configural stimulus comprised of the light and tone presented simultaneously (LT-). We have previously shown that NBM lesions cause a transient but significant impairment in negative patterning discrimination learning. Consequently, we hypothesized a similar NBM lesion-induced impairment in the current experiment. Because hippocampus lesions cause dramatic disruptions in the acquisition of the negative patterning task, it was hypothesized that lesions of the cholinergic neurons of the MS would cause a greater degree of impairment than NBM lesions. Consistent with our hypotheses, NBM lesions retarded but did not prevent acquisition. MS lesions, in contrast, caused significantly greater impairments than NBM lesions. Rats in both lesion groups responded normally to L+ and T+ but responded more often to LT-. These findings demonstrate intact simple association learning but disrupted configural association following damage to the cholinergic neurons of the NBM or MS. Results suggest that cholinergic basal forebrain modulation of neocortex and hippocampus contributes to configural association learning.

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Steroid sulfatase inhibitor (p-O-sulfamoyl) – tetradecanoyl tyramine (du-14) enhances memory retention in rats with cholinergic lesion

Abitoye PA, Li P, Gibbs RB, Johnson DA (2006) Steroid sulfatase inhibitor (p-O-sulfamoyl) – tetradecanoyl tyramine (du-14) enhances memory retention in rats with cholinergic lesion. Neuroscience 2006 Abstracts 163.15. Society for Neuroscience, Atlanta, GA.

Summary: Previous studies have shown that altering the metabolism of neurosteroids via inhibition of steroid sulfatase (SSI) would reverse scopolamine induced amnesia. In this study we tested whether the SSI, DU-14 could enhance memory retention of foot shock in rats with a selective lesion of cholinergic neurons projecting from the medial septum to the hippocampus using a passive avoidance paradigm. Male Sprague-Dawley rats were infused with either 0.2 μg of 192 IgG-saporin (SAP), a selective cholinergic immunotoxin, or artificial cerebrospinal fluid (CSF) into the medial septum. One week later, the animals were placed into a passive avoidance apparatus and administered footshock trials (1 mA / 1 sec) until criterion (2 consecutive trials with a crossover latency of at least 5 min). On the next day, rats from SAP and CSF groups were then randomly assigned to receive DU-14 (30mg / kg) or corn oil (vehicle) daily for 6 days. Rats were tested for memory retention three hours after the last day dosing. DU-14 increased crossover latency by 74.5% in the CSF control group and 54.8% in SAP treated animals. In order to determine whether DU-14 or SAP treatment inhibited locomotor activity independent of memory, other animals were dosed with vehicle or DU-14 and crossover latency was tested before acquisition of footshock. There were no significant differences between treatment groups. These results suggest that steroid sulfatase inhibition may enhance memory retention in rats with hippocampal cholinergic lesion.

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Brain-derived neurotrophic growth factor from p75-expressing sensory afferents drives spinal noradrenergic fiber sprouting following nerve injury in rats

Hayashida K, Clayton B, Ma W, Eisenach J (2006) Brain-derived neurotrophic growth factor from p75-expressing sensory afferents drives spinal noradrenergic fiber sprouting following nerve injury in rats. Neuroscience 2006 Abstracts 248.19. Society for Neuroscience, Atlanta, GA.

Summary: We previously showed that peripheral nerve injury in mice results in sprouting of noradrenergic (NA) fibers in the spinal cord, possibly reflecting a substrate for increased efficacy of α2-adrenoceptor agonists such as clonidine. Here we tested whether spinal NA fiber sprouting also occurs in rats after peripheral nerve injury and examined the role of brain derived neurotrophic factor (BDNF) for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in mechanical hypersensitivity of the paw ipsilateral to injury and sprouting of NA fibers in the dorsal horn of the lumbar spinal cord. BDNF content increased in L4-L6 dorsal root ganglia (DRG) ipsilateral to injury and in lumbar spinal cord following nerve injury and intrathecal infusion of BDNF antiserum prevented spinal NA sprouting. Pro-BDNF immunoreactivity increased in L4-L6 DRG neurons ipsilateral to injury, especially in large-size neurons, and was highly co-localized with the low affinity neurotrophin receptor, p75NTR. Intrathecal injection of anti-p75NTR linked to saporin destroyed p75NTR expressing afferents and reversed NA sprouting after nerve injury. Manipulations which blocked NA sprouting (BDNF antiserum, anti-p-75NTR saporin) also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. These results suggest that increased BDNF synthesis and release from p75NTR expressing injured and uninjured sensory afferents drives spinal NA sprouting following nerve injury and this sprouting increase the capacity for analgesia from drugs which utilize the NA pathway.

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Selective cholinergic lesions of the medial septum disrupt dead reckoning-based navigation

Martin MM, Schultz MD, Winter SS, Wallace DG (2006) Selective cholinergic lesions of the medial septum disrupt dead reckoning-based navigation. Neuroscience 2006 Abstracts 66.10. Society for Neuroscience, Atlanta, GA.

Summary: Recent investigations using selective lesion techniques have suggested that the septohippocampal cholinergic system may not be critical for spatial orientation. These studies employ spatial tasks that provide the animal with access to both allothetic and idiothetic cues; therefore, the spared performance may reflect intact spatial orientation or compensatory mechanisms associated with one class of spatial cues. The present study examined the contribution of the septohippocampal cholinergic system to spatial behavior by examining performance in foraging tasks in which cue availability was manipulated. Female Long-Evans rats were either given a sham surgery or a selective medial septum/ vertical limb of the diagonal band cholinergic lesion using the neurotoxin 192 IgG-saporin. Rats were then trained to find food pellets randomly located on an open field which they then carried back to a visible home base (“cued”) to eat. Once they became proficient at returning to their home base location, cued training was alternated with probes. The three probes included 1) replacing the visible home base with a hidden home base to measure ability to use cues not associated with the home base (“uncued”); 2) moving the hidden home base to a new location to pit use of allothetic cues against idiothetic cues (“reversal”); and 3) testing under completely dark conditions thereby limiting access only to idiothetic cues (“dark”). Although both groups could use allothetic cues as evidenced by intact performance on cued and uncued probes, rats with compromised septohippocampal cholinergic systems were impaired during the reversal and dark probes. These observations are consistent with a selective role for the septohippocampal cholinergic system in idiothetic cue processing necessary for dead reckoning based navigation.

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Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats.

van der Staay FJ, Bouger P, Lehmann O, Lazarus C, Cosquer B, Koenig J, Stump V, Cassel JC (2006) Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats. Hippocampus 16(12):1061-1079. doi: 10.1002/hipo.20229

Summary: 192-Saporin (Cat. #IT-01) has been used to make extremely specific lesions in the septohippocampal cholinergic system of the brain. The specificity of these lesions is allowing researchers to more accurately map the involvement of the septohippocampal cholinergic system in spatial learning and memory. Here, rats received 0.8 µg of 192-Saporin in the medial septum and the vertical limb of diagonal band of Broca. Lesioned animals only exhibited deficits in attentional learning.

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Up-regulation of cation-independent mannose 6-phosphate receptor and endosomal-lysosomal markers in surviving neurons after 192-IgG-saporin administrations into the adult rat brain.

Hawkes C, Kabogo D, Amritraj A, Kar S (2006) Up-regulation of cation-independent mannose 6-phosphate receptor and endosomal-lysosomal markers in surviving neurons after 192-IgG-saporin administrations into the adult rat brain. Am J Pathol 169(4):1140-1154. doi: 10.2353/ajpath.2006.051208

Summary: The cation-independent mannose 6-phosphate receptor (CI-MPR) plays a major role in the endosomal-lysosomal (EL) system. One of the tasks carried out by the EL system is clearance of abnormal proteins after injury. By administering 2.0 µg bilateral injections of 192-Saporin (Cat. #IT-01) to rats, the researchers were able to increase CI-MPR expression levels, as well as other EL markers in response to the lesion. The upregulation of EL components suggests that the EL system may be able to repair neuronal abnormalities induced by injury.

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Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release.

Marcos B, Gil-Bea FJ, Hirst WD, Garcia-Alloza M, Ramirez MJ (2006) Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci 24(5):1299-1306. doi: 10.1111/j.1460-9568.2006.05003.x

Summary: The authors investigated a potential link between 5-HT6 receptors, cholinergic activity, and learning. After 0.067 µg of 192-Saporin (Cat. #IT-01) was injected into each hemisphere of the nucleus basalis magnocellularis in the basal forebrain of rats, 5-HT6 receptor mRNA and protein expression were measured. Results demonstrate the involvement of multiple neurotransmitter systems in neurochemical actions following 5-HT6 receptor blockade.

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Long-term effects of neonatal basal forebrain cholinergic lesions on radial maze learning and impulsivity in rats.

Scattoni ML, Adriani W, Calamandrei G, Laviola G, Ricceri L (2006) Long-term effects of neonatal basal forebrain cholinergic lesions on radial maze learning and impulsivity in rats. Behav Pharmacol 17(5-6):517-524. doi: 10.1097/00008877-200609000-00018

Summary: Work in the last decade has focused on clarifying the role of cholinergic dysfunction in Alzheimer’s disease. 7 day-old rats received 0.21 µg of 192-Saporin (Cat. #IT-01) administered to the third ventricle, and were tested at 5 months of age in delay tolerance and a radial maze. Test results suggest that prolonged basal forebrain cholinergic hypofunction is detectable only when using highly complex tasks.

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Adenosine and sleep homeostasis in the basal forebrain.

Blanco-Centurion C, Xu M, Murillo-Rodriguez E, Gerashchenko D, Shiromani AM, Salin-Pascual RJ, Hof PR,Shiromani PJ (2006) Adenosine and sleep homeostasis in the basal forebrain. J Neurosci 26(31):8092-8100. doi: 10.1523/JNEUROSCI.2181-06.2006

Summary: It has been shown that adenosine induces sleep and levels of adenosine increase during times of wakefulness. The authors investigated whether basal forebrain cholinergic neurons are involved in adenosine regulation of sleep. 6 µg of 192-IgG-SAP (Cat. #IT-01) was administered to the lateral ventricle of rats. In treated animals, adenosine levels did not increase with prolonged waking. The treated animals did, however, retain intact sleep drive.

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Effect of N-methyl-d-aspartate receptor blockade on plasticity of frontal cortex after cholinergic deafferentation in rat.

Garrett JE, Kim I, Wilson RE, Wellman CL (2006) Effect of N-methyl-d-aspartate receptor blockade on plasticity of frontal cortex after cholinergic deafferentation in rat. Neuroscience 140(1):57-66. doi: 10.1016/j.neuroscience.2006.01.029

Summary: Acetylcholine from the nucleus basalis magnocellularis (NBM) plays roles in neocortical function and plasticity. Here the authors examined whether N-methyl-D-aspartate receptors mediate the increase in the GluR1 subunit of the a-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor in the frontal cortex following treatment of the NBM with 0.15 µg of 192-IgG-SAP (Cat. #IT-01). The data indicates that upregulation of GluR1 and spine density after cholinergic deafferentation is regulated by N-methyl-D-aspartate receptors.

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Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer’s Disease: Effects on locomotor activity and memory functions in rats.

Traissard N, Herbeaux K, Cosquer B, Jeltsch H, Ferry B, Galani R, Pernon A, Majchrzak M, Cassel JC (2007) Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer's Disease: Effects on locomotor activity and memory functions in rats. Neuropsychopharmacology 32(4):851-871. doi: 10.1038/sj.npp.1301116

Summary: Two characteristics of Alzheimer’s disease (AD) are cholinergic dysfunction in the basal forebrain, and neuronal damage in the entorhinal cortex. Using 5 µg intracerebroventricular (icv) injections of 192-IgG-SAP (Cat. #IT-01), and 2.3 µg icv injections of OX7-SAP (Cat. #IT-02), locomotor activity, working, and reference memory of rats were examined. Although 192-IgG-SAP lesions caused limited deficits, rats receiving both lesions exhibited several behaviors associated with AD. The authors suggest that combining these lesions may be a more accurate model for AD than 192-IgG-SAP alone.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion.

Grimaldi P, Rossi F (2006) Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion. Eur J Neurosci 23(10):2657-2668. doi: 10.1111/j.1460-9568.2006.04803.x

Summary: Although neurogenesis occurs in very specific areas of the mammalian brain, neural progenitors can be found in many central nervous system sites. Here the authors examined neurogenesis in the rat cerebellum. 2.2 µg of 192-IgG-SAP (Cat. #IT-01) was injected into each lateral ventricle, and some animals were given exogenous EGF, bFGF, or FGF8. In this model, the local environment was not sufficient to direct neuronal differentiation, even with the addition of growth factors.

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Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections.

Fitz NF, Gibbs RB, Johnson DA (2006) Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections. Brain Res Bull 69(6):660-665. doi: 10.1016/j.brainresbull.2006.03.011

Summary: It is known that infusion of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats impairs acquisition of a delayed matching to position (DMP) T-maze task. Here, the authors evaluated whether introduction of an aversive stimulus 30 minutes prior to training would attenuate this deficit. Treated rats received 0.22 µg of 192-IgG-SAP injected into the medial septum. Data indicate that treated rats receiving an intraperitoneal injection of saline 30 minutes prior to training displayed less impairment than rats not receiving the aversive stimulus.

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Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior.

Knox D, Berntson GG (2006) Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior. Behav Neurosci 120(2):307-312. doi: 10.1037/0735-7044.120.2.307

Summary: Neurons in the nucleus basalis magnocellularis and substantia innominata (NBM/SI) may play a role in mediating some aspects of aversive states. The authors used 0.1 µg injections of 192-IgG-SAP (Cat. #IT-01) into the NBM/SI of rats to investigate the role these neurons play in elevated maze behavior and fear-conditioned behavioral suppression. The lesions did not affect the elevated maze behavior, but behavioral suppression was attenuated. The results indicate that NBM/SI cholinergic neurons are involved in the mediation of anxiety-like states.

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Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals.

Parikh V, Sarter M (2006) Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals. J Neurochem 97(2):488-503. doi: 10.1111/j.1471-4159.2006.03766.x

Summary: A major projection of brain attention systems passes through the cholinergic portion of the cortical mantle. The authors investigated the role of high-affinity choline transporters (CHT) in the clearance of exogenous choline, as well as choline from newly released acetylcholine. 0.085 µg of 192-IgG-SAP (Cat. #IT-01) was injected into each hemisphere of the basal forebrain of rats (mouse IgG-SAP, Cat. #IT-18, was used as a control). The results demonstrate that no matter the source, increases in choline concentrations are cleared by CHT’s.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

The septohippocampal cholinergic system and spatial working memory in the Morris water maze.

Frielingsdorf H, Thal LJ, Pizzo DP (2006) The septohippocampal cholinergic system and spatial working memory in the Morris water maze. Behav Brain Res 168(1):37-46. doi: 10.1016/j.bbr.2005.10.008

Summary: The authors examined whether an optimized Morris water maze test could reveal the role of the septohippocampal cholinergic system in spatial working memory. Rats were treated with bilateral 75-ng injections of 192-IgG-SAP (Cat. #IT-01) followed by acquisition of the water maze task, and two independent phases of working memory testing. Test optimization was followed by icv infusion of nerve growth factor in unlesioned animals. The data demonstrate that working memory impairments cannot be revealed by the Morris water maze test.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Estrogen contributes to structural recovery after a lesion.

Saenz C, Dominguez R, de Lacalle S (2006) Estrogen contributes to structural recovery after a lesion. Neurosci Lett 392(3):198-201. doi: 10.1016/j.neulet.2005.09.023

Summary: The authors evaluated the trophic effects of 17ß-estradiol (E2) on cholinergic neurons of the basal forebrain after lesioning with 192-IgG-SAP (Cat. #IT-01). Ovariectomized female rats received 200 nl of 0.075 mg/ml 192-IgG-SAP followed by a subcutaneous pellet of E2, which was released over 60 days. Dendritic size in ovariectomized rats receiving the E2 was the same as in control animals, while ovariectomized rats receiving a placebo displayed a significant reduction in dendritic arborization.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons.

Emgard M, Paradisi M, Pirondi S, Fernandez M, Giardino L, Calza L (2007) Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons. Neurobiol Aging 28(1):112-121. doi: 10.1016/j.neurobiolaging.2005.11.015

Summary: Women at risk of preterm delivery are commonly treated with synthetic glucocorticoids such as dexamethasone and betamethasone. Here the authors examined adult rats that were prenatally exposed to glucocorticoids. After 2.5 µg intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01) or 0.44 µg of saporin (Cat. #PR-01), the rats were tested in a water maze pool. The evidence suggests that not only do prenatal glucocorticoids affect adult cognitive function, they also make cholinergic neurons more susceptible to challenges later in life.

Related Products: 192-IgG-SAP (Cat. #IT-01), Saporin (Cat. #PR-01)

Cholinergic lesions produce selective effects on cognitive performance in rats

Gibbs RB, Fitz NF, Johnson DA (2005) Cholinergic lesions produce selective effects on cognitive performance in rats. Neuroscience 2005 Abstracts 881.1. Society for Neuroscience, Washington, DC.

Summary: Cholinergic projections from the basal forebrain play an important role in cognitive processes; however, the degree to which damage to specific projections contributes to impairment within specific cognitive domains is unclear. In the present study, cholinergic projections to the hippocampus and/or frontal cortex of young adult, ovariectomized Sprague-Dawley rats were selectively destroyed by injecting 192 IgG-saporin (SAP) into the medial septum (MS), the nucleus basalis magnocellularis (NBM), or both the MS and NBM (MSNBM). Controls received injections of sterile saline. Animals were then tested for learning and memory impairments using a series of tasks, including a delayed matching-to-position (DMP) T-maze task, an operant configural association (CA) negative patterning task, and a 12-arm radial maze (RAM) task, administered in that order. Results reveal different effects of the lesions on the different tasks. For example, SAP lesions of the MS, as well as combined lesions of MS and NBM significantly impaired acquisition the DMP task; however, once animals had reached criterion, cholinergic lesions did not alter decrements in performance produced by increasing the intertrial delay. In contrast, SAP lesions of the MS had no significant effect on acquisition of the CA task, although combined lesions of MS and NBM produced a trend toward impairment on the CA task among animals with the most severe cholinergic depletion. Likewise, combined lesions significantly impaired acquisition of the RAM task. In general, combined lesions produced greater impairments than lesions of either the MS or NBM alone. Significant correlations between acquisition of the DMP and RAM tasks and ChAT activity in the hippocampus, frontal cortex, and occipital cortex, were also detected. These data demonstrate that removal of cholinergic projections to the hippocampus and frontal cortex produce cognitive impairments that are lesion specific as well as task dependent.

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192 IgG-saporin lesions to the nucleus basalis magnocellularis (NBM) do not disrupt the retention of learning set formation

Bailey AM, St Germain J, Tyler MM (2005) 192 IgG-saporin lesions to the nucleus basalis magnocellularis (NBM) do not disrupt the retention of learning set formation. Neuroscience 2005 Abstracts 881.2. Society for Neuroscience, Washington, DC.

Summary: Male Long Evans rats (Rattus norvegicus) were used to investigate the role of the nucleus basalis magnocellularis (nBM) in the retention of a previously acquired learning set rule. All rats had successfully acquired an olfactory discrimination learning set by demonstrating above chance performance on trial 2 across 42 olfactory discrimination problems. Following the initial acquisition of learning set, animals were given bilateral 192 IgG-saporin (0.375 µg/µl; 0.4 µl per hemisphere) lesions to the nBM. Assessment of open field activity indicated that there were no group differences in general activity levels or emotionality before or after surgery. Retention of learning set was tested 10 days following surgery with 20 novel, odor-unique olfactory discrimination learning set problems. Control and nBM lesioned animals performed significantly higher than expected by chance on trial 2 of the novel problems suggesting retention of a learning set hypothesis. However, rats with 192 IgG-saporin nBM lesions performed learning set at a significantly lower level than control animals as measured by trial 2 percentage correct. Results suggest that damage to the nBM disrupts general performance on a cognitively demanding task, but does not block retention of the learning set rule.

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Facilitation of conditioned odor aversion by entorhinal cortex lesion in the rat is reversed by cholinergic lesion in the basal forebrain

Ferry B, Herbeaux K, Petoukhova-Traissard N, Galani R, Cassel J, Majchrzak M (2005) Facilitation of conditioned odor aversion by entorhinal cortex lesion in the rat is reversed by cholinergic lesion in the basal forebrain. Neuroscience 2005 Abstracts 881.6. Society for Neuroscience, Washington, DC.

Summary: In the rat, conditioned odor aversion (COA) corresponds to the avoidance of an odorized-tasteless solution (conditioned stimulus, CS) previously associated with toxicosis (unconditioned stimulus, US). Evidence suggests that the entorhinal cortex (EC) is part of the neural substrate involved in the acquisition of COA. Indeed, we showed that EC lesion facilitated CS-US association and rendered it resistant to lengthening of the interstimulus interval (ISI). This facilitation phenomenon might correspond to a lengthening of the olfactory CS memory trace, rendering the association with the subsequent US possible. Because i) all our EC-lesioned rats showed septo-hippocampal cholinergic sprouting, and ii) scopolamine infusions into the dentate gyrus reversed performance in EC-lesioned but not in sham-operated rats in a spontaneous olfactory preference test, we suggested that COA facilitation resulted from enhanced cholinergic activity in the hippocampus. In order to test this hypothesis, we studied the effect of a cholinergic basal forebrain lesion combined to an EC-lesion during COA. Male Long-Evans rats subjected to bilateral EC lesions and intraventricular infusions of the selective toxin 192 IgG-saporin received odor-US pairings with a short or long ISI. Results showed that sham-lesioned rats displayed COA with the short, but not the long ISI, whereas EC-lesioned rats showed COA with both ISI. More interestingly, rats with double lesions did not differ from controls, suggesting that the cholinergic lesion suppressed the effect of EC-lesions. These results strongly suggest that the facilitative effects observed in EC-lesioned animals during COA are due, at least in part, to the septo-hippocampal cholinergic sprouting elicited by the EC lesion. Moreover, they suggest that the hippocampal cholinergic system is involved in the control of memory processes underlying the association between the olfactory CS and the US during acquisition of COA.

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Time-dependent neurotrophins effect on cholinergic denervation and hippocampal sympathetic ingrowth following 192 IgG-saporin lesioning of medial septum

Kolasa K, Parsons D, Harrell LE (2005) Time-dependent neurotrophins effect on cholinergic denervation and hippocampal sympathetic ingrowth following 192 IgG-saporin lesioning of medial septum. Neuroscience 2005 Abstracts 1004.4. Society for Neuroscience, Washington, DC.

Summary: In rat,injection of specific cholinotoxin,192 IgG-saporin into the medial septum results not only in a selective denervation of hippocampus(CD),but in an ingrowth of peripheral sympathetic fibers,originating from the superior cervical ganglion,into the hippocampus.This process has been termed hippocampal sympathetic ingrowth(HSI).A similar process,in which sympathetic noradrenergic axons invade hippocampus,may also occur in Alzheimer's disease(AD). The severity of cognitive decline in AD patients has been linked to multiple factors including cholinergic and neurotrophic factors and their receptors,which undergo selective alterations throughout the progression of AD.It is known that the sites of synthesis of NGF(nerve growth factor),BDNF(brain derived-neurotrophic factor)and LIF (leukemia inhibitory factor)in rat septo-hippocampal system are predominantly hippocampal neurons.By using 192 IgG-saporin we have been able to mimic some of the cardinal features of AD e.x.cholinergic denervation and hippocampal sympathetic ingrowth and to study their effect on neurotrophins in dorsal hippocampus.Thus,2,8,and 12 weeks after injection of 192 IgG-saporin we measured NGF, BDNF and LIF protein and mRNA expression using Western blot and RT-PCR techniques, respectively.Choline acetyltransferase activity(ChAT) and norepinephrine(NE) concentration was also detected. Significant alterations were found in NGF and LIF protein expression(decrease at 8 weeks and increase at 12 weeks post lesions)in HSI group. Significant decrease of BDNF(mature form) protein expression was found in CD group over whole period of time. There was significant decrease found in BDNF mRNA expression in CD,with normalization in HSI group 12 weeks post lesions. Results of the study suggest that neurotrophins are affected by cholinergic denervation and may play an important role in regulation and development of HSI,which might be a beneficial phenomenon for restoration at least some of cognitive function.

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What does acetylcholine do in the posterior parietal cortex (PPC)? Attentional performance-associated increases in PPC ACh efflux.

Kozak R, Parikh V, Martinez V, Brown H, Bruno JP, Sarter S (2005) What does acetylcholine do in the posterior parietal cortex (PPC)? Attentional performance-associated increases in PPC ACh efflux. Neuroscience 2005 Abstracts 644.1. Society for Neuroscience, Washington, DC.

Summary: Medial prefrontal cortex (mPFC) ACh efflux has been demonstrated to mediate attentional performance, particularly under conditions that require increases in attentional effort or the processing of distractors. Activation of the mPFC, in part as a result of cholinergic activity, is thought to orchestrate top-down effects for optimization of input processing elsewhere in the cortex. We previously demonstrated that mPFC cholinergic mechanisms influence PPC ACh efflux, suggesting that PPC ACh efflux is a component of the prefrontal circuitry mediating top-down effects. The present experiment was designed to characterize attentional performance-associated increases in PPC ACh efflux in animals performing a regular sustained attention task, following the presentation of a visual distractor, and following loss of cholinergic inputs to the mPFC. Attention task-performing animals were equipped with a guide cannula for insertion of a microdialysis probe and to collect dialysates in the PPC. Cholinergic projections to the mPFC were lesioned bilaterally by infusing 192-IgG saporin into the mPFC. Regular attentional performance was associated with increases in PPC ACh efflux that mirrored those observed previously in the mPFC. In contrast to evidence indicating a cholinergic role in the processing of distractors in the mPFC, PPC ACh efflux was not affected by the distractor and associated impairments in performance. The performance effects of the distractor were augmented in animals with mPFC cholinergic deafferentation. Performance-associated increases in PPC ACh efflux of deafferented animals were higher following the presentation of the distractor than in intact rats. These data support the hypotheses that mPFC cholinergic inputs contribute to the suppression of the effects of distractors and to the recruitment of posterior cortical cholinergic inputs to optimize processing under challenging conditions.

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Basal forebrain cholinergic lesions produce a dissociation of impairment in delay and trace conditioning in rats

Butt AE, Cabrera S, Chavez C, Corley S, Cortez A, Figueroa J, Kitto M, Torner E (2005) Basal forebrain cholinergic lesions produce a dissociation of impairment in delay and trace conditioning in rats. Neuroscience 2005 Abstracts 644.2. Society for Neuroscience, Washington, DC.

Summary: Recent research suggests that Pavlovian trace conditioning, but not delay conditioning, requires awareness or attention, where these processes appear to depend on specific brain systems. For example, Clark, Manns, and Squire (2002) have shown that although amnesiac humans with damage to the hippocampus (HPC) acquire a normal conditioned response (CR) in delay conditioning paradigms where the conditioned stimulus (CS) and unconditioned stimulus (US) partly overlap, they fail to acquire the CR in trace conditioning paradigms where the CS and US are separated in time. Han and colleagues (2003) have shown that the anterior cingulate cortex (ACC) is similarly necessary for trace but not delay conditioning in rats. The medial prefrontal cortex (mPFC) is also involved in trace but not delay conditioning (Kronforst-Collins & Disterhoft, 1998). The basal forebrain cholinergic system (BFCS) has projections to mPFC, ACC, and HPC. Given that each of these regions is critical for trace but not delay conditioning, we hypothesized that lesions of the BFCS using 192 IgG-saporin (SAP) would selectively impair trace but not delay appetitive conditioning in rats. Rats received bilateral injections of SAP or saline only (control group) into BFCS prior to conditioning with a tone CS and sucrose pellet US in either a delay or 10 s trace conditioning paradigm. Preliminary results support this hypothesis. Compared to controls, rats in the BFCS lesion group showed moderate impairment in delay conditioning but more severe impairment in the trace conditioning paradigm. Rats in both groups showed an increase in differential responding to the CS in the delay paradigm, although the BFCS lesion group showed less conditioned responding than controls. In contrast, only the controls showed progressive differential responding to the CS in the trace conditioning paradigm. These data suggest that the BFCS contribute critically to the maintenance of attention in Pavlovian trace conditioning.

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Role of the medial septum in a repeated acquisition task

Strait TA, Montoya D, Pang KCH (2005) Role of the medial septum in a repeated acquisition task. Neuroscience 2005 Abstracts 647.14. Society for Neuroscience, Washington, DC.

Summary: The medial septum/diagonal band of Broca (MSDB) provides a major afferent pathway to the hippocampus and both regions are important in learning and memory. The two major projection cells of the MSDB are cholinergic and GABAergic neurons. Although nonselective lesions of the MSDB impair spatial memory, the role of the different MSDB neuronal population in memory is an active area of research. In the present study, rats with preferential cholinergic or GABAergic lesions of the MSDB will be tested on the repeated acquisition task. The task assesses how well a rat can learn the location of a reward that changes from day to day. All sessions are performed on an 8-arm radial arm maze using one arm for reward. Each daily session consists of 5 trials with rats starting from a different arm on each trial. Rats are tested for a total of 9 days; each day a new rewarded arm is used. Our preliminary data suggest that rats with selective cholinergic lesions using 192-IgG saporin are not impaired in acquisition of the task. These results with selective cholinergic lesions contrast with our previous work showing that preferential GABAergic MSDB lesions impair performance of a repeated acquisition task in a water maze. We are currently investigating the effects of preferential GABAergic MSDB lesions on this task. Our preliminary data suggests that cholinergic and GABAergic MSDB neurons may have differential roles in acquisition of a spatial memory task.

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Cholinergic therapy does not rescue spatial learning deficits induced by ICV injection of 192 IgG-saporin

Lohals R, Veng LM (2005) Cholinergic therapy does not rescue spatial learning deficits induced by ICV injection of 192 IgG-saporin. Neuroscience 2005 Abstracts 653.5. Society for Neuroscience, Washington, DC.

Summary: The cholinergic hypothesis states that central cholinergic dysfunction is responsible for age-dependent cognitive decline. To model this in rats, we induced cholinergic basal forebrain loss the neurotoxin IgG192-saporin (SAP). Following ICV infusion of 2.5 or 5 microgram (ug) SAP, or saline, rats were tested in the radial 12-arm water maze (RAWM), a spatial learning and memory task. While saline sham or 2.5 ug SAP lesioned rats showed normal learning over 4 trials in the RAWM, 5 ug SAP rats were impaired. However, when trained over 20 trials, 5 ug SAP rats eventually attained the same level of performance as 2.5 ug SAP or saline sham rats, and 28 days later all rats showed intact memory for this platform location. In the open field, 5 ug SAP rats failed to habituate. However, SAP or saline sham lesioned rats did not differ in basal activity, rotarod, or visually cued RAWM performance. SAP lesion resulted in severe depletion of ChAT activity in hippocampus and cortex, which significantly correlated with learning impairment in the RAWM. In a second experiment, we used 5 ug ICV SAP to investigate the effect of cholinergic therapy on SAP-induced spatial learning deficits in the RAWM. However, neither galantamine (0.30, 1.25, 5.0 mg/kg) nor RJR-2403 (0.08, 0.31, 1.25 mg/kg) could reverse the SAP induced deficit in RAWM learning. In conclusion, we found that spatial learning in the RAWM was consistently impaired following severe (5.0 ug SAP) cholinergic basal forebrain lesion in rats. This learning deficit was not confounded by general behavioral disturbances. However, with excessive training SAP lesioned rats could learn and later recall spatial information, suggesting that recall is intact in cholinergic lesioned animals. Severe SAP lesion also impaired habituation in an open field and this was not due to hyperactivity. Finally, treatment with galantamine and RJR-2403 did not alleviate the cognitive deficit induced by the SAP lesion, likely due to the severity of cholinergic depletion.

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The potential role of the corticopetal cholinergic system in mediating anxiogenic states in rats

Knox DK, Berntson GG (2005) The potential role of the corticopetal cholinergic system in mediating anxiogenic states in rats. Neuroscience 2005 Abstracts 659.10. Society for Neuroscience, Washington, DC.

Summary: Previous research has demonstrated that the corticopetal cholinergic system is important in mediating defensive tachycardia which suggests that this system may be important in mediating aversive states such as fear and anxiety. The aim of this study was to determine how corticopetal cholinergic lesions affect behavioral models of aversive states. The cholinergic immunotoxin 192 IgG saporin (ATS, San Diego CA) was infused into the nucleus basalis of rats in order to accomplish corticopetal cholinergic lesions. Lesioned and control rats were then evaluated on three behavioral models of anxiogenic states: behavior in the elevated plus maze, behavioral suppression induced by classical and contextual fear conditioned stimuli, and heightened arousal induced by a footshock. Lesioned and control rats did not differ on any anxiogenic behavioral measure in the elevated plus maze indicating that corticopetal cholinergic lesions did not affect behavioral indices of unconditional fear. In contrast, both classical and contextual fear conditioned stimuli induced behavioral suppression in control rats, and these effects were attenuated in lesioned rats indicating that corticopetal cholinergic lesions attenuated conditioned fear. Lastly, heightened arousal was evaluated in lesioned and control rats by monitoring behavioral suppression and changes in the electroencephalogram (EEG) over the retrosplenial cortex after a footshock. The footshock induced decreases in the integral area of the delta band and increases in the integral area of the theta band of the EEG in control rats. Both of these effects were attenuated in lesioned rats. In addition, changes in delta and behavioral suppression induced by the footshock were significantly correlated. These results indicated that corticopetal cholinergic lesions attenuated the heightened arousal induced by an aversive event. Taken together, the results of the study suggest that the corticopetal cholinergic system may be important in mediating components of anxiogenic states.

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Distinct roles for amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex in attention for learning and action

Maddux JM, Chatterjee S, Kerfoot EC, Holland PC (2005) Distinct roles for amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex in attention for learning and action. Neuroscience 2005 Abstracts 411.16. Society for Neuroscience, Washington, DC.

Summary: Many theories of associative learning claim that the accuracy with which an event predicts its consequences affects the allocation of attention to that event. More reliable predictors are more likely to control action, but less reliable predictors often are more likely to capture attention for purposes of new learning about those events. Previous studies from our lab showed the amygdala central nucleus (ACe) to be important for both sustained attention guiding performance to predictive cues, and for enhanced new learning about less predictive cues. This study investigated the possibility that ACe affects these distinct aspects of attention by influencing different, specialized cortical regions, via its modulation of the basal forebrain cholinergic system. Rats were given either ibotenic acid lesions of ACe, 192 IgG-saporin lesions that reduced the basal forebrain cholinergic input to medial prefrontal cortex (mPFC) or posterior parietal cortex (PPC), or sham lesions of one of these regions. In an operant 5-choice reaction time task, responding to “CRF” ports was reinforced on 100% of the trials, whereas responding to “PRF” ports was reinforced on only 50% of such trials. Later, the ability of one CRF port and one PRF port to overshadow Pavlovian conditioning of auditory cues when port + tone compounds were paired with the delivery of a new, more valued reinforcer was examined. ACe lesions interfered with attention to the PRF cue for both learning and action, whereas reduction of cholinergic input to mPFC interfered only with attention for action, and reduction of cholinergic input to PPC interfered only with attention for new learning. The PRF port overshadowed conditioning of the tone significantly more than did the CRF port in both sham and mPFC rats, but not in ACe or PPC rats. By contrast, relative to CRF port responding, control of port-directed responding by the PRF cue was significantly greater in sham and PPC rats than in ACe or mPFC rats.

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Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in accumbens

Mattsson A, Schilstrum B, Svensson TH, Olson L (2005) Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in accumbens. Neuroscience 2005 Abstracts 557.8. Society for Neuroscience, Washington, DC.

Summary: Disturbances in cholinergic functions have been implicated in schizophrenia. We have recently shown that cholinergic denervation of neocortex produced by local injection of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis (nbm) leads to an increased sensitivity to d-amphetamine in adult female rats. The objective of the current study was to investigate if this effect was paralleled by an increased amphetamine-induced release of dopamine in accumbens. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into nbm in adult rats. D-amphetamine-induced dopamine release in nucleus accumbens was measured by in vivo microdialysis two to three weeks after lesioning. We find that amphetamine causes a greater release of dopamine in rats with cortical cholinergic denervation than in sham lesioned controls. The duration of the amphetamine-effect was also significantly longer in the 192 IgG-saporin lesioned group compared to controls. The results suggest that abnormal responsiveness of mesencephalic dopaminergic neurons could be secondary to cortical cholinergic deficiency. This in turn might constitute one possible contributing pathophysiological factor in schizophrenia.

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Intraventricular IgG192-saporin lesions lead to altered 5-HT2A receptor levels in the hippocampus

Pedersen AF, Kostova V, Christensen E, Veng LM, Lohals R, Knudsen GM, Aznar S (2005) Intraventricular IgG192-saporin lesions lead to altered 5-HT2A receptor levels in the hippocampus. Neuroscience 2005 Abstracts 559.17. Society for Neuroscience, Washington, DC.

Summary: Background: Alzheimer's disease (AD) is the most frequent neurodegenerative disorder in humans. One of the traits of the disease is the presence in the brain of beta-Amyloid plaques and loss of cholinergic neurons in the basal forebrain. Other transmittersystems especially serotonin may be involved in the patophysiology of AD. Clinical studies have observed a higher incidence of depression among AD patients and a higher risk of developing dementia when diagnosed with major depression. It is known that serotonin and serotonin receptors, among them 5-HT2A receptors (5-HT2AR), are involved in depression. Interestingly, recent PET-studies have shown lower 5-HT2AR levels in entorhinal cortex and hippocampus in early stages of AD. Objectives: Our aim was to investigate whether 5-HT2AR levels were affected in the hippocampus after lesioning the cholinergic neurons in the basal forebrain, thereby highlighting a possible interaction between the serotonergic and the cholinergic transmitter systems. Methods: Intraventricular injection of 5ug IgG192-Saporin or saline in adult Wistar male rats. After 20 weeks the rats were sacrificed and the hippocampus were isolated. After homogenisation the levels of 5-HT2AR were determined by western blot. Results: Downregulation of the 5-HT2AR levels were observed after 20 weeks. 5-HT2AR levels for animals receiving IgG192-Saporin for 1, 2 and 4 weeks will also be investigated. Conclusion: Our results show a direct effect of cholinergic lesions on hippocampal 5-HT2AR. This may be explained by a compensatory effect of the serotonergic system for the loss of cholinergic input as there may be a balance between these two systems in the hippocampus.

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Sortilin and p75NTR: localization in adult rat brain and their alterations following pharmacological manipulations

Kabogo DN, Kar S (2005) Sortilin and p75NTR: localization in adult rat brain and their alterations following pharmacological manipulations. Neuroscience 2005 Abstracts 148.14. Society for Neuroscience, Washington, DC.

Summary: Neurotensin receptor-3 is a single trans-membrane domain 100 kDa protein whose structure is identical to the human gp95/sortilin. This receptor is involved in intracellular trafficking of sphingolipid activator proteins, and may have a role in sorting other soluble lysosomal proteins. Recently, it has been shown that sortilin, under in vitro paradigm, acts as a co-receptor and molecular switch governing the low-affinity neurotrophin receptor p75NTR mediated cell death induced by pro-nerve growth factor. However, very little is currently known about the cellular distribution of sortilin and its possible localization in neurons expressing p75NTR and/or cholinergic markers in the adult rat brain. Using western blotting and immunohistochemistry, we report that immunoreactive sortilin is ubiquitously expressed in the adult rat brain, including the cortex, striatum, basal forebrain, hippocampus, brainstem and cerebellum. In the normal brain immunoreactive sortilin is not found to be present in the basal forebrain cholinergic neurons expressing p75NTR but localized in the cholinergic interneurons of the striatum and motoneurons of the brainstem. Additionally, neither the level nor the expression of sortilin is altered following immunotoxin 192-IgG saporin-induced death of the basal forebrain cholinergic neurons. However, systemic administration of kainic acid, a potent neurotoxin, was found to induce the expression of p75NTR in the subset of sortilin-containing striatal cholinergic neurons which are believed to undergo apoptosis. These results, taken together, suggest that sortilin in normal brain is not expressed in p75NTR containing neurons and may differentially influence p75NTR–mediated cell death in the brain.

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Medial-septal cholinergic denervation leads to synaptic glutamatergic dysfunction in hippocampus

Kanju PM, Sims CM, Parameshwaran K, Huggins K, Josephson EM, Suppiramaniam V (2005) Medial-septal cholinergic denervation leads to synaptic glutamatergic dysfunction in hippocampus. Neuroscience 2005 Abstracts 157.2. Society for Neuroscience, Washington, DC.

Summary: Accumulating evidences support the role of septohippocampal cholinergic projections in learning and memory mechanisms. Hence, a complete and selective destruction of the septal cholinergic neurons projecting to the hippocampus by immunotoxin 192 IgG-saporin results in memory impairment. Alterations in glutamate receptor (NMDA & AMPA receptors) binding properties have also been reported following septohippocampal cholinergic denervation. A decrease in NMDA binding and an increase or no change in AMPA binding was observed seven days after lesioning. Therefore, it is important to study the effects of cholinergic lesioning on functional properties of glutamate receptors. This study investigated the electrophysiological properties of AMPA and NMDA receptors 4 to 6 days after medial septal lesioning. Selective medial-septal lesioning was performed in rats with the immunotoxin 192-IgG saporin. Whole cell recording of mEPSC and sEPSC were performed in CA1 hippocampal region in slices from lesioned and sham lesioned animals. The single channel recordings of synaptosomes isolated from hippocampi of these animal groups incorporated into lipid bilayer were also performed. Our results indicate a reduction in the frequency and amplitude of AMPA and NMDA mediated mEPSCs and sEPSCs of animals lesioned with 192-IgG saporin. Furthermore, single channel recording of isolated synaptosomes demonstrate a reduction in channel open probability (30-50% for AMPA & 20-32% for NMDA receptors), and conductance (35-46% AMPA & 28-39% for NMDA receptors). Collectively, our results indicate that synaptic AMPA and NMDA receptor functions are altered 4-6 days following medial septal lesioning.

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Contributions of NMDA receptors to cortical plasticity after cholinergic deafferentation

Buse JE, Kim I, Wilson RE, Wellman CL (2005) Contributions of NMDA receptors to cortical plasticity after cholinergic deafferentation. Neuroscience 2005 Abstracts 214.21. Society for Neuroscience, Washington, DC.

Summary: Plasticity of frontal cortex is altered in aging rats: lesions of the nucleus basalis magnocellularis (NBM) increase both expression of the AMPA receptor subunit GluR1 and dendritic spines in frontal cortex of young adult but not aging rats. Others have shown that NMDA receptors are reduced in aged cortex. Given the role of NMDA receptors in synaptic plasticity, altered transmission at NMDA receptors may be responsible for the differential cortical plasticity in aging rats. To begin to test this hypothesis, we assessed the effect of NMDA receptor blockade on GluR1 subunit expression and dendritic spine density on pyramidal cells in layer II-III of frontal cortex after either sham or 192 IgG saporin lesions of the NBM. Young adult rats received unilateral sham or 192 IgG saporin lesions of the NBM, along with subscapular implants of osmotic minipumps delivering either MK801 (6 mg/ml; 0.5 μl/h) or phosphate-buffered saline. Two weeks after surgery, rats were euthanized and brains were processed for either immunohistochemical labeling of GluR1 subunit protein or Golgi-Cox histology. To quantify GluR1 expression, an unbiased stereological technique was used to estimate the number of intensely labeled neurons. To quantify spine density, second- and third-order basilar dendrites of Golgi-stained pyramidal cells were drawn and spines were counted. NBM lesions significantly increased both GluR1 expression and spine density, by 83% and 28% respectively. While NMDA blockade alone had no effect, it prevented the lesion-induced increases in GluR1 expression and spine density. Thus, transmission at NMDA receptors may be necessary for synaptic plasticity after cholinergic deafferentation, and age-related changes in NMDA receptors may contribute to altered plasticity of frontal cortex of aging rats.

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On the role of the basal forebrain cholinergic neurons in regulation of recovery sleep

Kalinchuk AV, Stenberg D, Rosenberg PA, Porkka-Heiskanen T (2005) On the role of the basal forebrain cholinergic neurons in regulation of recovery sleep. Neuroscience 2005 Abstracts 308.8. Society for Neuroscience, Washington, DC.

Summary: Basal forebrain (BF) is an critical site in regulation of propensity for sleep (Porkka-Heiskanen et al., 2000; Kalinchuk et al., 2003).We have recently shown that development of recovery sleep after sleep deprivation (SD) might be mediated by release of nitric oxide (NO) in the BF during SD (Kalinchuk et al., 2003; 2004). To further elucidate the role of BF neuronal mechanisms in regulation of NO-mediated recovery sleep we selectively destroyed BF cholinergic neurons and compared effects of SD and pharmacologically increased NO level (induced by NO donor infusion) to the effects observed in intact animals. Male rats were implanted with electrodes for EEG/EMG recording and guide cannulae for microdialysis probes targeting the BF. The experimental schedule for each rat included: recording of natural sleep-waking cycle; SD for 3h; infusion of NO donor (DETA NONOate) for 3h. In separate group of rats immunotoxin 192 IgG-saporin was injected into the BF and the same experimental schedule was performed. After the end of experiments brains were taken for validation of the quality of cholinergic cells lesion and/or probes locations. In all intact rats SD induced significant increase in subsequent NREM sleep by 30.2±3%. Infusion of DETA NONOate into the BF increased sleep by 35.2±4%. Relative delta power was increased by 44.4±8% and 44.1±19%, respectively. After lesion of the BF cholinergic cells recovery NREM sleep after SD was significantly attenuated (9.5±3% increase as compared with baseline). Effect of DETA NONOate infusion was also inhibited (3.1±4% decrease as compared with baseline). Increases in relative delta power were totally abolished. Our data allow to conclude that cholinergic neurons in the BF play an important role in regulation of SD-induced recovery sleep which is mediated by release of NO.

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Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.

Mattsson A, Lindqvist E, Ogren SO, Olson L (2005) Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation. Neuroreport 16(16):1815-1819. doi: 10.1097/01.wnr.0000185018.29316.87

Summary: A potential contribution to schizophrenia is altered cholinergic function. The authors investigated how lesioning cholinergic corticopetal projections might affect glutaminergic activity. Rats were injected with 0.134 µg of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. The authors found that cholinergic lesioning of the neocortex led to enhanced sensitivity to phencyclidine, which has been shown to induce clinical symptoms similar to those of schizophrenia. These data suggest that glutaminergic dysfunction may be relevant to schizophrenia pathophysiology.

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Septal innervation regulates the function of alpha7 nicotinic receptors in CA1 hippocampal interneurons.

Thinschmidt JS, Frazier CJ, King MA, Meyer EM, Papke RL (2005) Septal innervation regulates the function of alpha7 nicotinic receptors in CA1 hippocampal interneurons. Exp Neurol 195(2):342-352. doi: 10.1016/j.expneurol.2005.05.006

Summary: The authors examined whether hippocampal innervation by medial septum/diagonal band of Broca projections is necessary for normal a7 receptor function. 1 µg of 192-Saporin (Cat. #IT-01) was injected into the medial septum of rats. Various methods, including whole-cell patch clamping and immunohistochemistry, were used to evaluate the effects of these lesions. Lesioning with 192-Saporin did not affect a7 receptor currents, indicating that cholinergic neurons are not linked to a7 function.

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Selective acetylcholine and dopamine lesions in neonatal rats produce distinct patterns of cortical dendritic atrophy in adulthood.

Sherren N, Pappas BA (2005) Selective acetylcholine and dopamine lesions in neonatal rats produce distinct patterns of cortical dendritic atrophy in adulthood. Neuroscience 136(2):445-456. doi: 10.1016/j.neuroscience.2005.08.053

Summary: In this work the authors examined lesions of acetylcholine afferents in 7-day-old rat pups, and the effect on dendritic development. 600 ng of 192-IgG-SAP (Cat. #IT-01) were administered to the ventricles of test animals. Various morphological changes in the retrosplenial cortex were observed, including smaller apical tufts and fewer basilar dendritic branches in layer V medial prefrontal cells. The data demonstrate that ascending acetylcholine afferents are very important in the development of cortical cytoarchitecture.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning.

Fontan-Lozano A, Troncoso J, Munera A, Carrion AM, Delgado-Garcia JM (2005) Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning. Learn Mem 12(6):557-563. doi: 10.1101/lm.28105

Summary: Classical conditioning of eyeblink responses can be used to evaluate cognitive deficits. The authors lesioned the medial septum/diagonal band of rats with 200 ng of 192-IgG-SAP (Cat. #IT-01), then examined classical and instrumental conditioning paradigms. Lesioned animals displayed a deficit in the acquisition, but not retrieval of eyeblink classical conditioning. The deficit was reversed by carbachol, a cholinergic muscarinic agonist, suggesting a role for the muscarinic system in the acquisition of new motor abilities.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta.

Hawkes C, Jhamandas JH, Kar S (2005) Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta. J Neurochem 95(1):263-272. doi: 10.1111/j.1471-4159.2005.03363.x

Summary: Glycogen synthase kinase-3ß (GSK-3ß) is an enzyme involved in a variety of biological events. In this study the authors examined the potential role of GSK-3ß in degeneration of basal forebrain cholinergic neurons. Rats were treated with 2.0 µg per ventricle injections of 192-IgG-SAP (Cat. #IT-01), then GSK-3ß and other cholinergic marker levels were assayed. The results indicate that increased GSK-3ß activity can provide some protection from 192-IgG-SAP-induced degeneration of forebrain cholinergic neurons.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Nicotine-induced switch in the nicotinic cholinergic mechanisms of facilitation of long-term potentiation induction.

Yamazaki Y, Jia Y, Hamaue N, Sumikawa K (2005) Nicotine-induced switch in the nicotinic cholinergic mechanisms of facilitation of long-term potentiation induction. Eur J Neurosci 22(4):845-860. doi: 10.1111/j.1460-9568.2005.04259.x

Summary: The authors investigated cellular mechanisms underlying improved cognitive function in Alzheimer’s disease patients upon the administration of nicotine. To model Alzheimer’s disease in rats, 2 µg of 192-IgG-SAP (Cat. #IT-01) was injected into the lateral cerebral ventricle. Examination of the lesioned animals suggests that nicotine promotes the induction of long-term potentiation by enhancing N-methyl-D-aspartate responses, and suppressing acetylcholine-mediated mechanisms in pyramidal cells.

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Autonomic brainstem nuclei are linked to the hippocampus.

Castle M, Comoli E, Loewy AD (2005) Autonomic brainstem nuclei are linked to the hippocampus. Neuroscience 134(2):657-669. doi: 10.1016/j.neuroscience.2005.04.031

Summary: Stimulation of the vagal nerve has been reported to enhance memory, as well as be an effective treatment for epilepsy. The authors examined the underlying synaptic pathway. The right ventral CA1 hippocampal field of rats was lesioned with 42 ng of either anti-DBH-SAP (Cat. #IT-03), or 192-Saporin (Cat. #IT-01). The results indicate that both noradrenergic and cholinergic neurons are relay sites for this pathway.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03)

Susceptibility to seizure-induced injury and acquired microencephaly following intraventricular injection of saporin-conjugated 192 IgG in developing rat brain.

Koh S, Santos TC, Cole AJ (2005) Susceptibility to seizure-induced injury and acquired microencephaly following intraventricular injection of saporin-conjugated 192 IgG in developing rat brain. Exp Neurol 194(2):457-466. doi: 10.1016/j.expneurol.2005.03.002

Summary: It is thought that one mechanism for resistance to seizure-induced injury in immature animals is an abundance of neurotrophic growth factors. Rat pups were treated with 2 µg of 192-Saporin (Cat. #IT-01) injected into the left lateral ventricle to examine how cholinergic basal forebrain projections might affect this type of injury. The results indicate that these neurons may be critical for normal brain growth, and that they play a protective role in preventing excitotoxic neuronal injury.

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Neonatal lesion of forebrain cholinergic neurons: Further characterization of behavioral effects and permanency.

Pappas BA, Payne KB, Fortin T, Sherren N (2005) Neonatal lesion of forebrain cholinergic neurons: Further characterization of behavioral effects and permanency. Neuroscience 133(2):485-492. doi: 10.1016/j.neuroscience.2005.02.040

Summary: Neonatal rats treated with bilateral intracerebroventricular injections of 300 ng of 192-Saporin (Cat. #IT-01) showed basal forebrain cholinergic neuron loss that was still evident at 24 months of age. The authors tested the reference memory and attentional processing of these rats in a Morris water maze. The results suggest that impaired performance of the treated animals in complex maze tasks reflects reduced problem solving ability rather than a deficit in attentional processing.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Aging and cholinergic deafferentation alter GluR1 expression in rat frontal cortex.

Kim I, Wilson RE, Wellman CL (2005) Aging and cholinergic deafferentation alter GluR1 expression in rat frontal cortex. Neurobiol Aging 26(7):1073-1081. doi: 10.1016/j.neurobiolaging.2004.09.005

Summary: Neuronal plasticity is involved in several processes during adulthood, including learning and memory, and recovery from injury. Recent evidence suggests that aging reduces this plasticity. The authors used 0.15 µg injections of 192-Saporin (Cat. #IT-01) into the nucleus basalis magnocellularis of rats to investigate how the loss of cortical plasticity would affect the expression of GluR1. Younger animals displayed a marked increase in the number of GluR1-expressing neurons, a compensatory response not seen in older animals.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Pro- and anti-apoptotic evidence for cholinergic denervation and hippocampal sympathetic ingrowth in rat dorsal hippocampus.

Harrell LE, Parsons DS, Kolasa K (2005) Pro- and anti-apoptotic evidence for cholinergic denervation and hippocampal sympathetic ingrowth in rat dorsal hippocampus. Exp Neurol 194(1):182-190. doi: 10.1016/j.expneurol.2005.02.009

Summary: Cholinergic denervation of the hippocampus results in hippocampal sympathetic ingrowth (HSI) of fibers from the superior cervical ganglion; this ingrowth may exert an anti-apoptotic effect. After 1-µg injections of 192-Saporin (Cat. #IT-01) into the medial septum of rats, the authors investigated the levels of apoptotic protein expression and DNA fragmentation. The findings suggest that cholinergic denervation causes pro-apoptotic responses, but HSI exerts a protective effect against programmed cell death.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Molecular neurosurgery with targeted toxins

Wiley RG, Lappi DA (2005) Molecular neurosurgery with targeted toxins. Humana Press, Totowa, New Jersey.

Summary: The idea behind the book was to provide a road map for the users of Molecular Neurosurgery to see how experienced scientists used these exceptional reagents in their work. Experiments with several targeted toxins are described, and readers can get an idea either specifically about a targeted toxin that they’re using, or about how a type of molecule is used and at what dosage, in a paradigm similar to theirs.

Related Products: 192-IgG-SAP (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), SSP-SAP (Cat. #IT-11), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), IB4-SAP (Cat. #IT-10), CTB-SAP (Cat. #IT-14)

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Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention.

Paban V, Jaffard M, Chambon C, Malafosse M, Alescio-Lautier B (2005) Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention. Neuroscience 132(1):13-32. doi: 10.1016/j.neuroscience.2004.11.024

Summary: In this study the authors examined the effects of 192-Saporin (Cat. #IT-01) administration to the medial septum (37.5 ng/side) and nucleus basalis magnocellularis (75 ng/side) of rats. The results suggest that behavioral deficits immediately after lesioning are due to cholinergic depletion, while deficits later in life may be connected to a gradual degeneration process. Environmental enrichment had a significant positive effect on lesioned rats, indicating a level of cognitive plasticity.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning.

Mohapel P, Leanza G, Kokaia M, Lindvall O (2005) Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26:939-946. doi: 10.1016/j.neurobiolaging.2004.07.015

Summary: New hippocampal neurons that are thought to be involved in memory formation are generated in the dentate gyrus (DG) throughout adulthood. In this study, rats were injected at various sites with 192-Saporin (Cat. #IT-01). The authors found that acetylcholine levels, which are reduced upon administration of 192-Saporin, are linked to proliferation and/or short-term survival of DG neurons, rather than long-term survival or differentiation. Cognitive defects that could be linked to the reduced number of new neurons were also observed.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Compensatory changes in cortical cholinergic innervation in the rat following an immunotoxic lesion.

Hartonian I, de Lacalle S (2005) Compensatory changes in cortical cholinergic innervation in the rat following an immunotoxic lesion. Restor Neurol Neurosci 23(2):87-96.

Summary: The ability of damaged axons to grow and functionally reinnervate damaged areas of the brain is well documented. Here the authors study this process in the context of rats lesioned with 192-Saporin (Cat. #IT-01). 10.5 ng of the immunotoxin was injected into the right horizontal diagonal band of Broca, and animals were examined from 2 to 24 weeks later. Although the functionality of the neuronal ingrowth was not examined, surviving neurons did extend their terminals into the denervated area.

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Basal forebrain cholinergic lesions in 7-day-old rats alter ultrasound vocalisations and homing behaviour.

Scattoni ML, Puopolo M, Calamandrei G, Ricceri L (2005) Basal forebrain cholinergic lesions in 7-day-old rats alter ultrasound vocalisations and homing behaviour. Behav Brain Res 161(1):169-172. doi: 10.1016/j.bbr.2005.01.011

Summary: In this study the authors examined the effects of cholinergic depletion of the basal forebrain on the establishment and maintenance of mother-pup interaction in rats. Post-natal day 7 pups were lesioned with bilateral intracerebroventricular injections of 192-Saporin (0.42 µg, Cat. #IT-01). Treated animals displayed a reduced number of ultrasonic vocalizations, as well as apparent increased difficulty in identifying the nest “boundary.” The evidence shows that early damage to basal forebrain cholinergic nuclei can influence behavior as early as the second-postnatal week.

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Selective cholinergic immunolesioning affects synaptic plasticity in developing visual cortex.

Kuczewski N, Aztiria E, Leanza G, Domenici L (2005) Selective cholinergic immunolesioning affects synaptic plasticity in developing visual cortex. Eur J Neurosci 21(7):1807-1814. doi: 10.1111/j.1460-9568.2005.04014.x

Summary: In this study the authors examined the role of subcortical cholinergic inputs in the regulation of plastic events in the visual cortex during early postnatal development. Four-day-old mouse pups were treated with a total of 0.4 µg of 192-Saporin (Cat. #IT-01), using bilateral injections. Analysis of muscarinic receptor mRNA, long-term potentiation of cortex slices, and theta burst stimulation indicated that synaptic transmission and plasticity of the developing visual cortex depends on cholinergic input.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat.

Winters BD, Bussey TJ (2005) Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat. Eur J Neurosci 21(8):2263-2270. doi: 10.1111/j.1460-9568.2005.04055.x

Summary: The perirhinal cortex of the temporal lobe is crucial to object recognition memory. The authors examined the role of cholinergic input from the basal forebrain in this process. Rats were injected bilaterally with 0.2 µl of 0.02 µg/µl 192-Saporin (Cat. #IT-01) into 3 sites of the perirhinal cortex, and tested in object recognition and spatial working memory tasks. Spatial working memory remained intact, but object recognition was impaired, indicating a specific function for cholinergic input to the perirhinal cortex.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Acetylcholine in the orbitofrontal cortex is necessary for the acquisition of a socially transmitted food preference.

Ross RS, McGaughy J, Eichenbaum H (2005) Acetylcholine in the orbitofrontal cortex is necessary for the acquisition of a socially transmitted food preference. Learn Mem 12(3):302-306. doi: 10.1101/lm.91605

Summary: Cortical involvement in social transmission of food preference (STFP) has not been established, but the importance of the orbitofrontal cortex (OFC) in odor-guided learning is known. The OFC of rats was injected twice with 192-Saporin (Cat. #IT-01), then the rats were trained in STFP. Depletion of cholinergic neurons in the OFC impaired expression of the odor association, indicating that cholinergic function in the OFC is essential for this form of associative learning.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Evaluation of cholinergic markers in Alzheimer’s disease and in a model of cholinergic deficit.

Gil-Bea FJ, Garcia-Alloza M, Dominguez J, Marcos B, Ramirez MJ (2005) Evaluation of cholinergic markers in Alzheimer’s disease and in a model of cholinergic deficit. Neurosci Lett 375(1):37-41. doi: 10.1016/j.neulet.2004.10.062

Summary: Several markers of cholinergic function may be able to predict cognitive deficits due to disorders such as Alzheimer’s disease. The authors compared baseline measurements of acetylcholine, cholinacetyltransferase, and acetylcholinesterase (AChE) of rats against animals treated with 0.067 µg injections of 192-Saporin (Cat. #IT-01) into both hemispheres of the nucleus basalis magnocellularis. The results indicate that measurement of AChE activity is an inexpensive and reliable method to evaluate cholinergic function in rats as well as in humans.

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The effect of central cholinergic and noradrenergic denervation on hippocampal sympathetic ingrowth and apoptosis-like reactivity in the rat.

Harrell LE, Parsons DS, Kolasa K (2005) The effect of central cholinergic and noradrenergic denervation on hippocampal sympathetic ingrowth and apoptosis-like reactivity in the rat. Brain Res 1033(1):68-77. doi: 10.1016/j.brainres.2004.11.021

Summary: Cholinergic denervation of the hippocampus is followed by ingrowth of peripheral sympathetic fibers originating from the superior cervical ganglion. The authors injected 1 µg of 192-Saporin (Cat. #IT-01) into the medial septum of rats along with a noradrenergic fiber neurotoxin to investigate whether the noradrenergic system was involved with this ingrowth as well. The data provide more evidence that hippocampal sympathetic ingrowth can be stimulated by cholinergic denervation alone.

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Hebb-Williams performance and scopolamine challenge in rats with partial immunotoxic hippocampal cholinergic deafferentation.

Marques Pereira P, Cosquer B, Schimchowitsch S, Cassel JC (2005) Hebb-Williams performance and scopolamine challenge in rats with partial immunotoxic hippocampal cholinergic deafferentation. Brain Res Bull 64(5):381-394. doi: 10.1016/j.brainresbull.2004.09.007

Summary: Much of the recent work done on the role of cholinergic neurons in the hippocampus has been focused on detecting subtle learning deficits. In this study, the authors investigated the effect of 0.368 µg of 192-Saporin (Cat. #IT-01) administered to the medial septum of rats in four injections. A complex learning task, the Hebb-Williams maze, was used to define small deficits in the learning performance of the lesioned animals prior to, and after the injection of scopolamine.

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Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm.

Yoder RM, Pang KC (2005) Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm. Hippocampus 15(3):381-392. doi: 10.1002/hipo.20062

Summary: It is thought that hippocampal theta rhythm (HPCθ) is involved in attention and acquisition of sensory information. The HPCθ circuit includes the medial septum/diagonal band of Broca (MSDB), which projects to the hippocampus through GABAergic and cholinergic neurons. A total of 0.325 µg of 192-Saporin (Cat. #IT-01) was injected into the MSDB of rats. Hippocampal recordings measuring field potential oscillations were taken, indicating that both GABAergic and cholinergic neurons are involved in HPCθ.

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No facilitation of amphetamine- or cocaine-induced hyperactivity in adult rats after various 192 IgG-saporin lesions in the basal forebrain.

Jeltsch H, Lazarus C, Cosquer B, Galani R, Cassel JC (2004) No facilitation of amphetamine- or cocaine-induced hyperactivity in adult rats after various 192 IgG-saporin lesions in the basal forebrain. Brain Res 1029(2):259-271. doi: 10.1016/j.brainres.2004.09.053

Summary: Previous data have indicated that intracerebroventricular (icv) injections of 192-Saporin (Cat. #IT-01) induce a dramatic increase of the locomotor response to amphetamine. The authors of this study examined the locomotor effects of several lesions on the response to amphetamine or cocaine. Rats were injected with 5 µg 192-Saporin icv or 0.4 µg bilaterally into the septal region, or 0.4 µg into the nucleus basalis magnocellularis. While the results did not confirm the amphetamine effect, they did suggest that the effect of cocaine can be altered by these lesions.

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Sexually dimorphic effects of hippocampal cholinergic deafferentation in rats.

Jonasson Z, Cahill JF, Tobey RE, Baxter MG (2004) Sexually dimorphic effects of hippocampal cholinergic deafferentation in rats. Eur J Neurosci 20(11):3041-3053. doi: 10.1111/j.1460-9568.2004.03739.x

Summary: Studies of cholinergic neuron lesions have been performed almost exclusively in male animals. In this work, the authors examined the differences of cholinergic lesions between males and females. Rats were treated with four injections totaling 0.15 µg of 192-Saporin (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band. The results demonstrate differences in learning and memory processes between male and female rats.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine.

Ma J, Shen B, Rajakumar N, Leung LS (2004) The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine. Behav Brain Res 155(1):153-166. doi: 10.1016/j.bbr.2004.04.010

Summary: Deficits in sensorimotor gating, suppression of a motor response by a sensory stimulus are found in schizophrenic patients, as well as laboratory animals after administration of compounds such as phencyclidine (PCP). The authors lesioned the cholinergic system of the medial septum in rats with 0.14-0.21 µg injections of 192-Saporin (Cat. #IT-01) to examine the involvement of these neurons in sensorimotor gating. The authors suggest that GABAergic, but not cholinergic septohippocampal neurons mediate this deficit.

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Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates

Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28(7):771-784. doi: 10.1016/j.neubiorev.2004.09.006

Objective: To review current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex.

Summary: A greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.

Usage: Lesions of the cortically projecting cholinergic neurons of the nucleus basalis magnocellularis made using excitotoxins, or the highly selective cholinergic immunotoxin 192 IgG-SAP, generally impair discriminative performance.

Related Products: 192-IgG-SAP (Cat. #IT-01)

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Septohippocampal cholinergic lesion and hippocampal alpha-secretase activity in rat

Pokala VN, Fitz NF, Witt-Enderby PA, Johnson DA (2004) Septohippocampal cholinergic lesion and hippocampal alpha-secretase activity in rat. Neuroscience 2004 Abstracts 846.14. Society for Neuroscience, San Diego, CA.

Summary: Previously we have shown that selective cholinergic lesion of the septohippocampal pathway in the rat resulted in a significant decrease in hippocampal extracellular acetylcholine (ACh) concentration, a compensatory increase in muscarinic receptor binding, but a decrease in muscarinic receptor-coupled G protein activation. The intent of this study was to investigate the effect of selective cholinergic lesion of the septohippocampal pathway on hippocampal alpha-secretase activity and expression. Alpha-secretase is an enzyme responsible for the proteolytic cleavage of amyloid protein precursor (APP) to release a neuroprotective soluble amyloid protein precursor (sAPP). Sprague-Dawley rats were infused into the medial septum with either the selective cholinergic immunotoxin 192 IgG-saporin (0.22 mg in 1ml aCSF) or vehicle. After 6 weeks the rats were euthanized and the hippocampus dissected from the brain and quickly frozen. Hippocampal homogenate was analyzed for alpha-secretase activity and expression. The results demonstrated an 80% decrease in alpha-secretase activity in SAP treated animals compared to control.

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Modulation of late long-term potentiation in the hippocampus: Effect of cholinergic and GABAergic medial septal lesions

Montoya DA, Pang K (2004) Modulation of late long-term potentiation in the hippocampus: Effect of cholinergic and GABAergic medial septal lesions. Neuroscience 2004 Abstracts 972.12. Society for Neuroscience, San Diego, CA.

Summary: Long Term Potentiation (LTP) is an endurable change in synaptic efficacy produced by brief repetitive stimulation of specific afferents and is a cellular model of long term memory. The duration of LTP can vary depending on the intensity fo the inducing tetanic stimulation, which reflects the different phases of LTP. Early phase LTP does not require protein synthesis, whereas late-phase LTP is dependent on protein synthesis. Modulating transmitter systems may also be important in the conversion of early-phase to late-phase LTP. In previous studies, stimulation of the medial septum (MS) converted an early-phase LTP to a late-phase LTP in the dentate gyrus. These results suggest that cholinergic or GABA septohippocampal neurons may be important in late-phase LTP. The present study will evaluate whether cholinergic or GABAergic septohippocampal neurons are important in the development of long-lasting LTP after MS stimulation. LTP will be assessed in urethane anesthetized rats with prior intraseptal saline, 192 IgG-saporin (SAP; 0.245 micrograms/microliter) or kainic acid KA; 0.5 microgram/microliter) treatment. 192 IgG-saporin selectively destroys cholinergic MS neurons, while kainic acid preferentially damages GABAergic septohippocampal neurons. In preliminary studies, 5 trains of perforant path stimulation (15 pulses at 400 Hz/train) produced a transient LTP of the dentate population spike in urethane anesthetized rats. In this preparation, LTP lasted for about 90 minutes. In future experiments, we will assess whether late-phase LTP develops in the urethane anesthetized rats with MS stimulation followed by perforant path stimulation trains. If this occurs, rats with cholinergic or GABAergic MS lesions will be evaluated.

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Cell-body lesions of basal forebrain impair reversal learning but not attentional set-shifting in rats

Tait DS, Brown VJ (2004) Cell-body lesions of basal forebrain impair reversal learning but not attentional set-shifting in rats. Neuroscience 2004 Abstracts 779.12. Society for Neuroscience, San Diego, CA.

Summary: There is considerable evidence for a role of basal forebrain acetylcholine in a wide range of attentional tasks (see Sarter & Bruno, 2000, Neurosci, 95:933-952), but previous work from this laboratory found that basal forebrain cholinergic projections are not critical for the acquisition, maintenance and shifting of attentional set (Tait et al, 2002 SfN abstr 286.2). As GABAergic basal forebrain projections to cortex may be important for “cognitive flexibility” (Sarter & Bruno, 2002, Eur J Nsci, 15:1867-1873), the present study assessed the effects of non-specific basal forebrain lesions. Male Lister hooded rats received infusions of 200nl 0.06M ibotenic acid into basal forebrain, at coordinates: nosebar –3.3; AP –0.9; ML ±2.9; DV –6.9. We used the rat attentional-set shifting task (Birrell & Brown, 2000, JNsci, 20:4320-4324), in which rats forage in digging bowls for food rewards, to assess discrimination learning (based on the odor of the bowls or the medium in which the food was hidden), reversal learning and attentional-set shifting (when the relevant aspect of the stimulus is switched; for example, a rat previously attending to odor, now must attend to digging medium or vice versa). There was no impairment in discrimination acquisition or in shifting of attentional-set. Lesioned rats were impaired only on the first of three discrimination reversals, taking significantly longer to reach criterion than controls. Prior evidence indicating no effect of selective BF cholinergic depletion via 192-IgG-saporin administration on reversal performance (Tait et al, 2002) leads us to conclude that the non-cholinergic neurons – most likely the GABAergic projection to prefrontal cortex and thalamus – have an important role in reversal learning. These data are strikingly similar to the effects of excitotoxic basal forebrain lesions in monkeys (Roberts et al, 1992, NSci, 472:251-264).

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Attention, uncertainty, and acetylcholine: Effects of nucleus basalis cholinergic lesions on probabilistic inference

Cordova CA, Yu AJ, Chiba AA (2004) Attention, uncertainty, and acetylcholine: Effects of nucleus basalis cholinergic lesions on probabilistic inference. Neuroscience 2004 Abstracts 779.13. Society for Neuroscience, San Diego, CA.

Summary: Animal investigations suggest that the basal forebrain corticopetal cholinergic system helps to regulate attention to unpredictable events. In light of these findings, computational theorists propose that cholinergic neurons precisely alter the way that sensory stimuli are processed in the cortex in light of how well predicted they are. In an initial test of this theory, two groups of rats were trained to respond to probabilistic stimuli presented serially in one of four spatial locations with varying degrees of predictive uncertainty (arising from a 2-layer Hidden Markov model). Following training, one group of rats was given a selective cholinergic lesion of the nucleus basalis/substantia innominata region of the basal forebrain using 192-IgG Saporin. The lesioned rats were unable to allocate attention appropriately, as evidenced by the decreased accuracy of responses to less probable stimuli. These findings provide support for the notion that the basal forebrain corticoptetal cholinergic system facilitates attention by regulating the balance of learned expectations and sensory processing during stimulus inference.

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Hippocampal Arc and Homer 1a expression in behaviorally characterized 192 IgG-saporin lesioned rats

Fletcher BR, Guzowski JF, Baxter MG, Shapiro ML, Rapp PR (2004) Hippocampal Arc and Homer 1a expression in behaviorally characterized 192 IgG-saporin lesioned rats. Neuroscience 2004 Abstracts 436.4. Society for Neuroscience, San Diego, CA.

Summary: Fornix lesions impair hippocampal dependent learning and block behavioral induction of the immediate-early gene Arc. The present experiment tested the role of cholinergic innervation in the transcriptional induction of the activity related immediate-early genes Arc and Homer 1a. 192 IgG-saporin or vehicle was injected into the medial septal nucleus and vertical diagonal band. Behavioral characterization on cued and spatial delayed match-to-place tasks in a radial arm water maze revealed an impairment in cognitive flexibility, but not spatial memory in lesioned animals. Immediately after animals explored two novel environments their brains were processed for fluorescence in situ hybridization with probes for Arc and Homer 1a to reveal the recent activation history of individual neurons. Confocal stereological quantification of labeling in the CA1 and CA3 cell fields of the hippocampus revealed no dramatic difference in number of positive cells between groups. These results show that, unlike fornix lesions, cholinergic denervation of the hippocampus is not sufficient to block behavioral activation of Arc or Homer 1a transcription. Therefore, cholinergic innervation is not required for Arc or Homer 1a expression.

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192 IgG-saporin lesions of the nucleus basalis magnocellularis impair biconditional discrimination learning in rats

Kitto MR, Carbrera S, Corley S, Castillo A, Atkinson M, Andrews C, Casteneda M, Crawford D, Iliscupidez M, Monahan R, Rodriguez D, Salley T, Butt AE (2004) 192 IgG-saporin lesions of the nucleus basalis magnocellularis impair biconditional discrimination learning in rats. Neuroscience 2004 Abstracts 436.5. Society for Neuroscience, San Diego, CA.

Summary: Previous results from our laboratory suggest that the cholinergic nucleus basalis magnocellularis (NBM) is involved in configural association learning but not in simple association learning. In the current experiment, we hypothesized that 192 IgG-saporin lesions of the NBM in rats would impair biconditional visual discrimination learning, which requires configural association learning. In contrast, we hypothesized that NBM lesions would not impair acquisition of a simple visual discrimination, which requires only simple association learning. In Problem 1, rats were trained in a T-maze to solve a simple visual discrimination between a food-reinforced black goal arm (B+) and a non-reinforced white arm (W-), where the start arm of the maze was always striped (S). Next, in Problem 2, the reinforcement contingencies of the goal arms were reversed (W+ vs. B-), and the start arm visual cue was changed to gray (G). Finally, rats underwent biconditional discrimination training where half of the trials were of Problem 1 type and half were of Problem 2 type. Separately, Problems 1 (S: B+ vs W-) and 2 (G: W+ vs B-) can be solved using simple associations. However, in the biconditional discrimination, where Problems 1 and 2 are intermixed, configural association learning is required. Preliminary results supported our hypotheses. Acquisition of Problems 1 and 2, the simple association problems, did not differ between the NBM lesion group and the control group. However, performance in biconditional discrimination was impaired in the NBM lesion group compared to controls. These results are consistent with the argument that the NBM is involved in configural but not simple association learning.

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Effects of neonatal cholinergic lesions on fear conditioning in 18-day-old rats

Ricceri L, Scattoni ML, Cutuli D, Calamandrei G (2004) Effects of neonatal cholinergic lesions on fear conditioning in 18-day-old rats. Neuroscience 2004 Abstracts 436.9. Society for Neuroscience, San Diego, CA.

Summary: We have previously shown that neonatal intracerebroventricular (icv) injections of the selective cholinergic immunotoxin 192 IgG-saporin on postnatal day (pnd) 7 induces behavioural alterations already detectable in the third postnatal week. In the present study we injected 192 IgG-saporin icv, in the nucleus basalis magnocellularis (nbm) or in the medial septum (ms) in 7-day-old rats and we then analysed fear conditioning on pnd 18. Fear conditioning to both auditory cue and environmental context was evident in both control and lesioned rats on pnd 18. However, conditioning to the environmental context (measured by freezing duration) was significantly more marked in icv and MS lesioned rats, whereas no effect of the cholinergic lesion was evident on conditioning to the auditory cue. These results suggest that neonatal removal of the cholinergic input to the hippocampal region paradoxically facilitates processing of spatial information in young rats.

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Electrophysiological profile of IgG192saporin-lesioned rats in the pilocarpine model of epilepsy

Benassi SK, Blanco MM, Mello LE (2004) Electrophysiological profile of IgG192saporin-lesioned rats in the pilocarpine model of epilepsy. Neuroscience 2004 Abstracts 452.14. Society for Neuroscience, San Diego, CA.

Summary: In order to investigate the importance of the basal forebrain cholinergic reorganization to the epileptogenesis process, adult male Wistar EPM-1 rats (180-220g) were subjected to status epilepticus (SE) induction by pilocarpine injection (320mg/kg, i.p.), after cholinergic lesion through IgG192-saporin (5μg/5μL, i.c.v.). Two months after SE induction animals were deeply anesthetized (choral hydrate 400 mg/kg, i.p.) and subjected to the electrical stimulation of the right CA3 and recorded (3M NaCl, 1MΩ) in the contralateral (left) CA1 region. Histological analysis included Nissl staining for the location of stimulating and recording electrodes and histochemistry for acetylcholinesterase (AChE) for the assessment of IgG192-induced lesions. The administration of the IgG192-saporin consistently and specifically diminished AChE staining in the hippocampus and neocortex while not affecting other brain areas (e.g., amygdala, striatum, etc). As compared to naive control animals, pilocarpine-treated animals generally showed loss of paired-pulse inhibition and the presence of multiple population spikes. Epileptic animals that were pre-treated with the cholinergic toxin did not differ from untreated epileptic animals in terms of paired-pulse inhibition or the presence of multiple population spikes. Large paired-pulse facilitation (P2>10 P1) for interstimulus intervals varying from 20 to 200 ms was encountered for both groups of epileptic animals with no distinction between each other. We suggest that the basal forebrain cholinergic system does not have a major role in defining the hyperexcitability of hippocampal circuits in the pilocarpine model of epilepsy.

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Effects of cholinergic deafferentation of prefrontal cortex on working memory: A convergence of behavioral and modeling results

McGaughy JA, Koene R, Eichenbaum HB, Hasselmo ME (2004) Effects of cholinergic deafferentation of prefrontal cortex on working memory: A convergence of behavioral and modeling results. Neuroscience 2004 Abstracts 551.7. Society for Neuroscience, San Diego, CA.

Summary: In humans, the prefrontal and medial temporal lobe areas are differentially activated during working memory dependent upon the whether stimuli are familiar or novel. Prefrontal activation occurs with highly familiar stimuli whereas the medial temporal lobe is activated by novel stimuli (Stern, et al. Hippocampus v. 11, 2001). The maintenance of novel information in the entorhinal cortex (EC) is hypothesized to depend upon self-sustained spiking activity in single neurons produced by cholinergic activation of muscarinic receptors (Klink and Alonso, J. Neurophys. 77, 1997). The current study investigated whether cholinergic modulation of the prefrontal cortex regulates sustained spiking activity for familiar stimuli. Rats were trained in an odor-cued delayed non-matching to sample task. After reaching asymptotic performance, rats were infused bilaterally with either 192 IgG-saporin (SAP) or its vehicle into the prefrontal cortex(PFC;0.01μg/μl;1.0μl/injection). Following PFC-SAP lesions,rats were impaired in working memory with highly familiar odors when choice stimuli were probed sequentially but not simultaneously. Though PFC-SAP rats reliably sampled both choices, they failed if the first cup probed matched the sample. PFC-SAP rats were also unable to maintain multiple items in memory. These impairments cannot be explained by the loss of response inhibition, the conditional response rule, attentional or sensory abilities. It is hypothesized that in the absence of a functional frontal cortex, the PFC-SAP rats relied on the EC. Computational modeling of EC suggests repetitions of an odor or the presentations of multiple odors disrupt the pattern of self-sustained spiking in this area and, thus, the representation of the stimulus. These data elucidate the interplay between the PFC and EC during a working memory task.

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Impact of 192 IgG-saporin medial septum lesions on working memory

Pizzo DP, Samadzadeh L, Thal LJ, Frielingsdorf H (2004) Impact of 192 IgG-saporin medial septum lesions on working memory. Neuroscience 2004 Abstracts 436.1. Society for Neuroscience, San Diego, CA.

Summary: It is generally believed that cholinergic input to the hippocampus (hpc) is involved in learning and memory. The objective of the present study was to clarify whether working memory as assessed by the Morris water maze (mwm) is impaired by selective lesions of the cholinergic cells in the medial septum in adult male rats using 75 ng192IgG-saporin per side. Two weeks post-lesion, naive and lesioned rats were trained in the mwm task focusing on working memory, which was tested using a new platform location every day. The difference (improvement) in latency between trial 1 and 2 was used as an index of working memory function. Nine different platform locations were tested. The locations yielding the highest group difference were retested, with increasing intertrial intervals (ITI) from 30 min to 24 h between the 1st and 2nd trial. In a majority of the trial blocks there was a trend suggesting that lesioned rats had impaired working memory, however there was no consistent significant difference between groups in any of the tasks. To potentially further separate the groups rats were then infused with nerve growth factor (NGF; 5 µg/day), or vehicle into the ventricular system. After 17 days of infusion working memory was retested, however NGF treatment did not affect performance. The lesions were complete as measured by loss of choline acetyltransferase activity (ChAT) to less than 10% of levels of the naive, vehicle treated rats. NGF infusion increased hpc ChAT activity in naive but not in lesioned rats. In conclusion, selectively reducing ChAT activity by more than 90% in the hpc is not sufficient to significantly impair working memory as assessed by the mwm. We cannot exclude that a more sensitive working memory task would reveal a deficit in the lesioned animals, however it is also possible that intact septohippocampal cholinergic projections are not crucial for working memory function.

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Cholinergic basal forebrain lesions disrupt acquisition of cued and uncued differential reinforcement of low rate responding

Corley SR, Atkinson M, Cabrera S, Castillo A, Crawford D, Kitto M, Butt AE (2004) Cholinergic basal forebrain lesions disrupt acquisition of cued and uncued differential reinforcement of low rate responding. Neuroscience 2004 Abstracts 436.10. Society for Neuroscience, San Diego, CA.

Summary: The frontal cortex, medial septum/vertical diagonal band (MS/VDB), and hippocampus have been implicated in supporting differential reinforcement of low rate responding (DRL) behavior in rats. Because the frontal cortex and hippocampus receive cholinergic input from the basal forebrain, we hypothesized that 192 IgG-saporin (SAP) lesions of the basal forebrain would disrupt DRL acquisition in the current experiment. To distinguish between potential deficits in timing, as opposed to impairments in response inhibition, we trained rats in either the standard DRL task (which requires both timing of behavior and response inhibition) and on a cued version of the task (which does not require the ability to time behavior but does require response inhibition). Rats were first shaped to bar press before receiving either bilateral SAP lesions of the basal forebrain or sham lesions. Rats were returned to bar press training for 5 more days. Rats were then shifted to a DRL 20 s, LH 10 s (limited-hold 10 s) schedule of reinforcement. Half of the rats were provided with a cue light signaling the availability of reinforcement, whereas the other half underwent standard DRL 20 s LH 10 s testing without the visual cue. Rats with basal forebrain lesions showed a transient impairment in response inhibition in both the standard and the cued version of the DRL task. Both lesion groups made more responses at short inter-response-intervals than controls across the first 15 test days, although this impairment attenuated by the 20th test day. These data suggest that the cholinergic basal forebrain is involved in learning to withhold responding during acquisition in DRL.

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Effect of dehydroepiandrosterone sulfate on retention in passive avoidance in septal hippocampal cholinergic lesioned rats

Arshad S, Li P, Fitz NF, Johnson DA (2004) Effect of dehydroepiandrosterone sulfate on retention in passive avoidance in septal hippocampal cholinergic lesioned rats. Neuroscience 2004 Abstracts 436.11. Society for Neuroscience, San Diego, CA.

Summary: Infusions of 192 IgG-saporin (SAP) into the medial septum (MS) selectively destroys cholinergic neurons projecting to the hippocampus. Our previous study demonstrated that this lesion impairs retention but not acquisition of a passive avoidance (PA) task in rats. The present study determined whether the neurosteroid Dehydroepiandrosterone sulfate (DHEAS) (0, 1, 3, 10, 30 mg/ml) could reverse SAP induced impairments of PA retention. Male Sprague-Dawley rats were administered either SAP (.22μg/μl) or vehicle directly into the MS. Passive Avoidance training began 2 weeks later. Training consisted of placing the animal into the lighted chamber of the apparatus and then delivering a foot shock (.75mA, 1 sec), when the animal moved into the adjacent darkened chamber. Training was repeated until the animal avoided the dark chamber for 2 consecutive trials of 2 minutes duration. Retention (latency to crossover to the dark chamber) was tested after seven days. DHEAS was administered one hour prior to retention testing. Results showed a dose dependent increase in crossover latency in SAP treated animals. DHEAS treatment in control animals, however, resulted in a dose dependent decrease in crossover latency. Thus, DHEAS attenuated the impairment in retention in SAP treated animals with hippocampal cholinergic hypofunction, but impaired retention in cholinergically intact rats in PA.

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Effects of dehydroepiandrosterone sulfate on delayed match to position T-maze task performance in 192- IgG saporin lesioned rats

Fitz NF, Li P, Johnson DA (2004) Effects of dehydroepiandrosterone sulfate on delayed match to position T-maze task performance in 192- IgG saporin lesioned rats. Neuroscience 2004 Abstracts 436.2. Society for Neuroscience, San Diego, CA.

Summary: Prior studies have shown that infusion of 192 IgG-saporin (SAP), a cholinergic neurotoxin, into the media septum (MS) of rats selectively lesions cholinergic neurons that project to the hippocampus, resulting in impaired acquisition of a delayed matching to position (DMP) T-maze task. Since the neurosteriod dehydroepiandrosterone sulfate (DHEAS), displayed memory enhancing properties in rodents, the present study investigated the effects of DHEAS administration on MS SAP lesioned animals. Male Sprague-Dawley rats received intraseptal infusions of either cerebrospinal fluid or SAP (0.22 μg/μl). Fourteen days later, the rats were administered IP injections of either DHEAS (20mg/ml) or vehicle one hour prior to DMP testing. During the acquisition phase of testing, each rat completed 8 trial pairs per day until reaching criterion (15 of 16 correct choices). Treatment with DHEAS resulted in a 10% shortening of the number of days to reach criterion in the SAP treated animals compared to SAP non-treated animals.

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Neuronal correlates of signal detection in rat posterior parietal cortex

Broussard JI, Sarter M, Givens B (2004) Neuronal correlates of signal detection in rat posterior parietal cortex. Neuroscience 2004 Abstracts 331.6. Society for Neuroscience, San Diego, CA.

Summary: The posterior parietal cortex (PPC) has been shown to be involved in the attentional processing of visual stimuli. Recent evidence has indicated that neuronal activity in the PPC is increased during the detection of signals, and this activation is modulated by visual distractors. We tested the hypothesis that detected signals are associated with increased PPC unit activity. Animals were trained in a sustained attention task using signal and nonsignal trials. After training to criterion (>75% accuracy), we implanted moveable stereotrodes into the PPC. A visual distractor was presented in a block of trials during testing sessions and effects on performance and single unit activity were examined. We also evaluated the effects of varying signal duration on performance and single unit activity. PPC neurons (39/111) exhibited a significantly greater response during signal trials than during nonsignal trials. The presentation of visual signals produced a robust increase in neuronal activity prior to the performance of a hit, but not prior to a miss, both of which required a lever press. Analysis of signal duration indicated that shorter signals resulted in fewer hits. PPC neurons became active when the signal was accurately detected, independent of signal duration. Shorter signals activated the PPC on fewer trials, which was associated with a lower likelihood for detection. The visual distractor reduced both the signal-driven unit activity and the relative number of hits. These findings suggest that activation of the PPC is associated with the detection of visual signals. We are currently investigating the effects of local cholinergic deafferentation (via 192 IgG saporin) on signal driven neuronal activity in the PPC. These studies will elucidate the contribution of basal forebrain cholinergic innervation to attentional processing in the PPC.

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Estrogen supports structural plasticity of the basal forebrain cholinergic system in vivo

Saenz C, Dominguez R, de Lacalle S (2004) Estrogen supports structural plasticity of the basal forebrain cholinergic system in vivo. Neuroscience 2004 Abstracts 72.11. Society for Neuroscience, San Diego, CA.

Summary: It is known that estrogen (E2) modulates the structural plasticity of a variety of neurons, involving the activation of second messenger systems. We have previously described a strong E2-induced outgrowth in cholinergic neurons in vitro, and in the present study we follow up those results and examine E2’s ability to enhance cholinergic arborization in vivo, under several conditions. Twenty F344 female rats were used, 10 of them gonadectomized. All the rats received a unilateral lesion (200 nl of 192 IgG-saporin) into the left HDB, and a month later were randomly assigned to receive E2 or placebo via s.c. pellets for 60 days, at which point the rats were sacrificed, the brains prepared for histology and series of sections stained with an antibody against p75NTR. Sections were carefully matched across individuals, 10 neurons selected from both lesioned and intact HDB, and photographed. Neurons were chosen from the same area in all cases, located in the periphery of the HDB, where the neuritic arborization could be easily identified. Image analysis was performed using Metamorph software, on a predetermined set of parameters. Each image was the result of a stack of photographs taken at 2 µm intervals through the depth of the section. We compared mean neurite number per neuron and total neurite length per neuron, and found that in the healthy cholinergic neurons (control side), E2 contributed to a significant increase in neurite length and number. By contrast, no effect was found on cholinergic neurons from the lesioned side, showing that E2 cannot reverse the neuronal degeneration induced by the immunotoxin. These results are important in that they provide additional support to the hypothesis that E2 may be beneficial in preventing cholinergic degeneration, but no longer useful once neuronal damage has occurred.

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Loss of basal forebrain cholinergic neurons by 192 igG-Saporin induces increased IGF-II/M6P receptor expression in select brain areas

Hawkes CA, Kar S (2004) Loss of basal forebrain cholinergic neurons by 192 igG-Saporin induces increased IGF-II/M6P receptor expression in select brain areas. Neuroscience 2004 Abstracts 92.1. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is characterized neuropathologically by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss in selected brain areas, including basal forebrain cholinergic neurons, which project to the hippocampus and neocortex. Increasing evidence supports a role of the endosomal-lysosomal (EL) system in the pathophysiology of AD. A key component of the EL system is the insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor, a single transmembrane domain glycoprotein which functions in the intracellular trafficking of lysosomal enzymes, and in the internalization of extracellular IGF-II and M6P-containing ligands. However, very little is known about the functional significance of this receptor in the brain. We examined expression of the IGF-II/M6P receptor and other markers of the EL system, at different time points following bilateral i.c.v. injection of 192 IgG-saporin. 192 IgG-saporin produced an almost complete loss of ChAT-positive neurons in the basal forebrain, as well as fibers in the hippocampus and frontal cortex, while striatal cholinergic neurons were unaffected. Western blotting and immunocytochemistry results indicate an upregulation of IGF-II/M6P receptor levels in the septum and frontal cortex. A modest increase was also observed in cathepsin D levels. The level of other EL markers, such as Rab5 and LAMP1, showed varied temporal and spatial changes. These results suggest that brain areas innervated by basal forebrain neurons, respond differently to the loss of cholinergic input and that elements of the EL system may be involved in cholinergic degeneration/compensatory responses of surviving neurons.

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Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin induces activation of glycogen synthase kinase-3β activity

Kar S, Hawkes C, Jhamandas JH (2004) Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin induces activation of glycogen synthase kinase-3β activity. Neuroscience 2004 Abstracts 92.2. Society for Neuroscience, San Diego, CA.

Summary: Glycogen synthase kinase-3β (GSK-3β) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is negatively regulated by phosphorylation of Ser9 and upregulated by Tyr216 phosphorylation. Activation of GSK-3β induces apoptosis in a variety of cultured neurons and the inhibitory control of its activity by Akt kinase is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192-IgG saporin was used to address the potential role of GSK-3β in the degeneration of the basal forebrain cholinergic neurons which are preferentially vulnerable in Alzheimer’s disease (AD) brain. Our results show that GSK-3β colocalizes with a subset of the forebrain cholinergic neurons and that loss of these neurons is accompanied by a transient decrease in phospho-Akt and phospho-Ser9 GSK-3β levels in the basal forebrain, hippocampus and the cortex. Neither total Akt, GSK-3β, nor phospho-Tyr216 GSK-3β levels were significantly altered in the aforesaid brain regions of treated animals. These results provide the very first evidence that increased GSK-3β activity is associated with in vivo degeneration of the forebrain cholinergic neurons and thus may be involved in the loss of these neurons as observed in AD brains.

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Neurotrophic modulation of cholinergic denervation and hippocampal sympathetic ingrowth following immunolesioning with 192 IgG-saporin

Kolasa K, Parsons D, Conger K, Harrell LE (2004) Neurotrophic modulation of cholinergic denervation and hippocampal sympathetic ingrowth following immunolesioning with 192 IgG-saporin. Neuroscience 2004 Abstracts 92.9. Society for Neuroscience, San Diego, CA.

Summary: Injection of specific cholinotoxin, 192 IgG-saporin into the medial septum (MS)of rat induces not only a selective cholinergic denervation of hippocampus (CD),but an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion,into the hippocampus (HSI).A similar process,in which sympathetic noradrenergic axons invade hippocampus,may also occur in Alzheimer’s disease(AD). The severity of cognitive decline in AD patients has been linked to multiple factors including cholinergic and neurotrophic factors and their receptors, which undergo selective alterations throughout the progression of AD.It is known that the sites of neurotrophin synthesis in the septo-hippocampal system are predominantly hippocampal neurons. By using 192 IgG-saporin we have been able to mimic some of the cardinal features of AD e.x.cholinergic denervation and hippocampal sympathetic ingrowth and study their effect on growth factors in dorsal hippocampus. Thus,12 weeks after injection of 192 IgG-saporin we measured neurotrophic protein and mRNA expression using Western blot and RT-PCR techniques,respectively. Choline acetyltransferase activity(ChAT)and norepinephrine(NE) concentration was also detected.There was no change in NGF,BDNF,NT3,GDNF mRNA expression,but we have found significant decrease in 240 bp and increase in 328 bp of persephin mRNA expression in CD, and “normalization” in HSI group. No significant alteration was found in NGF and persephin protein expression, but significant decrease in mature form of BDNF protein expression was found in CD, with “normalization”in HSI group.Results of the study suggest that growth factors are affected by cholinergic denervation and may play an important role in regulation and development of HSI,which might be a beneficial phenomenon for restoration of at least some cognitive function.

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Sound sequence discrimination learning is dependent on cholinergic inputs to the rat auditory cortex.

Kudoh M, Seki K, Shibuki K (2004) Sound sequence discrimination learning is dependent on cholinergic inputs to the rat auditory cortex. Neurosci Res 50(1):113-123. doi: 10.1016/j.neures.2004.06.007

Summary: The auditory cortex (AC) is thought to play a role in the discrimination of sound sequences. The authors investigated the role of cholinergic inputs to the AC in processing these sequences by injecting 5 µg of 192-Saporin (Cat. #IT-01) into either the lateral ventricle or bilateral AC of rats. Treated animals displayed suppressed sound discrimination learning, but discrimination between two sound components was unaffected. The results suggest that cholinergic neurons in the AC are highly involved in sound sequence learning.

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Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats.

Ricceri L, Minghetti L, Moles A, Popoli P, Confaloni A, De Simone R, Piscopo P, Scattoni ML, di Luca M, Calamandrei G (2004) Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats. Exp Neurol 189(1):162-172. doi: 10.1016/j.expneurol.2004.05.025

Summary: A distinctive feature of Alzheimer’s disease is the loss of cholinergic neurons in the basal forebrain (BF). The authors investigated long-term effects of BF cholinergic lesions on several parameters. Administration of 0.21 µg of 192-Saporin (Cat. #IT-01) to the third ventricle of 7 day-old rats was followed by an evaluation of protein levels and cortical EEG patterns at 6 months of age. The findings indicate that permanent neonatal BF cholinergic damage may provide a model for abnormal adult cholinergic function.

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Age-dependent effect of cholinergic lesion on dendritic morphology in rat frontal cortex.

Works SJ, Wilson RE, Wellman CL (2004) Age-dependent effect of cholinergic lesion on dendritic morphology in rat frontal cortex. Neurobiol Aging 25(7):963-974. doi: 10.1016/j.neurobiolaging.2003.08.003

Summary: Aged rats display more dramatic and longer lasting effects due to brain injury than young animals. The authors examined the role cholinergic neurons may play in brain plasticity after injury in rats of varying ages. 0.15 µg of 192-Saporin (Cat. #IT-01) was injected into the nucleus basalis magnocellularis of young, middle-aged, and aged rats. Some types of injury were only seen in middle-aged and aged rats, and changes in dendritic morphology were least marked in the young animals.

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Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation.

Gil-Bea FJ, Dominguez J, Garcia-Alloza M, Marcos B, Lasheras B, Ramirez MJ (2004) Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation. Neuropharmacology 47(2):225-232. doi: 10.1016/j.neuropharm.2004.03.014

Summary: Previous studies from this group demonstrated that 5-HT(3) receptor antagonists potentiated by GABA(A) antagonists increased acetylcholine (ACh) release in the rat cerebral cortex. This series of experiments investigated the effects of these antagonists on rats with 0.067 µg-bilateral infusions of 192-Saporin (Cat. #IT-01) into the nucleus basalis magnocellularis. Even after lesioning with 192-Saporin, rats treated with the 5-HT(3) and GABA(A) receptor antagonists displayed increased ACh release, indicating that these antagonists may have use as treatments for cognitive disorders.

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Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-Saporin-induced lesions of the medial prefrontal cortex.

Dalley JW, Theobald DE, Bouger P, Chudasama Y, Cardinal RN, Robbins TW (2004) Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-Saporin-induced lesions of the medial prefrontal cortex. Cereb Cortex 14(8):922-932. doi: 10.1093/cercor/bhh052

Summary: Prior work has demonstrated that lesions of the cortical cholinergic system of the basal forebrain impair performance in attentional tasks. The authors examined the effects of selective depletion of acetylcholine from the prefrontal cortex (PFC) on these same attentional tasks. 50 or 100 ng of 192-Saporin (Cat. #IT-01) was infused into the PFC of rats. Treated animals displayed deficits in specific aspects of the attentional tasks, indicating a modulatory role in PFC function by basal forebrain cholinergic neurons.

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Decreased neurogenesis after cholinergic forebrain lesion in the adult rat.

Cooper-Kuhn CM, Winkler J, Kuhn HG (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res 77(2):155-165. doi: 10.1002/jnr.20116

Summary: Adult mammalian brains can produce new neurons, mainly in two areas: the interconnected system of the lateral ventricle and the olfactory bulb, and the dentate gyrus of the hippocampus. The authors used a 3.5 µg-injection of 192-Saporin (Cat. #IT-01) into the right ventricle of rats to determine whether cholinergic input is necessary for adult neurogenesis. The results suggest that acetylcholine, a product of cholinergic neurons, is necessary for the survival of newly-formed neurons.

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Selective lesioning of the cholinergic septo-hippocampal pathway does not disrupt spatial short-term memory: a comparison with the effects of fimbria-fornix lesions.

Winters BD, Dunnett SB (2004) Selective lesioning of the cholinergic septo-hippocampal pathway does not disrupt spatial short-term memory: a comparison with the effects of fimbria-fornix lesions. Behav Neurosci 118(3):546-562. doi: 10.1037/0735-7044.118.3.546

Summary: The authors wished to investigate the role of the cholinergic system of the basal forebrain in delayed matching (DMTP)- and nonmatching (DNMTP)-to-position tasks after bilateral injections of 0.035 µg of 192-Saporin (Cat. #IT-01) into the dorsal and ventral hippocampus. The treated animals were compared to rats given fimbria-fornix (FF) lesions. Only the FF-lesioned animals showed impairment on DMTP and DNMTP tasks, demonstrating that the cholinergic septohippocampal system is not required for successful DMTP or DNMTP performance.

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Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone.

Blanco-Centurion C, Gerashchenko D, Salin-Pascual RJ, Shiromani PJ (2004) Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone. Eur J Neurosci 19(10):2741-2752. doi: 10.1111/j.0953-816X.2004.03366.x

Summary: Narcolepsy is linked to the loss of orexin (or hypocretin)-containing neurons in the brain. These neurons are located in the perifornical region of the posterior hypothalamus and innervate the locus coeruleus (LC). To investigate the role of the LC in sleep the authors injected 0.3 µl of 192-Saporin (Cat. IT-01) or anti-DBH-SAP (Cat. #IT-03) at 1 µg/µl. They also used 0.3 µl of orexin-SAP (Cat. #IT-20) at either 90 ng/µl or 60 ng/µl in a separate group of animals. The results indicate that orexin innervation to the pons plays a role in arousal from sleep.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03), Orexin-B-SAP (Cat. #IT-20)

Loss of cortical acetylcholine enhances amphetamine-induced locomotor activity.

Mattsson A, Pernold K, Ogren SO, Olson L (2004) Loss of cortical acetylcholine enhances amphetamine-induced locomotor activity. Neuroscience 127(3):579-591. doi: 10.1016/j.neuroscience.2004.05.038

Summary: The authors have recently shown that cholinergic denervation of the basal forebrain in rats leads to an increased motor response to d-amphetamine, a hallmark of schizophrenia. In the present study 192-Saporin (Cat. #IT-01) was injected into the nucleus basalis magnocellularis or the medial septum/diagonal band of Broca, and OX7-SAP (Cat. #IT-02) was injected intracerebroventricularly. The dopaminergic hyper-reactivity was induced by lesions to the cortex cerebri, but not by damage to the cerebellum or hippocampus.

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Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle.

Rajakumar N, Leung LS, Ma J, Rajakumar B, Rushlow W (2004) Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle. Biol Psychiatry 55(8):797-803. doi: 10.1016/j.biopsych.2003.12.015

Summary: Neurodevelopmental abnormalities are suspected to play a role in the pathogenesis of schizophrenia. The authors injected 0.75 µl of 192-Saporin (Cat. #IT-01) bilaterally into the prefrontal cortex of postnatal day 1 rats. The rats were then evaluated in tests designed to measure behavioral abnormalities relevant to schizophrenia. The behavior of the treated animals indicated that damage to p75-receptor-expressing neurons in the prefrontal cortex may be involved in the manifestation of schizophrenia.

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Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor.

Erhardt C, Galani R, Jeltsch H, Cassel JC, Klosen P, Menet JS, Pevet P, Challet E (2004) Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor. Eur J Neurosci 19(7):1773-1788. doi: 10.1111/j.1460-9568.2004.03281.x

Summary: The circadian clock in mammals is located within suprachiasmatic nuclei of the hypothalamus (SCN). The authors investigated how cholinergic afferents from the basal forebrain may be involved in control of the circadian clock. 3 µg of 192-Saporin (Cat. #IT-01) was injected intracerebroventricularly, or 1 µg was injected in SCN of rats, and various aspects of the circadian system were investigated. The data suggest that the forebrain cholinergic system is involved in the phase resetting properties of light.

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Habituation to stress and dexamethasone suppression in rats with selective basal forebrain cholinergic lesions.

Helm KA, Ziegler DR, Gallagher M (2004) Habituation to stress and dexamethasone suppression in rats with selective basal forebrain cholinergic lesions. Hippocampus 14(5):628-635. doi: 10.1002/hipo.10203

Summary: Basal forebrain cholinergic neurons may be involved in hippocampal and medial prefrontal cortex inhibition of glucocorticoid stress responses. The authors investigated the effects of 0.05 to 0.075 µg injections of 192-Saporin (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of rats by measuring corticosterone levels during a restraint stress test. Lesioned rats displayed less stress suppression on the administration of dexamethasone than controls, indicating that cholinergic neurons are involved in these stress responses.

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Environment-spatial conditional learning in rats with selective lesions of medial septal cholinergic neurons.

Janisiewicz AM, Jackson O, Firoz EF, Baxter MG (2004) Environment-spatial conditional learning in rats with selective lesions of medial septal cholinergic neurons. Hippocampus 14:265-273. doi: 10.1002/hipo.10175

Summary: 192-Saporin (Cat. #IT-01) has produced varied results when used to determine the role of cholinergic neurons of the medial septum/vertical limb of the diagonal band (MS/VDB) in spatial working memory. The authors used a total of 0.5 µl of 0.12 µg/µl 192-Saporin injected into the MS/VDB to examine “environment-spatial” conditional learning. The findings suggest that cholinergic neurons of the MS/VDB are involved in some aspects of conditional associative learning.

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Effects of complete immunotoxin lesions of the cholinergic basal forebrain on fear conditioning and spatial learning.

Frick KM, Jeansok JK, Baxter MG (2004) Effects of complete immunotoxin lesions of the cholinergic basal forebrain on fear conditioning and spatial learning. Hippocampus 14:244-254. doi: 10.1002/hipo.10169

Summary: The authors examined the hypothesis that basal forebrain cholinergic neurons are critical for acquisition and consolidation of fear conditioning by lesioning the medial septum/vertical limb of the diagonal band, the horizontal limb of the diagonal band of Broca, and the nucleus basalis magnocellularis of rats with 192-Saporin (Cat. #IT-01). The lesions did not impair contextual fear conditioning, implying that impairments induced by scopolamine may not be mediated by cholinergic input to the hippocampus and neocortex.

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The amygdala modulates the consolidation of memories of emotionally arousing experiences

McGaugh JL (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1-28. doi: 10.1146/annurev.neuro.27.070203.144157

Objective: This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories.

Summary: The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.

Usage: Selective lesions of cortical NB corticopetal cholinergic projections induced by 192-IgG saporin blocked the dose-dependent enhancement of inhibitory avoidance induced by posttraining intra-BLA infusions of NE.

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Selective cholinergic denervation of the cingulate cortex impairs the acquisition and performance of a conditional visual discrimination in rats.

Winters BD, Robbins TW, Everitt BJ (2004) Selective cholinergic denervation of the cingulate cortex impairs the acquisition and performance of a conditional visual discrimination in rats. Eur J Neurosci 19(2):490-496. doi: 10.1111/j.0953-816x.2003.03157.x

Summary: Performance in conditional discrimination tasks is thought to be controlled at least in part by the cingulate cortex and its basal forebrain afferents. Using bilateral 0.5 µl injections of 0.02 µg/ml 192-Saporin (Cat. #IT-01) into the cingulate cortex of rats, the authors investigated the role of cholinergic projections from the vertical limb nucleus of the diagonal band to the cingulate cortex in specific types of learning. The results reinforce the idea that cholinergic projections to the cortex are involved in processing sensory information as well as task-related stimuli.

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Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin.

Chang Q, Gold PE (2004) Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin. Hippocampus 14(2):170-179. doi: 10.1002/hipo.10160

Summary: 192-Saporin has been widely used to eliminate cholinergic neurons in the basal forebrain. These lesions can produce near-total loss of choline acetyltranferase (ChAT)-positive neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/VDB). There is evidence that this ChAT deficit produces an upregulation of cholinergic mechanisms providing input to the hippocampus. Using either 0.2 or 0.3 µl of 0.5 µg/µl 192-Saporin (Cat. #IT-01) injected into the MS/VDB the authors examined the residual release of acetylcholine in the hippocampus after lesioning.

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Septohippocampal acetylcholine: involved in but not necessary for learning and memory?

Parent MB, Baxter MG (2004) Septohippocampal acetylcholine: involved in but not necessary for learning and memory?. Learn Mem 11:9-20. doi: 10.1101/lm.69104

Summary: In this review the authors describe some of the methods and rationale behind the investigation of hippocampal acetylcholine and its role in the support of learning and memory processes. Results produced by the use of 192-Saporin (Cat. #IT-01) are discussed, as well as the differences that have been found between the effects of 192-Saporin and those of less specific lesioning agents.

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Involvement of cholinergic neuronal systems in intravenous cocaine self-administration.

Smith JE, Co C, Yin X, Sizemore GM, Liguori A, Johnson WE 3rd, Martin TJ (2004) Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neurosci Biobehav Rev 27(8):841-850. doi: 10.1016/j.neubiorev.2003.11.002

Summary: Recent studies have demonstrated that cholinergic neurons take part in the process of cocaine self-administration. In this study the authors used 0.25 µg-injections of 192-Saporin (Cat. #IT-01) into the posterior nucleus accumbens (Nacc)-ventral pallidum (VP) region of rats to identify specific subsets of cholinergic neurons that are involved. The results indicate that cholinergic innervations of the VP, the medial septum/diagonal band of Broca, and the Nacc are inhibitory to the underlying processes of cocaine self-administration.

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Transfer effects and conditional learning in rats with selective lesions of medial septal/diagonal band cholinergic neurons.

Janisiewicz AM, Baxter MG (2003) Transfer effects and conditional learning in rats with selective lesions of medial septal/diagonal band cholinergic neurons. Behav Neurosci 117(6):1342-1352. doi: 10.1037/0735-7044.117.6.1342

Summary: Conditional learning appears to require cholinergic input to the hippocampus and cingulate cortex. Using a total of 0.5 µl of 0.12 µg/µl 192-Saporin (Cat. #IT-01) injected into the medial septal area of rats, the authors investigated the role of cholinergic input in conditional learning. The results suggest that cholinergic neurons of the medial septum/vertical limb of the diagonal band play a role in the transfer of behavioral experience rather than in conditional learning itself.

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Cholinergic modulation of visual attention and working memory: Dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine.

Chudasama Y, Dalley JW, Nathwani F, Bouger P, Robbins TW (2004) Cholinergic modulation of visual attention and working memory: Dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine. Learn Mem 11(1):78-86. doi: 10.1101/lm.70904

Summary: It is hypothesized that cortical cholinergic dysfunction underlies the cognitive impairments associated with dementia and normal aging. The authors examined the role of these neurons in both attentional and mnemonic functions, using either bilateral infusions of 125 ng of 192-Saporin (Cat. #IT-01) into the bregma of rats or infusions of scopolamine. The results suggest that attentional and working memory capacities can be tested separately during the same session. It is also indicated that the CBF system is a modulator of both attentional and mnemonic processing.

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Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats.

Harmon KM, Wellman CL (2003) Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats. Brain Res 992:60-68. doi: 10.1016/j.brainres.2003.08.029

Summary: The authors used 0.15 µg of 192-Saporin (Cat. #IT-01) injected into the nucleus basalis magnocellularis of rats to study whether dendritic spine density is altered by cholinergic deafferentation. While the spine density decreased in young rats, middle-aged and aged animals did not display a density significantly different than controls.

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Extensive lesions of cholinergic basal forebrain neurons do not impair spatial working memory.

Vuckovich JA, Semel ME, Baxter MG (2004) Extensive lesions of cholinergic basal forebrain neurons do not impair spatial working memory. Learn Mem 11:87-94. doi: 10.1101/lm.63504

Summary: The authors wished to examine whether cerebellar Purkinje cells damaged during a cholinergic basal forebrain lesion might be the cause of impaired working memory. Four injections of 0.2-0.3 µl (0.12-0.15 µg/ml, 192-Saporin, Cat. #IT-01) into the medial septum/vertical limb of the diagonal band, two injections into the horizontal limb of the diagonal band of Broca, and four injections into the nucleus basalis magnocellularis/ substantia innominata of rats were used to produce a very specific lesion. The results indicate that the cholinergic basal forebrain does not play a substantial role in spatial working memory.

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Effect of selective cholinergic lesion of the septohippocampal pathway on the carbachol stimulated GTPγS binding in rat hippocampus

Pokala VN, Witt-Enderby PA, Johnson DA (2003) Effect of selective cholinergic lesion of the septohippocampal pathway on the carbachol stimulated GTPγS binding in rat hippocampus. Neuroscience 2003 Abstracts 799.7. Society for Neuroscience, New Orleans, LA.

Summary: Previously we have shown that selective lesion of the septohippocampal cholinergic pathway in the rat resulted in a significant decrease in hippocampal extracellular acetylcholine concentration and an increase in muscarinic receptor binding. The intent of this study was to investigate the effect of selective cholinergic lesion of the septohippocampal pathway on muscarinic receptor-coupled G protein activation. Measurement of agonist-stimulated GTP〔γ-35S〕 binding was used as a function of ligand-receptor interactions. Sprague-Dawley rats were infused into the medial septum with either the selective cholinergic immunotoxin 192 IgG-saporin (SAP) (0.22 μg in 1μl aCSF) or vehicle. After 6 weeks the rats were euthanized and the hippocampus dissected from the brain and quickly frozen. Hippocampal homogenate was analyzed for GTPγS binding following exposure to the muscarinic agonist carbachol (1 nM-10 mM). Data were analyzed to obtain EC50 of carbachol and Emax values for GTPγS binding using non-linear regression analysis. The results demonstrated, in control animals carbachol stimulated 35S GTPγS binding to be 150% over basal with an EC50 value of approximately 100 μM. However, in SAP lesioned animals no concentration dependent increase in 35S GTPγS binding occurred. Therefore, though we saw an increase in the muscarinic receptor binding at the hippocampus on SAP lesioning, these receptors seem to be nonfunctional.

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Combined lesions of central cholinergic and noradrenergic denervation in the rat using 192 IgG-saporin and DSP-4 as an animal model of Alzheimer’s disease

Kolasa K, Harrell LE (2003) Combined lesions of central cholinergic and noradrenergic denervation in the rat using 192 IgG-saporin and DSP-4 as an animal model of Alzheimer's disease. Neuroscience 2003 Abstracts 842.6. Society for Neuroscience, New Orleans, LA.

Summary: To better model the consequences of persistent cholinergic hypofunction observed in Alzheimer’s disease, medial septum (MS) lesions were made by using specific cholinotoxin 192-IgG saporin. In this study the effect of simultaneous hippocampal cholinergic denervation, induced by intraseptal injection of 192-IgG saporin, and central noradrenergic denervation, induced by systemic injection of DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) was examined in the rat dorsal hippocampus. DSP-4, an adrenergic neurotoxin selective for locus coeruleus innervated brain regions, induced a decrease in norepinephrine (NE) concentration in hippocampus. MS lesions resulted not only in selective cholinergic denervation of hippocampus (CD; superior cervical ganglion removed to prevent ingrowth of peripheral NE fibers), but also ingrowth of NE fibers into the hippocampus (HI; superior cervical ganglion left intact). MS lesions also resulted in a significant loss of choline-acetyltransferase activity in HI and CD groups, and an increase in NE in the HI group. In the HI group, but not in CD or control groups, visualization of hippocampus revealed a dense NE innervation with fine NE fibers with varicosities. Combination of MS lesion and DSP-4 treatment resulted in a reduction of NE concentration in HI group, with concomitant decrease in visualization of NE fibers. Those that remained were thick with sparse varicosities, possibly derived from peripheral sympathetic ingrowth. Elevated NE concentration and NE fiber number following specific cholinergic lesions might reflect compensatory sprouting of both central and peripheral adrenergic fibers into the hippocampus. Thus, noradrenergic sprouting in response to cholinergic denervation of hippocampus might be a valuable model for studying mechanisms as well as the consequences of neuronal plasticity in the mature CNS.

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Lateralization of the attentional functions mediated via cortical cholinergic inputs

Sarter MF, Martinez V, Bruno JP (2003) Lateralization of the attentional functions mediated via cortical cholinergic inputs. Neuroscience 2003 Abstracts 921.20. Society for Neuroscience, New Orleans, LA.

Summary: The role of basal forebrain (BF) corticopetal cholinergic projections in mediating attentional processing has been well established. For example, bilateral cortical cholinergic deafferentation produces robust impairments in attention. Neuropsychological and neuroimaging studies have postulated that attentional functions and capacities are mediated primarily via a lateralized, right-hemispheric network. The present study tested the general hypothesis that the attentional functions of cortical cholinergic inputs likewise are lateralized and thus that right-hemisphere cortical cholinergic deafferentation yields more severe attentional impairments. Rats were trained to perform an operant sustained attention task. Upon reaching criterion performance, unilateral cortical cholinergic deafferentation was produced by infusions of 192-IgG saporin into either the left or right BF. Compared with the performance of sham-operated animals and animals with left-hemispheric lesions, right-hemispheric cortical cholinergic deafferentation resulted in a persistent and selective decrease in the detection of signals (hits), mirroring the more potent but similarly selective effects of bilateral lesions. In contrast, left cortical cholinergic deafferentation did not affect hits but decreased the number of rejections in non-signal trials. These data extend previous studies suggesting that the integrity of the right cortical cholinergic input system is necessary for signal detection (Bushnell et al. 1998). Furthermore, the present data substantiate the assumption that the detection of signals and the rejection of non-signals are based on fundamentally different cognitive operations, and that the cholinergic mediation of these two operations is lateralized.

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Noradrenergic, but not cholinergic, deafferentation of the infralimbic/prelimbic cortex impairs attentional set-shifting

Eichenbaum HB, Ross R, Raji A, McGaughy JA (2003) Noradrenergic, but not cholinergic, deafferentation of the infralimbic/prelimbic cortex impairs attentional set-shifting. Neuroscience 2003 Abstracts 940.7. Society for Neuroscience, New Orleans, LA.

Summary: Damage to the prefrontal cortex in humans produces deficits in the ability to shift attention to a previously irrelevant stimulus dimension (extra-dimensional shift; EDS) while sparing reversal and intra-dimensional shifts (a novel discrimination without a change in the relevant dimension; IDS). Data from human subjects has also shown the administration of noradrenergic agonists and antagonists disrupts EDS suggesting a role for coeruleal-cortical norepinephrine (NE). Usher and colleagues have proposed that high, tonic levels of NE may maximize behavioral flexibility to allow an optimal responsiveness to changes in the environment e.g. the predictability of reinforcement (Usher et al., Science 283, 1999). Based on these data, a loss of NE would be predicted to impair attentional set-shifting. In a rodent model of attentional set-shifting developed by Brown and colleagues, excitotoxic lesions of the infralimbic/prelimbic cortex (IL/PL) produced impairments in EDS but not IDS or reversal learning (J. Neurosci. 20, 2000). This study confirmed the importance of IL/PL to EDS, but did not address the role of NE in this type of cognition. In the current study, rats were infused with anti-dopamine beta-hydroxylase-saporin (NE-SAP)in IL/PL (0.01 µ g/ µl; 0.5 µl/hemisphere) to produce noradrenergic deafferentation, 192 IgG saporin (ACH-SAP; 0.01 µ g/ µl; 0.5 µl/hemisphere)to produce cholinergic deafferentation, or vehicle then tested in an attentional set-shifting task. NE-SAP rats were impaired in EDS but not in IDS or reversal learning. In contrast, ACH-SAP rats showed no impairment in any aspect of the task. The effect of DBH-SAP lesions on EDS support the hypothesis that NE, but not ACH, is critical to the adaptation of behavior to changes in reinforcement contingencies. The lack of effect of these lesions on reversal learning suggest the robustness of this effect may vary with the extent of behavioral adaptation required.

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Sleep deprivation impairs retention performance on an olfactory discrimination task

Pan S, Borowski T, de Lacalle S (2003) Sleep deprivation impairs retention performance on an olfactory discrimination task. Neuroscience 2003 Abstracts 616.21. Society for Neuroscience, New Orleans, LA.

Summary: Sleep deprivation is known to adversely affect learning and memory. We examined the effects of sleep deprivation on attentional and memory processes in rats that received unilateral cholinergic lesions with 192IgG-saporin. Young Fisher 344 male rats were evaluated on an olfactory discrimination learning task both before and after exposure to 8 hours of sleep deprivation. Prior to testing, rats were trained to associate a particular scent with a food reward. They were then tested on their ability to successfully distinguish between two randomly placed, differently scented cups to retrieve the food reward. On a second experiment we investigated the effect that chronic estrogen administration may exert on the cognitive response to sleep deprivation. Gonadectomized rats were implanted s.c. with a pellet containing estrogen or placebo, and tested before and after sleep deprivation, one month after treatment. Untreated rats displayed impaired performance on the retention of the olfactory discrimination task; sleep deprivation resulted in an inability to remember the association of the baited scent from the previous day of testing. However, hormonal treatment appeared to have no significant effect on olfactory discrimination performance. These findings suggest a beneficial effect of sleep in learning and memory. Further research is needed to unravel the role of steroid hormones in modulating sleep-deprived learning deficits in rodents.

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A novel nitrate ester enhances performance in a spatial memory task in rats with forebrain cholinergic depletion

Reynolds JN, Sutherland JM, Sutherland RJ (2003) A novel nitrate ester enhances performance in a spatial memory task in rats with forebrain cholinergic depletion. Neuroscience 2003 Abstracts 626.11. Society for Neuroscience, New Orleans, LA.

Summary: Forebrain acetylcholine (ACh) depletion is associated with a variety of cognitive problems, including memory deficits. Here we evaluate the efficacy of a novel nitrate ester, GT 1061, a potential cognition enhancer, in reversing the memory deficit produced by ACh depletion. Long-Evans hooded rats were stereotaxically injected with 192-IgG-saporin intraventricularly or into basal forebrain cell regions to effect loss of cholinergic cells in the basal forebrain and depletion of cholinergic input to neocortex and hippocampus. The rats were postoperatively tested in a version of the Morris water task in which the location of the hidden platform was changed every second day. This version allows for repeated testing of new spatial learning and 24-hr memory retention. ACh depletion causes statistically reliable deficits in new learning and retention components of the task. We examined the effects of oral (0.5, 1, 5, and 10 mg/kg) and intraperitoneally injected (1, 10, 25 and 50 mg/kg) GT 1061 and donepezil oral (0.05, 0.5, 0.1, 1 mg/kg) and intraperitoneal (0.5 mg/kg) on performance of ACh depleted rats. Both oral and injected GT1061 (10 mg/kg oral, and 1 mg/kg i.p.) and donepezil improved new learning and retention performance. The improvement was especially evident during the 24-hr retention tests when GT1061 treated rats performed as well as normal rats. On this measure 10 mg/kg GT 1061 and 1 mg/kg donepezil administered orally were equipotent.

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Cholinergic deafferentation increases expression of the glur-1 subunit of the AMPA receptor in frontal cortex of young adult but not aging rats

Kim I, Wilson RE, Wellman CL (2003) Cholinergic deafferentation increases expression of the glur-1 subunit of the AMPA receptor in frontal cortex of young adult but not aging rats. Neuroscience 2003 Abstracts 633.9. Society for Neuroscience, New Orleans, LA.

Summary: Previously, we demonstrated that plasticity of frontal cortex is altered in aging rats: cholinergic lesions of the nucleus basalis magnocellularis (NBM) produce larger declines in dendritic morphology in frontal cortex of aged rats compared to young adults. In addition, these lesions result in upregulation of dendritic spines in frontal cortex of young adult but not aging rats. To begin to identify possible mechanisms underlying age-related differences in plasticity after NBM lesion, we assessed immunohistochemical labeling of the AMPA receptor subunit GluR1 in young adult and aging rats after either sham or 192 IgG saporin lesions of the NBM. Young adult (N=17), middle-aged (N=16), and aged rats (N=13) received unilateral sham or 192 IgG saporin lesions of the NBM. Two weeks later, brains were processed for immunohistochemical labeling of the GluR1 subunit of the AMPA receptor. An unbiased stereological technique was used to estimate density of labeled neurons in layer II-III of frontal cortex. Cells were identified as neurons based on standard morphological criteria and counted. Using a computerized image analysis system interfaced with a microscope, the average optical density of the white matter below frontal cortex was determined; neurons with optical densities at least one standard deviation above this mean were identified as intensely labeled. In young adult rats, lesions produced a 55% increase in the density of intensely GluR1-immunopositive neurons in frontal cortex. On the other hand, lesions had no effect on counts of GluR1-immunoreactive neurons in middle-aged and aged rats. This age-related difference in lesion-induced expression of AMPA receptor subunit protein could underlie the age-related differences in dendritic plasticity after NBM lesions.

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Combined bilateral perforant path lesions with lesions of the cholinergic system: an ultrastructural immunogold analysis of nmdar1 representation within the dentate gyrus

Janssen WG, Andrews G, Tomey MI, Baxter MG, Morrison JH (2003) Combined bilateral perforant path lesions with lesions of the cholinergic system: an ultrastructural immunogold analysis of nmdar1 representation within the dentate gyrus. Neuroscience 2003 Abstracts 676.26. Society for Neuroscience, New Orleans, LA.

Summary: Alzheimer’s disease is characterized by deterioration of cholinergic input to the hippocampus, as well as degeneration of input from the entorhinal cortex to the dentate gyrus(DG). Studies have demonstrated an upregulation of the NMDA receptor subunit, NR1, following unilateral ablatement of the perforant path(pp). We hypothesized that cholinergic innervation might be essential for DG plasticity following pp ablation. Our study was designed to investigate the synaptic distribution of NR1 following combined 192 IgG-Saporin lesions of the medial septum/vertical diagonal band(MS/VDB) and bilateral(bilat) pp knife cut ablation. Animals received bilat-pp lesions 2-3 weeks days post MS/VDB and were sacrificed 17 days following pp lesion. Four groups of rats were tested: 1)MS-VDB with sham bilat-pp; 2)sham MS-VDB with bilat-pp; 3)MS-VDB with bilat-pp; 4)sham MS-VDB with sham bilat-pp. Using postembedding immunogold electron microscopy and SynBin, a program designed for quantification and compartmentalization of immunogold particles at the synaptic level, we investigated these effects in the outer molecular layer of the DG in a pilot study with 2 animals/group. Initial results suggest that the synaptic pools of NR1 within post-synaptic compartments were not affected with single MS/VDB, but that a long term synaptic down regulation of NR1 follows bilat pp lesion that is not affected by the additional removal of cholinergic input. While these combined lesions do not alter the pattern of synaptic NR1 receptor distribution following pp lesions, these data has important implications for lesion-induced hippocampal plasticity as well as structural and functional recovery.

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Medial septal and entorhinal cortical involvement in hippocampal theta rhythm

Yoder RM, Pang KCH (2003) Medial septal and entorhinal cortical involvement in hippocampal theta rhythm. Neuroscience 2003 Abstracts 719.19. Society for Neuroscience, New Orleans, LA.

Summary: Hippocampal theta rhythm (HPCΘ) may be involved in various phenomena, including attention and the acquisition of sensory information. Two projections to HPC, the medial septum-diagonal band of Broca (MSDB) and entorhinal cortex (EC), are involved in the activation or synchronization of HPCΘ. MSDB contains excitatory (cholinergic) and inhibitory (GABAergic) hippocampal projections via the fimbria/fornix. EC contains excitatory (glutamatergic) hippocampal projections via the perforant path (PP). MSDB GABAergic, MSDB cholinergic, or bilateral PP lesions eliminate HPCΘ during urethane anesthesia (HPCΘ-II). In unanesthetized recordings, each of these lesions reduced but did not eliminate HPCΘ during locomotion (HPCΘ-I); MSDB cholinergic and EC lesions caused similar reductions in HPCΘ, and MSDB GABAergic lesions produced a greater amplitude reduction. In an attempt to determine whether interactions exist between MSDB projections and EC, we examined the effects of MSDB GABAergic or cholinergic lesions combined with PP lesions on HPCΘ-I. MSDB GABAergic and cholinergic lesions were produced by intraseptal injection of kainic acid and 192 IgG-saporin, respectively. Bilateral PP lesions were produced by passing cathodal current through an electrode located in the medial PP. HPCΘ amplitude was calculated as the square root of power at peak frequency (Fourier analysis) within the HPCΘ range. The combination of MSDB GABAergic and PP lesions eliminated HPCΘ-I. The combination of MSDB cholinergic and PP lesions did not reduce HPCΘ-I amplitude further than MSDB cholinergic or PP lesions alone. These results suggest the inhibitory (MSDB GABAergic) and excitatory (MSDB cholinergic or EC glutamatergic) projections interact to support HPCΘ-I. Furthermore, MSDB cholinergic and EC glutamatergic projections may be redundant for HPCΘ-I.

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Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed non-match to sample task (DNMS)

McGaughy JA, Jindal M, Eichenbaum HB, Hasselmo ME (2003) Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed non-match to sample task (DNMS). Neuroscience 2003 Abstracts 425.4. Society for Neuroscience, New Orleans, LA.

Summary: Muscarinic cholinergic receptor activation in entorhinal cortex (EC) activates intrinsic depolarizing membrane currents which cause self-sustained spiking activity in single neurons (Klink and Alonso, J. Neurophys. 77, 1997). This effect may underlie delay activity and match-dependent activity changes in delayed match to sample tasks (Fransen et al., J. Neurosci. 22, 2002) and could allow accurate maintenance of novel information without dependence on synaptic modification associated with previous exposure (familiarization). Consistent with this, research in human subjects suggest that the medial temporal lobes are specifically activated during working memory for novel but not familiar stimuli (Stern, et al. Hippocampus v. 11, 2001), and cholinergic deafferentation of the rhinal cortex in non-human primates has been shown to impair memory for trial-unique (novel) stimuli (Turchi et al., SFN abstracts v. 28). The current study tests the hypothesis that cholinergic deafferentation of the EC produces impairments in working memory for novel but not familiar stimuli. Prior to surgery rats were trained in an odor DNMS task with a brief delay. After reaching asymptotic performance, rats were infused with either 192-IgG-saporin (SAP) or its vehicle into the EC (0.01 µg/µl; 1.0 µl/injection; 6 infusions/hemisphere). Rats were not impaired at any delay when tested with familiar odors but showed significant, persistent impairments when tested with novel odors. An increase in task difficulty alone was insufficient to explain these effects. These data support the hypothesis that cholinergic afferents to the EC activate cellular mechanisms of sustained spiking activity necessary for maintenance of novel but not familiar stimuli in a working memory task. Support Contributed By: NIH MH61492, MH60013, DA16454.

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Altered neurogenesis after cholinergic forebrain lesion in the adult rat.

Cooper-Kuhn CM, Winkler J, Kuhn H (2003) Altered neurogenesis after cholinergic forebrain lesion in the adult rat. Neuroscience 2003 Abstracts 348.9. Society for Neuroscience, New Orleans, LA.

Summary: Adult hippocampal neurogenesis has been shown to be functionally connected to learning and memory and at the same time to be regulated by a multitude of extracellular cues, including hormones, growth factors, and neurotransmitters. The cholinergic forebrain system is one of the key transmitter systems for learning and memory. Within the hippocampus and olfactory bulb, two regions of adult neurogenesis, cholinergic innervation is quite extensive. This experiment aims at defining the role of cholinergic input during adult neurogenesis by using an immunotoxic lesion approach. The immunotoxin 192IgG-saporin was infused into the lateral ventricle of adult rats to selectively lesion the cholinergic neurons of the cholinergic basal forebrain (CBF), which project to the dentate gyrus and the olfactory bulb. Five weeks after lesion the rate of neurogenesis declined significantly in the dentate gyrus and olfactory bulb granule cell layers, whereas the generation of neurons in the periglomerular region of the olfactory bulb was unaffected. The number of apoptotic cells increased specifically in the progenitor region of the dentate gyrus as well as in the periglomerular layer of the olfactory bulb. Therefore, one of the possible mechanisms by which acetylcholine could promote neurogenesis is by increasing the survival of progenitor and immature neurons. Neurotransmitters can alter the microenvironment of neural progenitor cells, whether directly or indirectly, and these changes lead to significant alterations in neurogenesis. In principle, the data suggest that acetylcholine is stimulatory to adult hippocampal neurogenesis, since neurotoxin lesions specific to this neurotransmitter system lead to a reduced number of new neurons.

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The effects of IgG-192-saporin lesions of limbic forebrain on rat cocaine self-administration

Co C, Yin X, Johnson WE, Martin TJ, Smith JE (2003) The effects of IgG-192-saporin lesions of limbic forebrain on rat cocaine self-administration. Neuroscience 2003 Abstracts 422.3. Society for Neuroscience, New Orleans, LA.

Summary: The involvement of cholinergic neurons in cocaine self-administration has been recently demonstrated. This study was undertaken to further assess the role of cholinergic innervations of/ or interneurons in limbic brain regions previously shown to receive enhanced dopamine input during cocaine self-administration. Rats were trained to self-administer cocaine on an FR2 schedule using a within session dose intake procedure (3½ hour session with 1 hour access each to 0.17, 0.33 and 0.67 mg/infusion). The doses were then decreased systematically to threshold levels where only the highest dose was self-administered during the session. The cholinergic neurotoxin IgG-192-saporin (0.25 µg in 1 µl) or vehicle was then bilaterally administered into the posterior nucleus accumbens (NAcc) - ventral pallidum (VP). The saporin lesion resulted in a shift to the left in the dose intake relationship for cocaine self-administration with all three doses maintaining responding. The sham-vehicle treated rats continued to only sample the higher dose. Real time RT-PCR was used to assess the magnitude and extent of the lesion. Gene expression for p75 (the target for 192 IgG) and choline acetyltransferase (ChAT) were assessed in the NAcc, VP, caudate nucleus (CP) and diagonal band (DB) of these rats. Significant reductions in p75 and ChAT gene expression were seen in the DB and VP while only small decreases were seen in the NAcc and CP of the saporin treated rats. These data suggest that the overall influence of cholinergic neurons in the DB and VP are inhibitory to the processes underlying cocaine self-administration.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Inhibition within the nucleus tractus solitarius (NTS) ameliorates social deficits due to specific acetylcholine (ACh) or Purkinje cell lesions

Parikh T, Lee S, Walker BR (2003) Inhibition within the nucleus tractus solitarius (NTS) ameliorates social deficits due to specific acetylcholine (ACh) or Purkinje cell lesions. Neuroscience 2003 Abstracts 423.18. Society for Neuroscience, New Orleans, LA.

Summary: Previously, we demonstrated that enhancement of GABA transmission, or blockade of ionotropic glutamate within rat brainstem structures, which mediate limbic-motor seizure control, attenuated behavioral deficits, which were similar to those seen in human patients with autism, due to developmental cerebellum lesions. Evidence suggests that within autism spectrum disorders, there is a decrease in cholinergic neurons in the forebrain and/or a loss of purkinje cells in the cerebellum which might account for these behavioral deficits. Therefore, in the present study, we tested the hypothesis that specific lesions to the rat ACh system or reduction of purkinje cells in the rat cerebellum would lead to specific alterations of social behavior. Furthermore, alterations in GABA and glutamate transmission within the NTS would correct these social deficits. We examined the effect of ACh or purkinje cell lesions on social behavior in rats by recording social interactions before and after bilateral saporin injections (192-IgG or OX-7; 2 µg/side). As compared to preinjection behavior, saporin injections decreased social interaction of adult rats. Bilateral microinjections of the GABA agonist muscimol (256 pmol) into the mNTS at least 10 minutes prior to behavioral testing returned the amount of social investigation of the lesioned animals to pre-saporin levels. These findings suggest that specific neuronal populations are responsible for mediating social behavior in rats, and that there is a functional connection between those systems and the brainstem structures utilized for seizure control.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Selective cholinergic lesion of the medial septum impairs retention but not acquisition of a passive avoidance memory task

Ukairo OT, Arshad S, Gibbs RB, Johnson DA (2003) Selective cholinergic lesion of the medial septum impairs retention but not acquisition of a passive avoidance memory task. Neuroscience 2003 Abstracts 425.16. Society for Neuroscience, New Orleans, LA.

Summary: Infusion of 192 IgG-saporin (SAP) into the medial septum (MS) selectively destroys cholinergic neurons projecting to the hippocampus. This study examined the effect of such lesions on acquisition and retention using a passive avoidance paradigm. Male Sprague-Dawley rats received either SAP (.22 μg in 1 μl) or vehicle directly into the MS. Passive avoidance training began two weeks later. Training consisted of placing an animal into the lighted chamber of the apparatus and then delivering footshock (.75 mA, 1 sec.) when the animal moved into the adjacent darkened chamber. Training was repeated until animals avoided the dark chamber for 2 consecutive trials of 5 min. duration. Retention (latency to enter the dark chamber) was tested 1 week later. Results showed no effect of SAP lesion on the number of trials necessary to acquire avoidance behavior. In contrast, SAP-lesioned animals showed a significant impairment in retention, as evidenced by a 72% decrease in crossover latency one week following training. These results suggest that selective destruction of cholinergic septo-hippocampal projections impairs retention, but not acquisition, of passive avoidance behavior to aversive stimuli.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Arousal enhances delayed match to position T-maze performance independent of septo-hippocampal cholinergic projections

Fitz NF, Gibbs RB, Johnson DA (2003) Arousal enhances delayed match to position T-maze performance independent of septo-hippocampal cholinergic projections. Neuroscience 2003 Abstracts 425.17. Society for Neuroscience, New Orleans, LA.

Summary: Infusion of the selective cholinergic immunotoxin, 192 IgG-saporin (SAP) into the medial septum (MS) of rats selectively lesions cholinergic neurons projecting to the hippocampus and impairs acquisition of a delayed matching to position (DMP) T-maze task. The intent of the present study was to determine if enhanced performance associated with arousal is dependent on septo-hippocampal cholinergic projections. Male Sprague-Dawley rats received MS infusions of SAP 0.22 µg in 1µl or vehicle. Fourteen days later, animals were trained on the DMP spatial memory task. SAP and control animals were randomized into an “arousal” group that was injected with saline (IP; 1 ml/Kg) 30 min before testing each day or a “non-arousal” group that was not. SAP lesions significantly impaired acquisition of the DMP task in both the arousal and non-arousal groups. Conversely, arousal significantly enhanced acquisition in both control and SAP lesioned rats. There was no significant interaction between the effects of cholinergic lesions and arousal. These results suggest that septo-hippocampal cholinergic projections are not engaged in enhanced spatial learning mediated by arousal.

Related Products: 192-IgG-SAP (Cat. #IT-01)

192 IgG-saporin lesions of the nucleus basalis magnocellularis in rats fail to disrupt acquisition or retention of differential reinforcement of low rate responding

Butt AE, Corley S, Cabrera S, Chavez C, Kitto M, Ochetti D, Renovato A, Salley T, Sarpong A (2003) 192 IgG-saporin lesions of the nucleus basalis magnocellularis in rats fail to disrupt acquisition or retention of differential reinforcement of low rate responding. Neuroscience 2003 Abstracts 425.5. Society for Neuroscience, New Orleans, LA.

Summary: The frontal cortex has been implicated in supporting timing behavior in tests of differential reinforcement of low rate responding (DRL) in rats. DRL performance is similarly influenced by anticholinergic drugs; scopolamine interferes with DRL performance by increasing the number of nonreinforced responses and thus decreasing DRL efficiency. Because the frontal cortex receives significant cholinergic input from the nucleus basalis magnocellularis (NBM) in rats, we hypothesized that NBM lesions would disrupt DRL performance in the current experiment. Male Long-Evans rats were placed first in a DRL 10 s schedule of reinforcement before advancing to a DRL 20 s schedule. Rats received 50 trials per day for 20 consecutive days on both DRL schedules. When rats reached stable performance, they received either bilateral 192 IgG-saporin lesions of the NBM or sham lesions. Upon recovery, rats were reintroduced to the DRL 20 s task for 10 days of post-operative testing. Finally, rats were tested using a novel delay interval in a DRL 30 s task. Testing continued for 10 additional days. Results showed that the NBM lesion group showed no significant change in either the total number of responses or in DRL efficiency (reinforced responses / total responses) between pre- and post-operative DRL 20 s testing. Subsequent acquisition in the DRL 30 s task was similarly not disrupted by NBM lesions. The effectiveness of the lesions was verified by acetylcholinesterase (AChE) staining, which showed pronounced depletion of cortical AChE with normal AChE-positive staining in the hippocampus and medial septal area. These data suggest that the NBM is not critically involved in either the acquisition or retention of DRL performance.

Related Products: 192-IgG-SAP (Cat. #IT-01)

192-IgG saporin lesions of the medial septum and vertical diagonal band impair cognitive flexibility.

Fletcher BR, Baxter MG, Rapp PR, Shapiro ML (2003) 192-IgG saporin lesions of the medial septum and vertical diagonal band impair cognitive flexibility. Neuroscience 2003 Abstracts 425.8. Society for Neuroscience, New Orleans, LA.

Summary: Learning and memory remain largely intact following selective basal forebrain cholinergic lesions. By comparison, single unit recording studies have documented reliable effects of such lesions, including abnormally rigid hippocampal place fields when animals are confronted with changes in the configuration of the testing environment. The present experiment tested the prediction that cholinergic lesions of the basal forebrain would impair performance of tasks requiring cognitive flexibility. Rats received 192-IgG saporin or control vehicle injections into the medial septal nucleus and vertical diagonal band, and were tested on cued and spatial delayed match-to-place tasks in a radial arm water maze. Test sessions consisted of four sample trials in which animals searched for a cued or hidden escape platform located in a fixed position at the end of one arm (60 sec cutoff, inter-trial interval = 15 sec). A memory delay was imposed by returning rats to the home cage for a variable delay (15 sec. – 6 hrs), followed by two test trials. The lesion and control groups learned at similar rates in both versions of the task, and performed comparably on the critical test trials, independent of the length of the retention interval. However, lesioned rats were impaired during the transition from the cued to spatial variants of testing. Specifically, the lesion group made significantly more errors on an early sample trial in the spatial task, returning to the location that was previously correct during cued training. Pending histological confirmation of the extent and selectivity of the experimental lesions, this pattern of results suggests that damage to the basal forebrain cholinergic system spares spatial learning but impairs cognitive flexibility when task contingencies are changed.

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Dendritic dysgenesis in midline cortical regions following selective acetylcholine and dopamine lesions in neonatal rats

Sherren N, Pappas BA (2003) Dendritic dysgenesis in midline cortical regions following selective acetylcholine and dopamine lesions in neonatal rats. Neuroscience 2003 Abstracts 457.11. Society for Neuroscience, New Orleans, LA.

Summary: Both acetylcholine (ACh) and dopamine (DA) afferents reach their cortical targets during periods of synaptogenesis, and are perfectly positioned to influence the cytoarchitectural development of cortical neurons. Thus the behavioural outcomes of these lesions may be related to the development of appropriate dendritic morphology in neurons from cortical regions involved in cognition. Previous studies have either used non-specific lesion techniques or have not examined long-term effects. We lesioned rat pups at P7 with either 600 ng of the selective immunotoxin 192 IgG-saporin, or 150 ug of 6-hydroxydopamine preceded by desmethylimipramine, or both, and aged them to four months. One squad of rats was sacrificed for neurochemistry and another was prepared for morphological analysis using Golgi-Cox stain. The ACh lesion caused a 32% decrease in choline acetyltransferase activity in the frontal/cingulate cortex and a 72% reduction in retrosplenial cortex (RSC). This was associated with reductions in total dendritic length of the apical tree of layer V pyramidal cells in the medial prefrontal cortex (mPFC), the apical tree of layer III pyramidal cells in the anterior cingulate cortex (ACC), and the basal tree of layer III pyramidal cells in RSC. The DA lesion caused a 76% reduction in DA levels in frontal/cingulate cortex and no change in RSC levels. This was associated with reductions in total dendritic length of the basal and apical trees of layer V pyramidal cells in mPFC, and the basal tree of layer III pyramidal cells in ACC. No changes in layer III pyramidal cells were noted in RSC following the DA lesion. These data demonstrate that ascending ACh and DA afferents play a vital role in the cytoarchitectural development of the cortex. This is particularly important considering that hypofunction in these systems is a characteristic feature of neurodevelopmental disorders involving mental retardation, such as Rett and Down syndrome.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cholinergic activity enhances hippocampal CA1 long-term potentiation during walking in rats

Leung LS, Shen B, Ma J, Rajakumar N (2003) Cholinergic activity enhances hippocampal CA1 long-term potentiation during walking in rats. Neuroscience 2003 Abstracts 255.5. Society for Neuroscience, New Orleans, LA.

Summary: Long-term potentiation (LTP) at the basal dendrites of CA1 pyramidal cells was induced by a single 200-Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states - awake-immobility (IMM), walking, slow-wave sleep (SWS) and rapid-eye-movement sleep (REMS). Field excitatory postsynaptic potentials (fEPSPs) generated by basal dendritic excitation of CA1 were recorded before and up to 20 hours after the tetanus. Following a tetanus during any behavioral state, basal dendritic LTP was > 170% of the baseline for the first 30 min after the tetanus and decayed to ~125% at 20 hours after. LTP induced during walking was significantly larger than that induced during IMM, SWS or REMS. LTP induced during IMM, SWS and REMS was not significantly different from each other. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking than during immobility, rats were either pretreated with muscarinic cholinergic antagonist scopolamine (5 mg/kg i.p.) or given selective cholinotoxin IgG192-saporin in the medial septum. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between LTP induced during walking and IMM was abolished. In IgG192-saporin injected rats, there was no difference in the LTP induced during walking and during IMM, and scopolamine did not reduce the LTP induced during walking. In contrast, sham-lesioned rats, like other control rats, showed larger LTP induced during walking than during IMM, and LTP induced during walking was attenuated by scopolamine. This appears to be the first demonstration of an enhancement of hippocampal LTP by physiologically activated septal cholinergic inputs. LTP of the CA3 to CA1 synapses may serve important behavioral functions.

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H3 receptor antagonists modulate behaviour in a visual spatial attention task in rats with selective lesions of the nucleus basalis magnocellularis

Muir JL, Harrison FE (2003) H3 receptor antagonists modulate behaviour in a visual spatial attention task in rats with selective lesions of the nucleus basalis magnocellularis. Neuroscience 2003 Abstracts 296.7. Society for Neuroscience, New Orleans, LA.

Summary: It is well known that the cholinergic system suffers a large amount of damage in Alzheimer’s Disease (AD). The histaminergic system is known to interact with the cholinergic system but is thought to be largely spared in AD. Compounds which affect histaminergic transmission therefore offer a new further therapeutic avenue to be considered. The effects of two selective H3 receptor antagonists, Thioperamide (1.0, 3.0, 10.0mg/kg) and Ciproxifan (1.5, 3.0, 5.0mg/kg), were investigated for their ability to modulate visual spatial attention using the Five Choice Serial Reaction Time Task. The animal model used was that of cholinergic lesions of the nucleus basalis Magnocellularis (nbM) in the basal forebrain using the selective immunotoxin IgG Saporin. Thioperamide, without affecting overall accuracy, showed very strong trends towards a reduction in anticipatory responses in both sham and lesion groups and also showed a slight reduction in perseverative responses. The more potent Ciproxifan showed no overall change in accuracy but led to a reduction in the anticipatory responses in nbM lesioned animals at all three doses of the drug, returning them to equivalent levels of responses to the sham group. This effect was independent of any overall decrease in activity levels as there were no concomitant changes in response latencies or number of trials completed. Hence these pharmacological manipulations reduced the levels of impulse behaviours manifest by lesioned animals.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Progressive effects of cholinergic depletion on cortical functional properties in the somatosensory cortex of rats

Herron P, Ismail NS (2003) Progressive effects of cholinergic depletion on cortical functional properties in the somatosensory cortex of rats. Neuroscience 2003 Abstracts 61.11. Society for Neuroscience, New Orleans, LA.

Summary: The amount and duration of cholinergic depletion of basal forebrain input appear to be important for how significant the functional capacity of cortical neurons and behavior are affected. Firstly, it is not known whether there is a correlative relationship between the level of cholinergic depletion and the level of degraded functional properties or whether there is a threshold of depletion, beyond which no further degradation occurs. Secondly, it is not known whether similar levels of cholinergic depletion over different periods cause the similar or different effects on functional capacities and behavior. These experiments were done in the posteromedial barrel subfield (PMBSF) cortex of young adult Sprague-Dawley rats. Selective lesion of cholinergic neurons in the NBM was achieved with cortical or intraventricular injections of the immunotoxin (IT), 192 IgG saporin. Electrophysiological recordings and whisker use in exploratory behavior were monitored for different post-injection survival periods. Results show that cholinergic depletion causes a significant decrease in the magnitude of evoked activity and an increase in the size of receptive fields for different periods. Observations of exploratory behavior showed that animals used whiskers controlled by cholinergic depleted cortex less than the whiskers controlled by non-cholinergic depleted cortex. Thus, cholinergic depletion leads to effects that significantly alter the functional capacity of the cortex and the behavioral use of those whiskers.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory

Sarter M, Bruno J, Givens B (2003) Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory. Neurobiol Learn Mem 80:245-256. doi: 10.1016/s1074-7427(03)00070-4

Related Products: 192-IgG-SAP (Cat. #IT-01)

Extrinsic regulation of injury/growth-related gene expression in the inferior olive of the adult rat.

Buffo A, Carulli D, Rossi F, Strata P (2003) Extrinsic regulation of injury/growth-related gene expression in the inferior olive of the adult rat. Eur J Neurosci 18(8):2146-2158. doi: 10.1046/j.1460-9568.2003.02940.x

Summary: Inferior olive (IO) cells of the CNS have the ability to regenerate axons after injury, even when the injury is close to the terminal field. After administration of 2.2 µg of 192-Saporin (Cat. #IT-01) and a control immunotoxin (mouse IgG-SAP, Cat #IT-18) to each ventricle in rats, two subsets of IO cells were discovered. Each subset responded differently to injury indicating that multiple mechanisms are responsible for their intrinsic regenerative potential.

Related Products: 192-IgG-SAP (Cat. #IT-01), Mouse IgG-SAP (Cat. #IT-18)

Cholinergic activity enhances hippocampal long-term potentiation in CA1 during walking in rats.

Leung LS, Shen B, Rajakumar N, Ma J (2003) Cholinergic activity enhances hippocampal long-term potentiation in CA1 during walking in rats. J Neurosci 23(28):9297-9304. doi: 10.1523/JNEUROSCI.23-28-09297.2003

Summary: To investigate the role of the cholinergic system in long term potentiation (LTP) the authors lesioned the left and right medial septum of rats with 0.14 µg of 192-Saporin (Cat. #IT-01). LTP induced in lesioned walking animals is less robust than in control animals.

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Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin.

Tomaszewicz M, Rossner S, Schliebs R, Cwikowska J, Szutowicz A (2003) Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin. J Neurochem 87(2):318-324. doi: 10.1046/j.1471-4159.2003.01983.x

Objective: To investigate whether cortical cholinergic input affects acetyl-CoA metabolism in cholinoceptive cortical target regions.

Summary: Alzheimer’s disease subjects often show deficits in cerebral glucose metabolism. The data show evidence of differential distribution of acetyl-CoA in subcellular compartments of cholinergic and non-cholinergic nerve terminals.

Usage: Rats received 4 µg 192-IgG-SAP (Cat. #IT-01) into the left lateral ventricle.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Neonatal cholinergic lesions and development of exploration upon administration of the GABAa receptor agonist muscimol in preweaning rats.

Scattoni ML, Calamandrei G, Ricceri L (2003) Neonatal cholinergic lesions and development of exploration upon administration of the GABAa receptor agonist muscimol in preweaning rats. Pharmacol Biochem Behav 76(2):213-221. doi: 10.1016/s0091-3057(03)00191-6

Summary: The authors investigated GABAergic development in young rats lesioned with two 0.42-ng injections of 192-Saporin (Cat. #IT-01) into the third ventricle. The rats were then treated with the GABA agonist muscimol chloride and observed during locomotor and exploration tests. No change was noted in GABAergic agonist reactivity in lesioned animals.

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Does the release of acetylcholine in septal slices originate from intrinsic cholinergic neurons bearing p75NTR receptors? A study using 192 IgG-saporin lesions in rats.

Birthelmer A, Lazaris A, Riegert C, Marques Pereira P, Koenig J, Jeltsch H, Jackisch R, Cassel JC (2003) Does the release of acetylcholine in septal slices originate from intrinsic cholinergic neurons bearing p75NTR receptors? A study using 192 IgG-saporin lesions in rats. Neuroscience 122(4):1059-1071. doi: 10.1016/j.neuroscience.2003.09.001

Summary: The authors used 0.8 µg injections of 192-Saporin (Cat. #IT-01) into the medial septum and diagonal band of Broca to investigate whether release of acetylcholine was due to neurons expressing the p75 NTR.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Hilar neuropeptide Y interneuron loss in the aged rat hippocampal formation.

Cadiacio CL, Milner TA, Gallagher M, Pierce JP (2003) Hilar neuropeptide Y interneuron loss in the aged rat hippocampal formation. Exp Neurol 183(1):147-158. doi: 10.1016/s0014-4886(03)00126-2

Summary: The authors investigate the loss of neuropeptide Y-immunoreactive (NPY-I) interneurons in the dentate gyrus of aged rats. Their results show a loss of a select group of interneurons in these animals. The behavioral as well as structural changes correlated with the results of previous studies on young rats treated with 192-Saporin (Cat. #IT-01). NPY-I neurons may therefore be affected by age-related losses of cholinergic neurons in the basal forebrain.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Targeted toxins in pain.

Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043-1054. doi: 10.1016/s0169-409x(03)00102-9

Summary: The authors discuss the use of 'molecular neurosurgery' in the study of nociception. Applications using targeted toxins, which include immunotoxins, protein-toxin conjugates, or peptide-toxin conjugates, are illustrated. The authors describe the use of these molecules as research tools, as well as their potential for therapeutics. A helpful table is included that lists neuronal surface markers and class of cells targeted for each targeted toxin. Reagents discussed: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-Saporin (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP (Cat. #IT-12), Orexin-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), and acetylated LDL-SAP (Cat. #IT-08).

Related Products: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-IgG-SAP (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Orexin-B-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), Acetylated LDL-SAP (Cat. #IT-08)

A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgG-saporin lesions of the nucleus basalis and/or the septal region.

Lehmann O, Grottick AJ, Cassel JC, Higgins GA (2003) A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgG-saporin lesions of the nucleus basalis and/or the septal region. Eur J Neurosci 18(3):651-666. doi: 10.1046/j.1460-9568.2003.02745.x

Summary: Using 0.4-µl injections containing 0.4 µg of 192-Saporin (Cat. #IT-01) into either the nucleus basalis magnocellularis, the medial septum/vertical limb of the diagonal band of Broca, or both, the authors examined the contributions of the p75 receptor-positive neurons on cognitive function in rats. Data indicate there is a functional dissociation between the two pathways in attention and memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

The role of the septo-hippocampal cholinergic projection in T-maze rewarded alternation.

Kirby BP, Rawlins JN (2003) The role of the septo-hippocampal cholinergic projection in T-maze rewarded alternation. Behav Brain Res 143(1):41-48. doi: 10.1016/s0166-4328(03)00005-6

Summary: 192-Saporin (Cat. #IT-01) has been used extensively to lesion cholinergic projections to the medial septum from the hippocampal region. It is not yet clear how post-lesion neural regeneration may affect the results. The authors used four 50-ng injections of 192-Saporin to investigate effects prior to any suspected neural regeneration. Significant microglia activation, loss of hippocampal acetylcholinesterase, and a clear inflammatory response were observed; but there was no impairment of spatial working memory.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Lesions of the basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning.

Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH (2003) Lesions of the basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron 38(5):819-829. doi: 10.1016/s0896-6273(03)00288-5

Summary: Neuronal plasticity has been associated with normal learning. The authors wished to investigate the role of the cholinergic basal forebrain (CBF) system in learning motor skills. Rats received bilateral 95-ng injections of 192-Saporin (Cat. #IT-01) in either the medial septum, the nucleus basalis magnocellularis, or both. The results indicate that lesioned animals, with many aspects of attention still preserved, are unable to adapt attention to meet the demands of a particular task. The authors conclude that the CBF system may be implicated in learning forms that require plasticity of cortical representations.

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Behavioral patterns under cholinergic control during development: lessons learned from the selective immunotoxin 192 IgG saporin.

Ricceri L (2003) Behavioral patterns under cholinergic control during development: lessons learned from the selective immunotoxin 192 IgG saporin. Neurosci Biobehav Rev 27(4):377-384. doi: 10.1016/s0149-7634(03)00068-x

Summary: The author reviews the effects of 192-Saporin (Cat. #IT-01) neonatal lesions (0.42 µg in each hemisphere) on the cholinergic basal forebrain system in rats. Short-term effects are seen in pups in learning tasks, as well as ultrasound vocalizations. Longer term effects are seen in task-specific behaviors. Data suggest that the extent of these effects are linked to the attentional load of the task. The age of the animal when lesioned may also play a role in the extent of the deficits caused by 192-Saporin; studies show that early in the first week of life is a particularly vulnerable period.

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Neonatal 192 IgG-saporin lesion of forebrain cholinergic neurons: focus on the life span?

Pappas BA, Sherren N (2003) Neonatal 192 IgG-saporin lesion of forebrain cholinergic neurons: focus on the life span?. Neurosci Biobehav Rev 27(4):365-376. doi: 10.1016/s0149-7634(03)00067-8

Summary: In this review, the authors discuss the use of 192-Saporin in the investigation of neurodevelopmental disorders, and propose that the effects of these lesions are amplified as the animal ages and experiences normal age-related synapse loss.

Related Products: 192-IgG-SAP (Cat. #IT-01)

A role for the basal forebrain cholinergic system in estrogen-induced disinhibition of hippocampal pyramidal cells.

Rudick CN, Gibbs RB, Woolley CS (2003) A role for the basal forebrain cholinergic system in estrogen-induced disinhibition of hippocampal pyramidal cells. J Neurosci 23(11):4479-4490. doi: 10.1523/JNEUROSCI.23-11-04479.2003

Summary: Estrogen plays a strong regulatory role in control of synaptic input to the hippocampus of female rats. Injection of 0.22 µg of 192-Saporin (Cat. #IT-01) directly into the medial septum eliminated NGFr-positive cholinergic neurons of the basal forebrain, producing evidence that estrogen-induced disinhibition is partially dependent on these neurons. GABAergic synapses were also found to be involved in this system.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Neural stem cells and cholinergic neurons: Regulation by immunolesion and treatment with mitogens, retinoic acid, and nerve growth factor.

Calza L, Giuliani A, Fernandez M, Pirondi S, D'Intino G, Aloe L, Giardino L (2003) Neural stem cells and cholinergic neurons: Regulation by immunolesion and treatment with mitogens, retinoic acid, and nerve growth factor. Proc Natl Acad Sci U S A 100(12):7325-7330. doi: 10.1073/pnas.1132092100

Summary: The authors explore the influence of exogenous administration of hormones, cytokines, and neurotrophins on stem cells following a lesion. Rats were treated with 2 or 3 µg of 192-Saporin (Cat. #IT-01) into the cerebral ventricles, which induced a lesion of the cholinergic system in the basal forebrain. The surgery was followed by infusion of EGF, bFGF, and NGF into the lesioned area, as well as addition of retinoic acid to the food pellets. This pharmacological control of endogenous neural stem cells increased the number of proliferating cells in both lesioned and non-lesioned animals, as well as improved performance in a water maze test.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Role of the medial septum diagonal band of Broca cholinergic neurons in oestrogen-induced spine synapse formation on hippocampal CA1 pyramidal cells of female rats.

Lam TT, Leranth C (2003) Role of the medial septum diagonal band of Broca cholinergic neurons in oestrogen-induced spine synapse formation on hippocampal CA1 pyramidal cells of female rats. Eur J Neurosci 17(10):1997-2005. doi: 10.1046/j.1460-9568.2003.02637.x

Summary: Estrogen effects on the hippocampus are known to be mediated by subcortical structures. The authors examined the role that the medial septum diagonal band of Broca (MSDB) plays in this mediation. An injection of 0.5 µg of 192-Saporin (Cat. #IT-01) into the right lateral ventricle of rats was used to specifically investigate the role of cholinergic MSDB neuron projections to the hippocampus, since many of these neurons express estrogen receptors. The data suggest that septo-hippocampal cholinergic neurons are involved in mediating estrogen effects on the hippocampus.

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Effects of hippocampal cholinergic deafferentation on learning strategy selection in a visible platform version of the water maze.

Bizon JL, Han JS, Hudon C, Gallagher M (2003) Effects of hippocampal cholinergic deafferentation on learning strategy selection in a visible platform version of the water maze. Hippocampus 13(6):676-684. doi: 10.1002/hipo.10113

Summary: To investigate the effect of depleted acetylcholine (Ach) levels in the hippocampus on learning strategies that are thought to utilize the hippocampus, the authors lesioned the medial septum/vertical limb of the diagonal band of Broca in rats with two injections of 75 and 50 ng of 192-Saporin (Cat. #IT-01). The unexpected result was that a hippocampal place strategy was promoted in the absence of Ach.

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192 IgG-saporin lesions to the nucleus basalis magnocellularis (nBM) disrupt acquisition of learning set formation.

Bailey AM, Rudisill ML, Hoof EJ, Loving ML (2003) 192 IgG-saporin lesions to the nucleus basalis magnocellularis (nBM) disrupt acquisition of learning set formation. Brain Res 969(1-2):147-159. doi: 10.1016/s0006-8993(03)02294-7

Summary: Previous studies by Bailey and others have used quisqualic acid to lesion the nucleus basalis (nBM) in order to understand Alzheimer’s disease. Injections of 75 ng of 192-Saporin (Cat. #IT-01) were made into each of four sites in the rat nBM. Behavioral tests showed initial learning set deficits followed by recovery, whereas with quisqualic acid lesions, the deficits were profound. The authors conclude noncholinergic neurons are involved in learning set formation.

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Effects of septal grafts on acetylcholine release from rat hippocampus after 192 IgG-saporin lesion.

Hilgert M, Hartmann J, Loffelholz K, Jeltsch H, Cassel JC, Klein J (2003) Effects of septal grafts on acetylcholine release from rat hippocampus after 192 IgG-saporin lesion. Neurochem Res 28(3-4):467-472. doi: 10.1023/a:1022852819018

Summary: A model for transplantation efficacy was created using injections of 400 ng each into the vertical limb of the rat diagonal band of Broca and the medial septum for the specific removal of cholinergic neurons. Thirteen months after lesioning, sham-operated animals had measured acetylcholine release at 20% of control. 192-Saporin (Cat. #IT-01)-lesioned animals were transplanted with fetal septal cells 15 days after lesioning. Thirteen months later, their septal level of acetylcholine release was near normal (71%) of controls. A serotonin uptake inhibitor briefly stimulated acetylcholine release similar to sham control animals.

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Effects of septal cholinergic lesion on rat exploratory behavior in an open-field.

Lamprea MR, Cardenas FP, Silveira R, Walsh TJ, Morato S (2003) Effects of septal cholinergic lesion on rat exploratory behavior in an open-field. Braz J Med Biol Res 36(2):233-238. doi: 10.1590/s0100-879x2003000200011

Summary: Exploratory behavior triggered by novelty involves the medial septum. The authors lesioned the medial septum in rats with 237.5-ng injections of 192-Saporin (Cat. #IT-01) and examined the behavior of these animals in a model for novelty. The results suggest not only do septohippocampal cholinergic mechanisms contribute to the motivation to explore new environments, they also are related to the acquisition and storage of spatial information.

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Neurotransmitter release and its presynaptic modulation in the rat hippocampus after selective damage to cholinergic or/and serotonergic afferents.

Birthelmer A, Ehret A, Amtage F, Förster S, Lehmann O, Jeltsch H, Cassel JC, Jackisch R (2003) Neurotransmitter release and its presynaptic modulation in the rat hippocampus after selective damage to cholinergic or/and serotonergic afferents. Brain Res Bull 59(5):371-381. doi: 10.1016/s0361-9230(02)00930-9

Summary: Previous studies have investigated some of the modulatory mechanisms present in the denervated hippocampus. These studies have used nonselective denervation models, therefore it is difficult to assign results to the lesion of any specific system. This study examined the interaction of lesions caused by 192 Saporin (Cat. #IT-01, 0.4 µg injected into the medial septum/diagonal band of broca) and 5,7-DHT. The authors were able to establish controlled and selective damage to more than one transmitter system, allowing examination of the interaction between multiple-lesioned systems.

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Specific contributions of the basal forebrain corticopetal cholinergic system to electroencephalographic activity and sleep/waking behaviour.

Berntson GG, Shafi R, Sarter M (2002) Specific contributions of the basal forebrain corticopetal cholinergic system to electroencephalographic activity and sleep/waking behaviour. Eur J Neurosci 16(12):2453-2461. doi: 10.1046/j.1460-9568.2002.02310.x

Summary: There is a large amount of data suggesting the basal forebrain cholinergic system plays an important part in arousal and REM sleep. In this study the authors used 192-Saporin (Cat. #IT-01, 0.05 µg injected into the basal forebrain of each hemisphere) to lesion the corticopetal projection and examined cortical EEG activity across sleep/wake states. Lesioned animals displayed significantly reduced high frequency EEG activity across all stages of sleeping and wakefulness, indicating that the basal forebrain cholinergic system may exert a general activational effect on the cortical mantle.

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Effects of lesions of basal forebrain cholinergic neurons in newborn rats on susceptibility to seizures.

Silveira DC, Cha BH, Holmes GL (2002) Effects of lesions of basal forebrain cholinergic neurons in newborn rats on susceptibility to seizures. Dev Brain Res 139:277-283. doi: 10.1016/s0165-3806(02)00586-2

Summary: It has previously been shown that adult rats treated with the cholinergic lesioning agent 192-Saporin (Cat. #IT-01) display increased susceptibility to generalized seizures. Here, the authors studied the effects of 200 ng intracerebroventricular injections of 192-Saporin in neonatal rats. Although treated rats did not demonstrate differences in seizure duration or EEG ictal duration, a significantly shorter latency to seizure onset was observed. No significant differences were observed in spatial learning between treated and control rats.

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Long-term plastic changes in galanin innervation in the rat basal forebrain.

Hartonian I, Mufson EJ, de Lacalle S (2002) Long-term plastic changes in galanin innervation in the rat basal forebrain. Neuroscience 115(3):787-795. doi: 10.1016/s0306-4522(02)00453-0

Summary: One hallmark of Alzheimer’s disease is the hyperinnervation of surviving cholinergic basal forebrain neurons with galanin-IR fibers. This may exacerbate the cholinergic deficit. The authors injected 192-Saporin (140 nl of 0.075 mg/ml, Cat. #IT-01) into the diagonal band of Broca of rats. An increase in galanin immunoreactivity was observed as early as 1 hour post-injection, and persisted as long as 6 months.

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Effects of cholinergic lesions produced by infusions of 192 IgG-saporin on glucocorticoid receptor mRNA expression in hippocampus and medial prefrontal cortex of the rat.

Helm KA, Han JS, Gallagher M (2002) Effects of cholinergic lesions produced by infusions of 192 IgG-saporin on glucocorticoid receptor mRNA expression in hippocampus and medial prefrontal cortex of the rat. Neuroscience 115(3):765-774. doi: 10.1016/s0306-4522(02)00487-6

Summary: The authors investigated the loss of cholinergic support from the basal forebrain, a hallmark of aging, on glucocorticoid receptor mRNA expression in various target sites. 192-Saporin (Cat. #IT-01) was injected into either the nucleus basalis magnocellularis/substantia innominata (0.2 µl of 0.25 mg/ml) or the medial septum/vertical limb of the diagonal band (0.3 µl of 0.25 mg/ml). Treated rats sustained a significant decrease in glucocorticoid receptor mRNA levels in the hippocampus and medial prefrontal cortex.

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Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats.

Ricceri L, Hohmann C, Berger-Sweeney J (2002) Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats. Brain Res 954(2):160-172. doi: 10.1016/s0006-8993(02)03172-4

Summary: Previous data have shown that cholinergic lesions on postnatal day (pnd) 7 in rats produce learning impairments on pnd 15. Using 0.2 µg injections of 192-Saporin (Cat. #IT-01) into the lateral ventricles, the authors investigated the effect of lesioning animals at pnd 1 and 3. The treated animals demonstrated sex-specific deficits in some cognitive behaviors, as well as changes in neurochemistry and cortical organization.

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Effect of selective cholinergic lesioning of basal forebrain with 192 IgG-saporin on neurotransmitter concentrations in hippocampus of rat

Nagle RA, Liberatore MA, Zombon NJ, Pokala VN, Li PK, Pokala VN, Johnson DA (2002) Effect of selective cholinergic lesioning of basal forebrain with 192 IgG-saporin on neurotransmitter concentrations in hippocampus of rat. Neuroscience 2002 Abstracts 880.6. Society for Neuroscience, Orlando, FL.

Summary: In vivo microdialysis techniques were used to examine the effects of lesioning of cholinergic neurons of the medial septum using the selective cholinergic neurotoxin 192-IgG-Saporin (SAP), on hippocampal acetylcholine (ACh), glutamate and GABA in adult male Sprague Dawley rats. High and low (1.0 and 0.22 μg) doses of SAP were used for infusion into the basal forebrain. SAP treated rats showed a significant dose dependent decrease of 74% and 59% in ACh for the high and low doses respectively, compared to controls. Glutamate decreased 50% in animals treated with 0.22 μg SAP. The data suggest that lesioning of basal forebrain neurons with SAP results in changes in neurotransmitter concentrations in the hippocampus.

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192 IgG-saporin-induced cortical, cholinergic deafferentation in rats produces a dissociation in the function of prelimbic/infralimbic and orbitofrontal cortex in an attentional set-shifting task

McGaughy JA, Rubin S, Stollstorff M, Baxter MG, Eichenbaum HB (2002) 192 IgG-saporin-induced cortical, cholinergic deafferentation in rats produces a dissociation in the function of prelimbic/infralimbic and orbitofrontal cortex in an attentional set-shifting task. Neuroscience 2002 Abstracts 674.4. Society for Neuroscience, Orlando, FL.

Summary: Converging data support the hypothesis that cholinergic afferents to the cortex mediate attentional processes. Rats with selective cholinergic lesions of the nucleus basalis magnocellularis produced by 192 IgG-saporin (SAP) show deficits in attentional performance. These deficits are highly correlated with diminished cholinergic efflux in the infralimbic/prelimbic (IL/PL) cortex during attentional testing. Excitotoxic lesions of the IL/PL in rats trained in an attentional set-shifting task did not impair the initial discimination, a novel discrimination with the previously relevant dimension (intradimensional shift; IDS) or reversal learning, but did impair the ability to shift attention to the previously irrelevant stimulus dimension (extradimensional shifting; EDS). It is not known from the previous study whether the loss of cortical, cholinergic afferents alone would be sufficient to produce the EDS deficit. Consequently, infusions of SAP(0.01 μg/μl; 0.25 μl) were made into either the IL/PL or the orbitofrontal (OF) cortex. Rats were then trained in the same attentional set-shifting task. Subjects had to discriminate between stimuli based on one of two perceptual dimensions, odor or digging media with both dimensions present on all trials. Preliminary analyses show that neither OF nor IL/PL lesions impair the initial discrimination or the IDS. However, IL/PL lesions impair the EDS whereas OF lesions impair reversal learning. These data support dissociable roles of cholinergic afferents to OF and IL/PL in attentional set-shifting.

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Effects of septohippocampal cholinergic deafferentation on attention and learning

Sarter MF, Draut A, Herzog CD, Bruno JP (2002) Effects of septohippocampal cholinergic deafferentation on attention and learning. Neuroscience 2002 Abstracts 674.8. Society for Neuroscience, Orlando, FL.

Summary: In contrast to the extensively studied attentional functions mediated via basal forebrain corticopetal cholinergic projections, the role of septohippocampal cholinergic projections in attention and memory have remained poorly understood. For example, selective lesions of this system have limited, if any, effects on spatial memory performance. The present experiment initially tested the effects of intraseptal injections of the cholinergic neurotoxin 192-IgG saporin (SAP) on the performance of rats in an operant procedure designed to assess sustained attention. Despite almost complete hippocampal cholinergic deafferentation, the lesioned animals' attentional performance remained identical to that of controls. Task parameter manipulations designed to further increase the demands on attentional processing also failed to reveal an effect of the lesions. However, lesioned animals were superior in acquiring a version of this task in which the propositional rules of the task were reversed. Lesioned rats achieved >65% hits after 14 training sessions, while intact rats did not reach this level of performance after 50 sessions of training. As the acquisition of the reversal of such extensively practiced response rules suffers from interference from the rather automatic processing of the original rules, loss of hippocampal cholinergic inputs may have reduced the interference that resulted from the processing of the original rules. Thus, hippocampal cholinergic inputs are speculated to modulate, but not to be necessary for, the recall of propositional rules. Collectively, the available data completely dissociate the functions of septo-hippocampal and corticopetal cholinergic projections.

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Estrogen-induced disinhibition of hippocampal CA1 pyramidal cells depends on basal forebrain cholinergic neurons

Rudick CN, Gibbs RB, Woolley CS (2002) Estrogen-induced disinhibition of hippocampal CA1 pyramidal cells depends on basal forebrain cholinergic neurons. Neuroscience 2002 Abstracts 740.6. Society for Neuroscience, Orlando, FL.

Summary: Estrogen (E) increases dendritic spine and synapse density on hippocampal pyramidal cells, both in vivo and in vitro. In both cases, the increase in spine/synapse density is preceded by transient disinhibition. Based on in vitro studies, this transient disinhibition is likely to be involved in the mechanism of the subsequent increase in spine density. In adult female rats, where E increases spine/synapse density on CA1 pyramidal cells, it is unknown whether E acts within the hippocampus itself and/or through hippocampal afferents to regulate synaptic changes. Considerable evidence suggests that the basal forebrain (BF) cholinergic system could be involved in mediating E’s effects in the hippocampus. Therefore, we tested the ability of E to disinhibit CA1 pyramidal cells in adult female rats in which BF cholinergic neurons were eliminated by infusion of 192IgG-saporin toxin (SAP) into the medial septum. Two weeks after SAP or SHAM lesion, rats were ovariectomized and treated with E or oil (O) 3 days later. Synaptically evoked inhibitory postsynaptic currents (eIPSCs) and miniature IPSCs (mIPSCs) in CA1 pyramidal cells were evaluated 24h after E or O, the timepoint at which disinhibition occurs. As previously shown, E decreased eIPSC amplitude and mIPSC frequency at 24h. Additionally, E-induced disinhibition was significantly reduced in SAP lesioned rats, but it was not completely blocked. These data demonstrate that the BF cholinergic system is involved in E-induced disinhibition of CA1 pyramidal cells, but that other cells may also be involved.

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Neonatal dopamine lesions: Cognitive impairment or hyper-sensitivity to stress

Sherren N, Pappas BA (2002) Neonatal dopamine lesions: Cognitive impairment or hyper-sensitivity to stress. Neuroscience 2002 Abstracts 782.19. Society for Neuroscience, Orlando, FL.

Summary: Neonatal rat pups given a selective cholinergic immunotoxin exhibit large reductions in cortical (30-70%) and hippocampal (75%) choline acetyltransferase (ChAT) activity which persist into adulthood. However these rats do not show spatial learning deficits in the Morris water maze despite the sensitivity of this task to muscarinic receptor blockade and hippocampal damage. We hypothesized that while the developing brain may be able to compensate for early loss of ACh transmission, it may also become more vulnerable to additional disruptions in other systems. We combined postnatal day 7 i.c.v. administration of 192 IgG-saporin with 6-hydroxydopamine (6-OHDA) to lesion either or both ACh and DA terminals respectively. 6-OHDA treatment produced a 90% loss in striatal and a 75% loss in frontocortical DA levels. No differences in exploratory behaviour were found between ACh, DA and ACh/DA lesioned rats. However upon placement in the Morris water maze, DA depleted rats displayed behaviour suggestive of panic and were unable to search for the hidden platform effectively. In order to determine whether the DA depletion was producing a spatial learning deficit or an exaggerated reaction to a stressor (the hidden platform task), a separate cohort of lesioned rats was tested in the cued platform version of the maze. Just prior to testing, the rats received 4 days of shaping in order to gradually habituate them to the pool and teach them the task. Platform location improved in half of the DA and ACh/DA rats, but never approached control or ACh only levels. Thus rats with neonatal DA lesions may be particularly sensitive to stressful tasks. This sensitivity may be partly dependent on lesion extent.

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Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task.

Gibbs RB (2002) Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task. Horm Behav 42(3):245-257. doi: 10.1006/hbeh.2002.1825

Summary: The author investigated the role of cholinergic neurons of the basal forebrain in cognitive function using a long-term hormone replacement model in rats. Septal infusions of either 1.0 µg or 0.22 µg 192-Saporin (Cat. #IT-01) prevented the therapeutic effects of hormone replacement on cognitive function.

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In vivo strategies for stem cells regulation in the adult brain: A chance for cholinergic neurons

Fernandez M, Giuliani A, Giardino L, Calza L (2002) In vivo strategies for stem cells regulation in the adult brain: A chance for cholinergic neurons. Neuroscience 2002 Abstracts 483.14. Society for Neuroscience, Orlando, FL.

Summary: Degenerative diseases represent a severe problem in view of very limited repair capability of nervous system. In order to use stem cells in the adult CNS for repair purpose, we are exploring the possibility to influence, in vivo, proliferation, migration and phenotype lineage of stem cells in adult brain using a growth factor, hormone and cytokine cocktail. In this study we used substances appropriate for in vitro cholinergic differentiation in animals lesioned with icv administration of the cholinergic neurons immunotoxin 195IgG-saporine (3microg/4,5microl). Four months after lesion, no ChAT-positive neurons were found in the basal forebrain, acetylcolinesterase-reactive fibres and ChAT activity in the cerebral cortex and hippocampus dramatically decrease, and animals are severely impaired in water maze learning task. An Alzet osmotic Minipump for chronic release (over 14 days) of the mitogen EGF (360ng/days) was then implanted and connected to a icv catheter. This treatment increases proliferation rate in SVZ in lesioned and unlesioned animals as indicated by the widespread distribution of BrDU-positive nuclei in the forebrain. Rats were then treated with retinoic acid (2.25 mg/day, orally). This treatment reduces Ki67 protein in the SVZ in lesioned rats, and this could indicate a progression toward differentiation. TrkA-positive innervation also increase in the basal forebrain of EGF+retinoic acid treated rats and ChAT activity is lightly, but significantly raises by combined EGF + retinoid acid treatment in the hippocampus.

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Spatial memory impairments in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis

Butt AE, Hamilton DA, Duerkop MS, King DD, Gibbs RB, Sutherland RJ (2002) Spatial memory impairments in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis. Neuroscience 2002 Abstracts 378.5. Society for Neuroscience, Orlando, FL.

Summary: In three experiments we test the hypothesis that the nucleus basalis magnocellularis (NBM) is involved in spatial learning and memory. Rats received 192 IgG-saporin lesions of the NBM or sham surgeries prior to testing in the Morris water maze task. In Exp. 1, rats were trained to find a hidden platform, receiving 4 trials per day. In Exp. 2, rats were trained with the hidden platform located in one position on the first 3 trials and in a second position on the 4th trial each day. In Exp. 3, rats were trained in a novel environment with the hidden platform located in a new position every 2 days. In Exp. 1, the NBM lesion group showed longer mean latencies to locate the platform than controls on the first several days of testing. Group differences were greatest on the earlier trials within the 4-trial blocks, with performance in the NBM lesion group recovering to control levels on later trials. In Exp. 2, performance in the NBM lesion group was again impaired, with greater group differences occurring on earlier trials within the 4-trial blocks. In Exp. 3, performance during the first block of trials for the different platform locations did not differ between groups, whereas performance on the 1st trial within the second block of trials was impaired in the NBM lesion group. Analysis of AChE staining and assay of ChAT activity confirm the selectivity of the lesions to the cortically-projecting neurons of the NBM and the sparing of cholinergic medial septal projections to hippocampus. Data suggest that NBM lesions interfere with consolidation of memory for spatial locations.

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Visual-spatial conditional discrimination learning in rats with lesions of cholinergic medial septal/diagonal band neurons

Janisiewicz AM, Rodefer JS, Baxter MG (2002) Visual-spatial conditional discrimination learning in rats with lesions of cholinergic medial septal/diagonal band neurons. Neuroscience 2002 Abstracts 378.6. Society for Neuroscience, Orlando, FL.

Summary: Loss of cholinergic neurons in the medial septum/vertical limb of the diagonal band (MS/VDB) seems to impair visual-spatial conditional learning tasks, in which the location of a correct spatial response is signaled by a visual cue. We examined visual-spatial conditional learning in several automated touchscreen tasks in male Long-Evans rats with selective lesions of MS/VDB cholinergic neurons produced by 192 IgG-saporin. One group of rats was first trained on a simple visual discrimination followed by two visual-spatial conditional tasks. In the first conditional task the rat responded to the left or right member of a pair of identical visual stimuli depending on which stimulus pair was displayed. In the second conditional task one of two centrally-displayed stimuli directed the rat to respond to an illuminated panel on the left or right, depending on which visual stimulus was displayed centrally. MS/VDB-lesioned rats were unimpaired on the simple visual discrimination and the first conditional task, but were severely impaired relative to controls on the second conditional task. However, in a second group of rats trained only on the second conditional task, MS/VDB-lesioned rats were superior to controls, who performed poorly. The different results between the two cohorts appear to reflect transfer effects present in the control rats that are absent in the MS/VDB-lesioned rats. These findings suggest that conditional learning deficits following MS/VDB cholinergic lesions may depend on the particular strategy used to solve the conditional task, which may in turn be influenced by the animal's testing history.

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Effect of 192-IgG saporin lesions of the entire basal forebrain on emotional and spatial learning

Frick KM, Kim JJ, Baxter MG (2002) Effect of 192-IgG saporin lesions of the entire basal forebrain on emotional and spatial learning. Neuroscience 2002 Abstracts 379.1. Society for Neuroscience, Orlando, FL.

Summary: Scopolamine administration studies suggest that acetylcholine appears to be important for acquisition of contextual fear conditioning (FC), but its involvement in consolidation of fear remains a matter of debate. We examined the role of the basal forebrain cholinergic system in emotional learning and memory by testing male Sprague-Dawley rats with 192 IgG-saporin lesions of basal forebrain cholinergic neurons in contextual and tone FC. Lesions were made either 7 days before (n=10) or one day after (n=10) FC and targeted all basal forebrain nuclei; sham-operated rats (n=5 per condition) served as a comparison. Spatial learning in a one-day water maze task provided a comparison for effects of the lesions on FC. Pretraining lesions had no effect on freezing to tone or context. Posttraining lesions produced a mild impairment in freezing to context, but had no effect on freezing to tone. Both groups were impaired in production of 22 kHz ultrasonic vocalization (USV) associated with fear. Performance on water maze training trials was surprisingly impaired in lesioned rats, although this impairment did not interact with training block and probe trial performance was unimpaired, suggesting that it did not reflect a learning impairment. Radioenzymatic assays of choline acetyltransferase activity in neocortex and hippocampus revealed substantial (>80%) decreases in cholinergic input. These data suggest that conditioned fear-induced USV is more sensitive to the loss of basal forebrain cholinergic neurons than conditioned fear-induced freezing.

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The effects of 17ß-estradiol on odor discrimination of ovariectomized and intact young and aged rats following unilateral lesions of the nucleus of the horizontal diagonal band of broca (HDB)

Bradley QR, Borowski TB, de Lacalle S (2002) The effects of 17ß-estradiol on odor discrimination of ovariectomized and intact young and aged rats following unilateral lesions of the nucleus of the horizontal diagonal band of broca (HDB). Neuroscience 2002 Abstracts 385.3. Society for Neuroscience, Orlando, FL.

Summary: Estradiol exerts beneficial effects on cognitive performance. The present study was designed to investigate the effect of estradiol on learning and memory following the destruction of cholinergic neurons of the HDB, a basal forebrain region that exhibits significant neuronal loss during aging and may underlie the cognitive deficits associated with Alzheimers disease. Young (3 months old) and aged (20 months old) ovariectomized and gonadally intact Fisher 344 female rats were given unilateral lesions of the HDB with the cholinergic immunotoxin 192 IgG-saporin (.075mg/ml). Starting one week after surgery rats were tested on an odor discrimination task whereby rats were trained to associate a food reward buried within a scented cup of sand relative to a dissimilar scented cup of sand that contained no reward. Following stable levels of acquisition and retention, subjects were exposed to a reversal procedure where the previously unrewarded cup was now baited. Odor discrimination acquisition, retention and reversal were assessed before and after one month of 17β-estradiol exposure or placebo. Analysis of learning curves revealed that young rats performed better than the aged animals independent of estradiol treatment during the reversal component of the task. However, within each age group 17β-estradiol treatment facilitated performance in ovariectomized rats relative to placebo controls. These findings shed new light on the cognitive enhancing properties of estradiol in age-related cholinergic neurodegenerative disorders.

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Stem cell transplantation strategies for a lesion model of Alzheimer’s disease

Sugaya K, Qu T (2002) Stem cell transplantation strategies for a lesion model of Alzheimer’s disease. Neuroscience 2002 Abstracts 237.1. Society for Neuroscience, Orlando, FL.

Summary: Stem cell transplantation strategies are advocated in Alzheimer's disease (AD) neuroregeneration therapy. Since basal cholinergic neurons, which selectively degenerate in AD, extend long projections into the cortex and hippocampus, a stumbling block for neuroreplacement treatment in AD is whether these degenerating cholinergic cells can be replaced by the transplantation of stem cells. To answer this question, we transplanted human neural stem cells (HNSCs) into nucleus basalis magnocelluerlis (NBM) lesion model rats. The lesion was induced either by an injection of ibotenic acid or by anti-NGF receptor antibody conjugated with saporin. HNSCs were labeled by the incorporation of bromodeoxy uridine (BrdU) into the nuclei and simultaneously injected into the contralateral side of the lateral ventricle (Qu, 2001) of the NBM lesioned animal. Four weeks after the surgery, the brain was examined by immunohistochemistry for choline acetyl transferase (ChAT), βIII-tubulin, glial fibrillary acidic protein (GFAP), and BrdU. We detected many GFAP-positive cells in the lesion area, but they were not BrdU-positive, indicating astrocytes activation in this area. We found BrdU-positive cells with ChAT or βIII-tubulin immunoreactivity in the lesion site, indicating that HNSCs migrated to the lesion site and had differentiated into cholinergic and other neuronal cells. These neuronally differentiating HNSCs were rather morphologically premature neurons, and although we have yet to confirm the physiological function or any projections into the hippocampus or cortex, our results could indicate that we have pioneered a positive study of neuroreplacement treatment for cholinergic neurons in AD.

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Effects of cholinergic depletion on the expression of synaptic proteins and functional properties in the rat somatosensory cortex

Herron P, Ismail NS (2002) Effects of cholinergic depletion on the expression of synaptic proteins and functional properties in the rat somatosensory cortex. Neuroscience 2002 Abstracts 256.1. Society for Neuroscience, Orlando, FL.

Summary: Loss of acetylcholine (ACh) has been shown to contribute to numerous cognitive, perceptual, and behavioral deficits in animal studies and in Parkinson and Alzheimer’s patients. The purposes of these experiments were to determine the effects of cholinergic depletion on the expression of glutamic acid decarboxylase (GAD), N-methyl-D-aspartate (NMDA) receptors, synaptophysin, and CaMKII and on functional properties of single neurons in the somatosensory cortex. These experiments were done in the posteromedial barrel subfield (PMBSF) cortex of young adult Sprague-Dawley rats. Selective lesion of cholinergic neurons in the NBM was achieved with intraventricular injections of the immunotoxin (IT), 192 IgG saporin. Electrophysiological recordings and Western blot analyses for the expressions of GAD, NMDA receptors, and synaptophysin were done after a two-week post-injection survival period. The magnitude of evoked and spontaneous activities and the receptive field size of single neurons in the somatosensory cortex were investigated. Recordings and Western blot analyses were obtained from the same area of the PMBSF cortex. Results show that cholinergic depletion causes a significant decrease (11.7%) in the magnitude of evoked activity and an increase (10.7%) in the size of receptive fields. GAD, NMDA receptors, and synaptophysin levels in the in the PMBSF cortex were reduced 25%, 12%, 29%, and 12.5% respectively, in cholinergic depleted animals. Thus, cholinergic depletion leads to effects that significantly alter the expression of synaptic proteins involved in plasticity, learning, and memory.

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192-IgG-saporin lesions of the cholinergic basal forebrain do not impair attentional set-shifting, but do increase latency to dig

Tait DS, McGaughy JA, Latimer MP, Brown VJ (2002) 192-IgG-saporin lesions of the cholinergic basal forebrain do not impair attentional set-shifting, but do increase latency to dig. Neuroscience 2002 Abstracts 286.2. Society for Neuroscience, Orlando, FL.

Summary: The cholinergic neurons of the basal forebrain which project to cortex, the thalamic reticular nucleus and the amygdala, have been implicated in vigilance and attention (Sarter and Bruno, 2000). This study examined the effects of basal forebrain cholinergic depletion on a shifting of attentional set. Male Lister hooded rats were stereotaxically injected with 192-IgG-saporin into basal forebrain to effect cholinergic depletion. Doses of 0.20mg or 0.25mg resulted in a loss of cholinergic cells in the basal forebrain and depletion of cholinergic input to frontal cortex and the thalamic reticular nucleus. The test of attentional set shifting task for the rat (Birrell and Brown, 2000) measures acquisition, reversal learning and shifting of attention between stimulus dimensions. Trials to criterion and latency to dig were recorded. There was no evidence of impairment in acquisition, reversal learning or set-shifting performance in the rats with cholinergic depletion compared to controls. There was a significant effect on dig latency. This was apparent only when the lesioned rats first approached an incorrect (i.e. unbaited bowl): although no more likely to dig in the incorrect bowl, the lesioned rats took longer to then move to the correct bowl. No effects were seen on dig latency if the rat by chance approached the correct bowl first. We conclude that attentional set-shifting is spared following basal forebrain lesions. Changes in latency in the task might be account for by deficits in sustained attention (attention to task) or related to frustration.

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Apoptotic affect of cholinergic denervation and hippocampal sympathetic ingrowth following selective immunolesioning with 192-IgG-saporin in rat hippocampus

Kolasa K, Harrell LE (2002) Apoptotic affect of cholinergic denervation and hippocampal sympathetic ingrowth following selective immunolesioning with 192-IgG-saporin in rat hippocampus. Neuroscience 2002 Abstracts 295.16. Society for Neuroscience, Orlando, FL.

Summary: In rat, injection of specific cholinotoxin, 192IgG-saporin, into the medial septum (MS) results not only in a selective denervation of hippocampus(CD), but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus(HSI). A similar process, in which sympathetic axons invade hippocampus, may also occur in Alzheimer's disease(AD). Our previous studies using MS electrolytic lesions suggested that HSI and CD appear to induce opposite effect on apoptotic markers. Apoptosis has also been implicated in some aspects of AD. By using 192IgG-saporin we have been able to more specifically and precisely study the affect of apoptosis on HSI and CD. Thus, 12 weeks after injection we measured apoptotic protein expression and DNA degradation using Western blot and in situ techniques e.x. TdT-mediated dUTP nick end labeling(TUNEL). Choline acetyltransferase activity (ChAT) and norepinephrine (NE) level was also detected. Like the previous results, we have found increase in apoptotic markers in CD group, while HSI reduced or normalized apoptotic effect to the control group level. We also found decrease in ChAT activity in HSI and CD groups of dorsal hippocampus.The results of the study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produced protective effect in the process of programmed cell death in rat dorsal hippocampus.

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Habituation and dexamethasone (DEX) suppression of the stress response following selective lesions of cholinergic input to hippocampus in rats

Helm KA, Ziegler DR, Gallagher M (2002) Habituation and dexamethasone (DEX) suppression of the stress response following selective lesions of cholinergic input to hippocampus in rats. Neuroscience 2002 Abstracts 370.1. Society for Neuroscience, Orlando, FL.

Summary: Hippocampal neurons have been identified as targets for glucocorticoids that exert inhibitory control over hypothalamic-pituitary-adrenocortical (HPA) axis activity. Prior research has shown that selective removal of cholinergic input to the hippocampus reduces mRNA expression for low-affinity glucocorticoid receptors, while leaving unaffected both mineralocorticoid receptor mRNA and basal levels of circulating corticosterone (CORT). The current study investigated the possibility that loss of cholinergic support from cells in the basal forebrain alters the CORT response to stress. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of 30 min restraint stress. Blood samples taken before, during and after stress on Day 1 revealed a prolonged elevation of CORT in response to acute stress in cholinergic lesioned rats. After 5 days of chronic stress, however, both groups significantly habituated to the stressor, as indicated by similarly low CORT profiles throughout both the response and recovery period. Against this similar background, rats were administered a Dexamethasone (DEX) challenge on Day 6, and DEX-induced suppression of endogenous CORT before, during and after stress was attenuated in lesioned rats. These results indicate a mechanism whereby loss of cholinergic function (e.g. in aging and Alzheimer's Dementia) may compromise the dynamic range of sensitivity to glucocorticoid mediated stress pathways in the brain.

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Effects of gabaergic or cholinergic medial septal lesions on anxiety

Yoder RM, Pang KCH (2002) Effects of gabaergic or cholinergic medial septal lesions on anxiety. Neuroscience 2002 Abstracts 378.1. Society for Neuroscience, Orlando, FL.

Summary: The hippocampus (HPC) is a structure important for spatial learning and memory. GABAergic and cholinergic neurons in the medial septal area (MSA) provide the two major projections to HPC. Complete destruction of HPC or MSA impairs spatial memory. MSA lesions have an anxiolytic effect, and rats with MSA damage appear be more exploratory. Spatial learning and memory may therefore be influenced by anxiety information reaching HPC through MSA. The present study assessed the effects of MSA GABAergic or cholinergic lesions on anxiety in the elevated plus maze and open-field task. Control rats received intraseptal saline; GABAergic lesions were induced by intraseptal domoic acid; cholinergic lesions were induced by intraseptal 192 IgG-saporin. An elevated plus maze was constructed with 2 open arms and 2 closed arms. Following habituation, each rat was placed in the center of the maze, then observed for 5 minutes. Time spent in the open vs. closed arms and number of entries into open vs. closed arms were compared between groups. The open-field task utilized a square arena with center and outer sections delineated on the floor. Following habituation, each rat was placed into the outer section, then observed for 5 minutes, during which the number of line crossings and amount of time spent in center vs. outer sections were calculated for comparison between groups. In both tasks, frequency of freezing, rearing, head dips, stretched-attend posture, grooming, and defecation was also compared between groups. Results of the present study may help elucidate the role of MSA in the effects of anxiety on learning and memory.

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Spatial strategies in rats with cholinergic or GABAergic lesions of the medial septum

Wright KM, Yoder RM, Pang KCH (2002) Spatial strategies in rats with cholinergic or GABAergic lesions of the medial septum. Neuroscience 2002 Abstracts 378.2. Society for Neuroscience, Orlando, FL.

Summary: The major projection neurons of the septohippocampal (SH) system are GABAergic and cholinergic. When both populations of neurons are damaged together, deficits in learning and memory occur. However, when only one population is damaged, spatial memory in the water maze and radial arm maze is intact. The present study evaluated whether spatial strategies differed between rats with either GABAergic or cholinergic septal lesions. Domoic acid or 192 IgG saporin (sap) was injected into the medial septum (MS) to damage GABAergic or cholinergic neurons, respectively. Spatial strategies were examined on the plus maze and water maze. In the plus maze, rats were started from a single arm and trained to enter a goal arm containing both the reward and an intra-maze cue. Probe trials assessed whether the rats used place, response or cue strategies. During a probe trial, the starting location and the intra-maze cue were moved from that during training. In the water maze, animals were trained for 9 days in 3-day cycles. The first two days of the cycle used a visible platform and the third day of training was performed with a submerged platform. A single probe trial was conducted on day 10. On the probe trial, the first quadrant visited determined whether rats were using cue, place, or response strategies. Preliminary results show that rats treated with domoic acid use the place strategy on all probe trials in the plus maze, but do not use a consistent strategy in the water maze. Sap-treated animals also use mainly a place strategy. The results of this study may help determine the role of MS neurons in spatial strategy selection.

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Effect of 192 IgG-saporin medial-septum lesion on hippocampal receptor density in rats

Pokala VN, Libertore MA, Zambon NJ, Nagle RA, Li PK, Witt-Enderby PA, Johnson DA (2002) Effect of 192 IgG-saporin medial-septum lesion on hippocampal receptor density in rats. Neuroscience 2002 Abstracts 82.7. Society for Neuroscience, Orlando, FL.

Summary: The aim of the study was to quantify the effect of selective cholinergic neurotoxin192 IgG-saporin (SAP) medial septal (MS), lesions on hippocampal muscarinic, GABAA and NMDA receptor density. Rats were injected with SAP (0.22 and 0.45 μg/μl) into the MS. After 6 weeks, hippocampal tissue was collected and saturation radioligand binding assays were performed to determine the receptor density. 3H-QNB was a muscarinic antagonist, 3H-muscimol a GABAergic agonist and 3H-MK-801 an NMDA antagonist were utilized. The results demonstrated a dose dependent increase in muscarinic receptor density (B-max) of 226 and 355% respectively. These results suggest changes in receptor density in response to hippocampal cholinergic denervation.

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Residual hippocampal cholinergic functions after 192 IgG-saporin lesions of the medial septum/ventral diagonal band (MS/VDB)

Chang Q, Gold PE (2002) Residual hippocampal cholinergic functions after 192 IgG-saporin lesions of the medial septum/ventral diagonal band (MS/VDB). Neuroscience 2002 Abstracts 82.8. Society for Neuroscience, Orlando, FL.

Summary: 192 IgG-saporin (SAP) injections into the MS/VDB reportedly destroy acetylcholine (ACh) neurons projecting to hippocampus (HC) without associated impairments of learning and memory on HC-dependent tasks. These findings contrast sharply with those obtained with many other methods showing close associations between ACh functions in the HC and learning and memory. The present experiment addressed this conflict. SAP was injected into MS/VDB 1 week before the start of neural and behavioral measures. We found: 1) Using in vivo microdialysis, release of ACh in the HC was not abolished but was ~30% of control values. The percent increase in ACh release during spontaneous alternation testing was greater in SAP-treated than in control rats. 2) SAP-treated rats had significant impairments on the HC-dependent alternation task. Moreover, intra-HC injections of physostigmine (20 ng in 1 µl), an indirect ACh agonist, enhanced alternation scores. 3) Physostigmine (0.6 mg/kg, IP) induced more intense tremors in SAP-treated than in control rats. 4) While SAP-treated rats had near-total depletion of cells in MS/VDB stained using immunocytochemistry for choline acetyltransferase (ChAT), quantitative densitometry showed no depletion of ChAT staining in either CA1 or the dentate gyrus in the SAP group. These findings suggest that there are residual and even heightened ACh functions which can compensate for the insult of MS/VDB SAP lesions, complicating the use of this lesion to evaluate the role of septohippocampal cholinergic projections in learning, memory or other functions.

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Neonatal basal forebrain cholinergic lesions disrupt retention of socially transmitted food preferences and alter EEG activity in adult rats

Ricceri L, Moles A, Pezzola A, Popoli P, Calamandrei G (2002) Neonatal basal forebrain cholinergic lesions disrupt retention of socially transmitted food preferences and alter EEG activity in adult rats. Neuroscience 2002 Abstracts 82.9. Society for Neuroscience, Orlando, FL.

Summary: Previous studies using selective neonatal lesions of basal forebrain cholinergic neurons showed mild long-term effects on spatial discrimination capabilities, whereas water maze learning appeared intact. In the present study we examined long-term effects of icv injections of 192 IgG saporin performed in 7-day-old rats on the social transmission of food preferences (a form of non-spatial associative memory) at adulthood. In 6-month-old rats the neonatal cholinergic lesion impaired 4-h and 24-h retention of a learned social food preference relative to controls, despite performance on an immediate retention trial was indistinguishable from controls. A second experiment excluded alterations in neophobia towards unfamiliar scented food after neonatal cholinergic lesions: level of novel food consumption did not differ between neonatally saporin-lesioned and control rats. Computerized EEG spectral analysis (FFT transform) performed in 6-month-old rats revealed that the neonatal cholinergic lesions increased δ power and reduced β power in both fronto-parietal and parieto-occipital cortex. Effectiveness of the neonatal lesion was confirmed by a marked cholinergic loss in both hippocampal and cortical regions. Altogether, behavioral and electrophysiological data suggest that the neonatal cholinergic lesion of the basal forebrain - more than the adult one - could represent a useful experimental model of Alzheimer-like memory dysfunctions.

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Amphetamine hyperresponses in cholinergically denervated rats and alpha7 nAChR knockout mice, and effects of nicotinic agonists

Mattsson A, Lindqvist E, Ögren SO, Olson L (2002) Amphetamine hyperresponses in cholinergically denervated rats and alpha7 nAChR knockout mice, and effects of nicotinic agonists. Neuroscience 2002 Abstracts 136.7. Society for Neuroscience, Orlando, FL.

Summary: We have recently shown that cholinergic denervation of the basal forebrain in adult rats, using intracerebroventricular injections of the cholinergic immunotoxin 192-saporin, leads to overreactivity in dopaminergic systems, in the form of enhanced amphetamine-induced hyperactivity. This increased sensitivity to amphetamine in cholinergically denervated rats can be partially counteracted by nicotine if given before the amphetamine challenge. The results provide a possible link between deficits in central cholinergic systems and overactivity in dopaminergic systems, which might be of relevance for the pathogenesis of schizophrenia. To further evaluate the role of cholinergic dysfunction for dopaminergic hyperactivity we have focused on the α7 nAChR due to its presumed involvement in schizophrenia. First, we tested if a selective α7 nAChR agonist, AR-R17779, could mimic the effect of nicotine (partial blockade of amphetamine hyperresponse) in cholinergically denervated rats. Second, we tested if mice lacking the α7 nAChR gene have a similar increased sensitivity to amphetamine, as cholinergically denervated rats. Preliminary results from these studies show that AR-R17779 normalizes the effect of amphetamine cholinergically denervated rats, and further, that lack of the α7 nAChR gene leads to an increased sensitivity to amphetamine. Cholinergic deficiencies that cause dopaminergic overactivity are compatible with a role of the α7 nAChR in schizophrenia and may suggest a role for the cholinergic system in other psychotic states.

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Alterations in forebrain acetylcholine influence hippocampal neurogenesis in the adult rodent

Mohapel P, Leanza G, Lindvall O (2002) Alterations in forebrain acetylcholine influence hippocampal neurogenesis in the adult rodent. Neuroscience 2002 Abstracts 23.9. Society for Neuroscience, Orlando, FL.

Summary: Little is known about how various experiential, environmental and pathological factors regulate neurogenesis in the adult hippocampus. Since the hippocampus receives abundant cholinergic innervation and contains some of the densest distributions of acetylcholine (ACh) fibers, we investigated its potential role in adult neurogenesis. Adult rats received multiple bromodeoxyuridine (BrdU) injections 3 weeks following lesions of the adult rodent forebrain cholinergic projections by intracerebroventricular infusions of 192 IgG-saporin. The day following BrdU administration we observed a significant 20% to 30 % decrease in proliferation in the subgranular cell layer of the dentate gyrus with ACh lesioning. This decrease persisted through to 4 weeks after BrdU administration, when most proliferated cells co-expressed neuronal markers. Conversely, in a separate experiment, naive rats receiving simultaneous injections of the ACh agonist physostigmine and BrdU demonstrated a 30 % increase in proliferated cells (1 day later) and neurons (4 weeks later) in the subgranular cell layer. Our data indicate that cholinergic mechanisms in the forebrain are involved in the regulation of neurogenesis and that this effect may be indirect or direct in the hippocampus.

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Steroid sulfatse inhibition potentiates working memory deficit induced by 192 IgG-saporin

Zambon NJ, Liberatore MA, Nagle RA, Pokala VN, Li P, Johnson DA (2002) Steroid sulfatse inhibition potentiates working memory deficit induced by 192 IgG-saporin. Neuroscience 2002 Abstracts 82.6. Society for Neuroscience, Orlando, FL.

Summary: Infusion of 192 IgG-saporin (SAP) into the medial septum (MS) of rats selectively lesions cholinergic neurons and impairs acquisition of a delayed matching to position T-maze task. Since steroid sulfatase inhibitors allosterically inhibit the GABA-A receptor and enhance cognition, the present study investigated the cognitive effects of sulfatase inhibition on SAP lesioned animals. Male Sprague-Dawley rats received intraseptal infusions of either cerebrospinal fluid (CSF) or 0.22 μg/μl SAP. Eight days after the infusion, the rats were given an IP injection of either the steroid sulfatase inhibitor DU-14 (30mg/ml) or vehicle daily for 14 days, then every other day during the testing period. In the acquisition phase of testing, each rat completed 8 trial pairs per day until reaching criterion (15 of 16 correct choices). The rats were then tested for retention of the task by inserting delays of 10, 20, and 30 seconds after the first trial of a pair. DU-14 potentiated the impairment in acquisition produced by SAP. The introduction of a delay resulted in deceased performance in all treatment groups except rats administered DU-14 without SAP lesioning. These results suggest that DU-14 may enhance cognition in cholinergically intact animals, but the combination of DU-14, with cholinergic lesioning of MS, impairs working memory by inhibition of both cholinergic and GABAergic neurotransmission.

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Motoneuron-derived neurotrophin-3 is a survival factor for PAX2-expressing spinal interneurons.

Bechade C, Mallecourt C, Sedel F, Vyas S, Triller A (2002) Motoneuron-derived neurotrophin-3 is a survival factor for PAX2-expressing spinal interneurons. J Neurosci 22(20):8779-8784. doi: 10.1523/JNEUROSCI.22-20-08779.2002

Summary: In the rat, half of motoneurons die between embryonic day 15 and postnatal day 1. Programmed cell death of interneurons is not as well characterized. The authors cultured explants of brachial neural tubes from rat embryos in the presence of 200 ng/ml of 192-Saporin (Cat. #IT-01). Although 192-Saporin had no direct effect on interneurons in culture, elimination of p75-neurotrophin receptor-expressing neurons caused the interneurons to die.

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Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion.

Zeitschel U, Schliebs R, Rossner S, Bigl V, Eschrich K, Bigl M (2002) Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion. J Neurochem 83(2):371-380. doi: 10.1046/j.1471-4159.2002.01127.x

Summary: The authors used intraventricular injections of 4 µg of 192-Saporin (Cat. #IT-01) in rats to investigate whether impaired cholinergic transmission may cause metabolic changes. Although the results demonstrate an initial increase in a cortical glucose metabolic marker, this increase was transient. The authors conclude that cholinergic systems do not control cortical glucose metabolic mechanisms affected by Alzheimer’s disease.

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Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis.

Ballmaier M, Casamenti F, Scali C, Mazzoncini R, Zoli M, Pepeu G, Spano PF (2002) Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis. Neuroscience 114(1):91-98. doi: 10.1016/s0306-4522(02)00234-8

Summary: The authors injected 300 nl of 400 ng/ml 192-Saporin (Cat. #IT-01) bilaterally into the nucleus basalis magnocellularis of rats, then treated the lesioned animals with rivastigmine, a cholinesterase inhibitor. Animals treated with rivistagmine exhibited raised levels of cortical acetylcholine, in contrast to undetectable acetylcholine levels in lesioned animals not treated with rivastigmine.

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Grafts of fetal septal cells after cholinergic immunotoxic denervation of the hippocampus: a functional dissociation between dorsal and ventral implantation sites.

Cassel J, Gaurivaud M, Lazarus C, Bertrand F, Galani R, Jeltsch H (2002) Grafts of fetal septal cells after cholinergic immunotoxic denervation of the hippocampus: a functional dissociation between dorsal and ventral implantation sites. Neuroscience 113(4):871-882. doi: 10.1016/s0306-4522(02)00226-9

Summary: The authors lesioned rats with intraseptal infusions of 0.8 µg 192-Saporin (Cat. #IT-01), then implanted fetal cells in either the dorsal or ventral hippocampus. Only grafts into the dorsal hippocampus counteracted the effect of cholinergic lesions on spatial working memory performance.

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Mnemonic deficits in animals depend upon the degree of cholinergic deficit and task complexity.

Pizzo DP, Thal LJ, Winkler J (2002) Mnemonic deficits in animals depend upon the degree of cholinergic deficit and task complexity. Exp Neurol 177:292-305. doi: 10.1006/exnr.2002.7993

Summary: In this study, the authors compared icv and intraparenchymal injections of 192-Saporin (Cat. #IT-01, 3.3 µg and 450 ng, respectively). While a similar reduction in choline acetyltransferase activity was observed with each strategy, and performance in certain allocentric tasks was similar, an egocentric task showed a marked difference between the two groups.

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Selective lesions of basal forebrain cholinergic neurons produce anterograde and retrograde deficits in a social transmission of food preference task in rats.

Vale-Martinez A, Baxter MG, Eichenbaum H (2002) Selective lesions of basal forebrain cholinergic neurons produce anterograde and retrograde deficits in a social transmission of food preference task in rats. Eur J Neurosci 16(6):983-998. doi: 10.1046/j.1460-9568.2002.02153.x

Summary: Injections of 0.2 µg 192-Saporin (Cat. #IT-01) were made into either the medial septum/vertical limb of the diagonal band (MS/VDB), or the nucleus basalis magnocellularis/substantia innominata (NBM/SI) of rats. MS/VDB lesions had no effect on anterograde memory, while NBM/SI lesions strongly impaired immediate and 24-hour retention. In contrast, MS/DVB lesions produced significant memory deficits in a long-delay retrograde memory test.

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Differential contribution of the cholinergic basal nuclei to attention and spatial memory in the rat

Lehmann O, Grottick AJ, Cassel JC, Higgins GA (2002) Differential contribution of the cholinergic basal nuclei to attention and spatial memory in the rat. FENS 2002 Abstracts 008.13. Federation of European Neuroscience Societies, Paris, France.

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Effect of 192 IgG-saporin on circadian activity rhythms, expression of P75 neurotrophin receptors, calbindin-D28K, and light-induced Fos in the suprachiasmatic nucleus in rats.

Beaule C, Amir S (2002) Effect of 192 IgG-saporin on circadian activity rhythms, expression of P75 neurotrophin receptors, calbindin-D28K, and light-induced Fos in the suprachiasmatic nucleus in rats. Exp Neurol 176(2):377-389. doi: 10.1006/exnr.2002.7969

Summary: The authors used bilateral icv injections of 200 ng of 192-Saporin (Cat. #IT-01) to investigate the contribution of p75NTR-expressing neurons to the determination of a circadian rhythm. The data show that p75NTR-expressing neurons are not essential for this process.

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Reactivity to object and spatial novelty is normal in older Ts65Dn mice that model Down syndrome and Alzheimer’s disease.

Hyde LA, Crnic LS (2002) Reactivity to object and spatial novelty is normal in older Ts65Dn mice that model Down syndrome and Alzheimer’s disease. Brain Res 945:26-30. doi: 10.1016/s0006-8993(02)02500-3

Summary: The authors hypothesized that a mouse model for Down syndrome may show some of the same cognitive deficits exhibited by rats lesioned with 192-Saporin (Cat. #IT-01), which eliminates cholinergic cells in the basal forebrain. The results suggest that in this Down syndrome model, cell loss has a much greater cognitive effect if it happens early in development as opposed to in adulthood.

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Short and long term-effects on the serotonergic system of a selective cholinergic lesion in rats.

Ramirez MJ, Garcia-Alloza M, Lasheras B (2002) Short and long term-effects on the serotonergic system of a selective cholinergic lesion in rats. FENS 2002 Abstracts 010.16. Federation of European Neuroscience Societies, Paris, France.

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Effects of mice EGF-responsive neural stem cells grafts and fetal septal cells grafts implanted into the dorsal hippocampus of rats after immunotoxic denervation

Jeltsch H, Aloy E, Schimchowitsch S, Caillard S, Mohier E Cassel JC (2002) Effects of mice EGF-responsive neural stem cells grafts and fetal septal cells grafts implanted into the dorsal hippocampus of rats after immunotoxic denervation. FENS 2002 Abstracts 141.13. Federation of European Neuroscience Societies, Paris, France.

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Selective neonatal lesions of the basal forebrain cholinergic neurons impair memory of socially-transmitted food preferences in adult rats

Ricceri L, Moles A, Scattoni ML, Calamandrei G (2002) Selective neonatal lesions of the basal forebrain cholinergic neurons impair memory of socially-transmitted food preferences in adult rats. FENS 2002 Abstracts 209.4. Federation of European Neuroscience Societies, Paris, France.

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Impairment and restoration of spatial abilities following 192 IgG-saporin or quisqualic acid lesions of the median septum in rats

Brandner C (2002) Impairment and restoration of spatial abilities following 192 IgG-saporin or quisqualic acid lesions of the median septum in rats. FENS 2002 Abstracts 210.3. Federation of European Neuroscience Societies, Paris, France.

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Combined 192 IgG-saporin and 5,7-dihydroxytryptamine lesions in the male rat brain: A neurochemical and behavioral study.

Lehmann O, Jeltsch H, Lazarus C, Tritschler L, Bertrand F, Cassel JC (2002) Combined 192 IgG-saporin and 5,7-dihydroxytryptamine lesions in the male rat brain: A neurochemical and behavioral study. Pharmacol Biochem Behav 72(4):899-912. doi: 10.1016/s0091-3057(02)00752-9

Summary: Female rats treated with both 192-Saporin (Cat #IT-01) and 5,7-DHT exhibited working memory impairments that were not seen with either treatment alone. For this paper, male rats were treated with 5,7-DHT and 1 µg per ventricle of 192-Saporin. While each compound produced a unique combination of effects, cognitive performance was only affected by treatment with both agents. These data indicate that interaction between the cholinergic and serotonergic mechanisms plays a role in cognitive functions for both sexes.

Usage: Injections of 1 µg per ventricle of 192-Saporin (Cat. #IT-01).

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Selective lesion of cholinergic neurons in the medial septum by 192 IgG-saporin impairs learning in a delayed matching to position T-maze paradigm.

Johnson DA, Zambon NJ, Gibbs RB (2002) Selective lesion of cholinergic neurons in the medial septum by 192 IgG-saporin impairs learning in a delayed matching to position T-maze paradigm. Brain Res 943(1):132-141. doi: 10.1016/s0006-8993(02)02623-9

Summary: The authors investigated the effects of selective cholinergic depletion in the medial septum on a spatial memory (DMP) task. Direct infusion of 0.22 or 1.0 µg 192-Saporin (Cat. #IT-01) produced a near complete depletion of cholinesterase-positive neurons for either dose. The DMP task provides a sensitive behavioral assay for deficits in cholinergic projections.

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5,7-DHT-induced hippocampal 5-HT depletion attenuates behavioural deficits produced by 192 IgG-saporin lesions of septal cholinergic neurons in the rat.

Lehmann O, Bertrand F, Jeltsch H, Morer M, Lazarus C, Will B, Cassel JC (2002) 5,7-DHT-induced hippocampal 5-HT depletion attenuates behavioural deficits produced by 192 IgG-saporin lesions of septal cholinergic neurons in the rat. Eur J Neurosci 15(12):1991-2006. doi: 10.1046/j.1460-9568.2002.02037.x

Summary: Although past data has shown that the cholinergic system of the basal forebrain is intrinsic to learning and memory, more recent data suggests that other neurotransmitter systems are also involved, perhaps serving modulatory functions. The authors used 5,7-DHT injections alone or with intraseptal 192-Saporin (Cat #IT-01, 0.4 µg/side) injections in rats. The results demonstrate that serotonergic denervation of the hippocampus attenuates deficits produced by a cholinergic denervation of the septal region of the basal forebrain.

Usage: The authors used 192-Saporin, 0.4 µg/side intraseptal (Cat. #IT-01).

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Selective immunolesioning of the basal forebrain cholinergic neurons in rats: effect on attention using the 5-choice serial reaction time task.

Risbrough V, Bontempi B, Menzaghi F (2002) Selective immunolesioning of the basal forebrain cholinergic neurons in rats: effect on attention using the 5-choice serial reaction time task. Psychopharmacology 164:71-81. doi: 10.1007/s00213-002-1170-7

Summary: The authors used 0.067 µg injections of 192-Saporin (Cat. #IT-01) into the nucleus basalis magnocellularis to investigate attentional performance in rats. The treated animals exhibited a very specific subset of attentional deficits, many centered around increased difficulty completing tasks in the presence of distractions.

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Effects of 192 IgG-saporin on acetylcholinesterase histochemistry in male and female rats.

Galani R, Jeltsch H, Lehmann O, Bertrand F, Cassel JC (2002) Effects of 192 IgG-saporin on acetylcholinesterase histochemistry in male and female rats. Brain Res Bull 58(2):179-186. doi: 10.1016/s0361-9230(02)00775-x

Summary: Male rats were treated with estradiol, and 2-µg i.c.v. injections of 192-Saporin (Cat #IT-01).

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Cholinergic depletion by IgG 192-saporin retards development of rat barrel cortex.

Zhu XO, de Permentier PJ, Waite PM (2002) Cholinergic depletion by IgG 192-saporin retards development of rat barrel cortex. Brain Res Dev Brain Res 136:1-16. doi: 10.1016/s0165-3806(02)00301-2

Summary: It has been shown that cholinergic afferents from the basal forebrain are necessary for normal cortical morphogenesis. However, the role of these projections in the development of the thalamocortical topographical map has not been investigated. Using the facial whisker barrel field in the rat somatosensory cortex as a development model, the authors administered 192-Saporin to newborn pups (0.1 µg, Cat. #IT-01). The data show a transient delay in the development of the barrel pattern over the first postnatal week.

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Septal grafts and evoked acetylcholine release in the rat hippocampus after 192 IgG-saporin lesions.

Birthelmer A, Dommes E, Jeltsch H, Cassel JC, Jackisch R (2002) Septal grafts and evoked acetylcholine release in the rat hippocampus after 192 IgG-saporin lesions. Neuroreport 13(7):973-976. doi: 10.1097/00001756-200205240-00015

Summary: The authors investigate the structural and behavioral effects of intrahippocampal grafts containing cholinergic neurons into a lesioned region of the brain. Previous studies in rats were complicated by the lack of a specific cholinergic lesioning agent. 0.4 µg 192-Saporin (Cat. #IT-01) in 0.4 µl was injected into the vertical limb of the diagonal band of Broca in rats, then 6 to 10 months later the animals received intrahippocampal grafts of septal cells containing cholinergic neurons. Measurement of noradrenaline and serotonin uptake indicate that the grafts were able to produce only modest cholinergic effects. The authors conclude that this may be a result of performing the graft too soon following administration of the immunotoxin.

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Interactions between aging and cortical cholinergic deafferentation on attention.

Burk JA, Herzog CD, Porter MC, Sarter M (2002) Interactions between aging and cortical cholinergic deafferentation on attention. Neurobiol Aging 23:467-477. doi: 10.1016/s0197-4580(01)00315-3

Summary: Trauma to forebrain cholinergic neurons is suspected to make these neurons more susceptible to future age-related loss of function. The authors tested this theory by making incomplete lesions of the basal forebrain cholinergic system using bilateral infusions of 192-Saporin (0.5 µl of 0.15 µg/µl, Cat. #IT-01) in rats trained prior to surgery. The attentional performance of the treated rats did not differ from control animals until the age of 31 months. The data indicate that pre-existing damage to the cholinergic basal forebrain region yields age-related attentional impairments.

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Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats.

Galani R, Lehmann O, Bolmont T, Aloy E, Bertrand F, Lazarus C, Jeltsch H, Cassel JC (2002) Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats. Physiol Behav 76:75-90. doi: 10.1016/s0031-9384(02)00674-1

Summary: Lesioning of the nucleus basalis magnocellularis (NBM) with 192-Saporin (Cat. #IT-01) has produced varied cognitive effects in numerous studies. The authors of this work suggest that several factors such as lesion procedure and the type of behavioral test used may cause these variations. Thirty-one rats were lesioned using 0.2 or 0.4 µg of 192-Saporin infused into the NBM, and locomotor activity, learning, and memory capabilities were tested using several test methods. Spatial memory appeared to remain intact, but evidence suggests that attentional processing is affected by NBM lesioning with 192-Saporin.

Usage: Rat NBM was lesioned using 0.2 or 0.4 µg of 192-Saporin (Cat. #IT-01).

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Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.

Berchtold NC, Kesslak JP, Cotman CW (2002) Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum. J Neurosci Res 68(5):511-521. doi: 10.1002/jnr.10256

Summary: Brain-derived neurotrophic factor (BDNF) enhances neuron function and plasticity. The authors lesioned rats with medial septal injections of 192-Saporin (Cat #IT-01, 375 ng in 0.5 µl PBS) or OX7-SAP (Cat #IT-02, 12.5 or 25 ng in 0.5 µl PBS). 192-Saporin affected the sedentary, but not exercise-induced levels of BDNF. OX7-SAP reduced levels in both groups in a dose-dependent manner.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis.

Butt AE, Noble MM, Rogers JL, Rea TE (2002) Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255. doi: 10.1037//0735-7044.116.2.241

Summary: 192-Saporin (Cat. #IT-01) administration to the basal forebrain has frequently been used in rats to create a model for Alzheimer’s disease. The authors used 0.2 µl bilateral injections of 0.4 µg/µl 192-SAP into the nucleus basalis magnocellularis (NBM). Previous studies using non-specific excitotoxic agents have suggested the involvement of the NBM in learning and memory. The authors confirm more recent findings that indicate some of the deficits produced by these excitotoxins are due to the non-specific lesioning caused by these agents. The highly selective cholinergic lesioning produced by 192-Saporin left simple association learning intact but impaired more complicated configural association processes.

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Transverse patterning reveals a dissociation of simple and configural association learning abilities in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis.

Butt AE, Bowman TD (2002) Transverse patterning reveals a dissociation of simple and configural association learning abilities in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis. Neurobiol Learn Mem 77:211-233. doi: 10.1006/nlme.2001.4013

Summary: Using 80 ng bilateral infusions of 192-Saporin (Cat. #IT-01) into each of the medial and lateral target sites of the nucleus basalis magnocellularis (NBM) in rats, the authors demonstrate that lesioning the cholinergic systems of the NBM impairs a more complicated learning technique, while leaving simple association learning intact. The results also show that the transition between these two learning strategies is impaired in lesioned animals.

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Facilitation of dopamine-mediated locomotor activity in adult rats following cholinergic denervation.

Mattsson A, Ögren SO, Olson L (2002) Facilitation of dopamine-mediated locomotor activity in adult rats following cholinergic denervation. Exp Neurol 174:96-108. doi: 10.1006/exnr.2001.7850

Summary: Using 80 ng bilateral infusions of 192-Saporin (Cat. #IT-01) into each of the medial and lateral target sites of the nucleus basalis magnocellularis (NBM) in rats, the authors demonstrate that lesioning the cholinergic systems of the NBM impairs a more complicated learning technique, while leaving simple association learning intact. The results also show that the transition between these two learning strategies is impaired in lesioned animals.

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Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task.

McGaughy J, Dalley JW, Morrison CH, Everitt BJ, Robbins TW (2002) Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task. J Neurosci 22(5):1905-1913. doi: 10.1523/JNEUROSCI.22-05-01905.2002

Summary: 192-Saporin (Cat. #IT-01) has been a very useful tool in determining the role of the basal forebrain cholinergic system in arousal and attention tasks. The authors lesioned the nucleus basalis magnocellularis of rats with an infusion of 0.5 µl per hemisphere of 0.15 µg/µl or 0.45 µg/µl 192-Saporin. The data show a correlation between the extent of the lesion and the amount of impairment in an attentional task. The authors also found that the accuracy deficits in the task could be ameliorated by lengthening the stimulus time, or exacerbated by increasing the event rate. Taken together the data indicate a direct relationship between basal forebrain damage and impaired attentional function.

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Lesions of the nucleus basalis magnocellularis induced by 192 IgG-saporin block memory enhancement with posttraining norepinephrine in the basolateral amygdala.

Power AE, Thal LJ, McGaugh JL (2002) Lesions of the nucleus basalis magnocellularis induced by 192 IgG-saporin block memory enhancement with posttraining norepinephrine in the basolateral amygdala. Proc Natl Acad Sci U S A 99(4):2315-2319. doi: 10.1073/pnas.022627799

Summary: There is evidence that memory consolidation (retention) can be modulated by drugs and stress hormones acting in the basolateral amygdala (BLA). The BLA sends projections to the nucleus basalis magnocellularis (NBM), which in turn sends cholinergic projections to the neocortex. The authors used 100 ng bilateral infusions of 192-Saporin (Cat. #IT-01) in 500 nl 0.1 M PBS to investigate whether lesions of the cholinergic NBM projections affect BLA modulation of memory. 192-Saporin lesions blocked memory enhancement normally induced by norepinephrine infusions into the BLA. This finding suggests NBM-cortex projections may mediate BLA modulation of memory storage or processing in the neocortex.

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Dissociation of memory and anxiety in a repeated elevated plus maze paradigm: Forebrain cholinergic mechanisms.

Lamprea MR, Cardenas FP, Silveira R, Morato S, Walsh TJ (2000) Dissociation of memory and anxiety in a repeated elevated plus maze paradigm: Forebrain cholinergic mechanisms. Behav Brain Res 117:97-105. doi: 10.1016/s0166-4328(00)00294-1

Summary: The septo-hippocampal pathway has been implicated in many behavioral processes such as learning, anxiety, and motivation. Using 192-Saporin (Cat. #IT-01) to lesion the cholinergic neurons of the medial septum of rats, the authors demonstrate changes in exploratory behavior associated with learning, but no changes in anxiety-associated behavior in their elevated plus maze paradigm.

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Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learning.

Cahill JFX, Baxter MG (2001) Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learning. Eur J Neurosci 14:1856-1864. doi: 10.1046/j.0953-816x.2001.01807.x

Summary: The authors compared ibotenic acid (IA)-treated rats with those injected with 45 ng and 30 ng of 192-Saporin (Cat. #IT-01) into two separate coordinates of the medial septum/vertical limb of the diagonal band (MS/VDB) to investigate the role of basal forebrain projections in modulating strategy selection in spatial learning. While rats with IA lesions in the MS/VDB demonstrated significant disruption of the learning process, the 192-Saporin-lesioned rats did not show this effect.

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Selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis impairs prepulse inhibition of acoustic startle.

Ballmaier M, Casamenti F, Zoli M, Pepeu G, Spano P (2001) Selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis impairs prepulse inhibition of acoustic startle. Neuroscience 108(2):299-305. doi: 10.1016/s0306-4522(01)00413-4

Summary: One of the measures for schizophrenia is a deficit in sensorimotor gating (the ability of the brain to filter sensory input to focus on selective stimuli) measured by prepulse inhibition (PPI) of the startle reflex. The authors injected 300 nl of 400 ng/µl 192-Saporin (Cat. #IT-01) into each side of the nucleus basalis magnocellularis (NBM) in rats to examine the effect of NBM cholinergic neuron elimination on the startle reflex. The data show a significant, persistent disruption of the PPI independent of the amplitude of the startle reflex. This suggests the NBM may play an important role in information processing in schizophrenia.

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The effects of manipulations of attentional demand on cortical acetylcholine release.

Himmelheber AM, Sarter M, Bruno JP (2001) The effects of manipulations of attentional demand on cortical acetylcholine release. Brain Res Cogn Brain Res 12(3):353-370. doi: 10.1016/s0926-6410(01)00064-7

Summary: Cortical cholinergic afferents from the basal forebrain are suspected to be involved in attentional tasks. Regulatory impairment of these afferents has been hypothesized to contribute to attentional deficits seen in conditions as diverse as Alzheimer’s disease and schizophrenia. The authors have previously shown that 192-Saporin (Cat. #IT-01) lesions result in severe impairments in tasks requiring sustained attentional processing. In these experiments the authors suggest that cell response is dependent on the level of demand. They demonstrate that removal of p75+ cells (0.5 µg/µl bilaterally infused into the nucleus basalis region in rat) impairs sustained attentional performance, but does not impact low-demand task performance.

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Lack of effect of moderate Purkinje cell loss on working memory.

Wrenn CC, Wiley RG (2001) Lack of effect of moderate Purkinje cell loss on working memory. Neuroscience 107(3):433-445. doi: 10.1016/s0306-4522(01)00326-8

Summary: When 192-Saporin (Cat. #IT-01) is injected intracerebroventricularly, some p75-expressing cerebellar Purkinje cells are eliminated along with cholinergic neurons. To verify that the effects of basal forebrain lesions on working memory were not caused by loss of these Purkinje cells the authors compared doses of 1 µg OX7-SAP (Cat. #IT-02) and either 2 µg or 4 µg of 192-Saporin injected into the lateral ventricle. The data show that although similar amounts of Purkinje cells were eliminated by OX7-SAP and the lower dose of 192-Saporin, no working memory deficits resulted. Only the 4-µg dose of 192-Saporin produced working memory deficits, they conclude that this is not due to Purkinje cell loss, but the loss of cholinergic neurons.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Bcl-2 improves survival of lesioned cholinergic neurons.

Lee KY, Leos R, Borowski TB, de Lacalle S (2001) Bcl-2 improves survival of lesioned cholinergic neurons. Neuroscience 2001 Abstracts 803.6. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease is associated with the progressive cell death of cholinergic neurons in the central nervous system (CNS). A current challenge is to develop therapeutic approaches that could prevent atrophy and loss of CNS neurons, and promote regeneration of their processes. The purpose of our study is to determine the therapeutic potential of the antiapoptotic gene B-cell lymphoma 2 (bcl-2) on the cholinergic system of the basal forebrain (BF). Retrograde degeneration in the BF of 3-month-old rats was induced by unilateral injection of the immunotoxin 192 IgG-saporin into the entorhinal cortex. Fifteen minutes later, an injection of 5 µg of the pa22bgala4bcl-2 plasmid was placed into the BF. Similar procedures were followed for BF injections of a control plasmid or vehicle alone. We found that a single injection of bcl-2 plasmid into the BF of the lesioned side increased survival of cholinergic neurons ~50%, as compared to vehicle controls. In addition, cell survival was close to 100% of intact side with bcl-2 injections, compared to a 50% cell loss in animals injected with a control DNA. Our results indicate that an injection of the bcl-2 gene into the BF prevents loss of cholinergic neurons that have been injured by IgG-saporin. Mechanisms by which bcl-2 may protect cholinergic neurons could include retrograde transport of the plasmid to the nucleus and subsequent neuroprotective effects of increased levels of bcl-2 protein. Our results, in conjunction with other studies, suggest that neurodegeneration might be amenable to gene therapy.

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α-1 adrenergic agonist effect on cholinergic muscarinic receptors.

Harrell LE, Kolasa K, Parsons DS, Conger K (2001) α-1 adrenergic agonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.16. Society for Neuroscience, San Diego, CA.

Summary: Degeneration of the basal forebrain cholinergic system and sympathetic ingrowth appear to be pathological changes in Alzheimer's Disease patients (AD), leading to an alteration in the balance between both systems and may mediate cognitive deficits in AD. In an attempt to model this situation, intraventricular injection (ivc) of a specific cholinergic immunotoxin, 192-IgG-saporin, has been used to induce peripheral noradrenergic fibers to grow into cortex and hippocampus after cholinergic denervation of rat cortex (CCD) and hippocampus (HCD). This adrenergic reorganization has been termed cortical (CSI) and hippocampal (HSI) sympathetic ingrowth. 192-IgG-saporin ivc injection was followed by intraperitoneal (ip) treatment with α1 agonist methoxamine. Thus the effects on choline acetyltransferase (ChAT) activity, norepinephrine (NE) level and muscarinic acetylcholine receptors (mAChR) were studied in rat hippocampal and cortical brain tissue. We found that 192-IgG-saporin produced significant decrease in ChAT activity in all experimental groups and areas. Methoxamine (3 and 6 mg/kg ip) did not affect NE levels. It produced significant decrease in mAChR affinity in the cholinergic denervation group and no significant increase in mAChR density in cholinergically denervation groups of dorsal hippocampal and cortical areass. Results of the present study indicate the influence of α1 agonist treatment on mAChR and may provide new concepts for the future combination drug therapy for AD patients.

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α-1 adrenergic antagonist effect on cholinergic muscarinic receptors.

Kolasa K, Harrell LE, Parsons DS, Conger K (2001) α-1 adrenergic antagonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.17. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic denervation of cortex and hippocampus in rat causes an unusual neuronal rearrangement, in which peripheral sympathetic fibers, originating from superior cervical ganglia, grow into the cholinergically denervated areas. This process has been termed cortical (CSI) and hippocampal sympathetic ingrowth (HSI). A similar process may occur in Alzheimer's Disease (AD). Recent studies suggest that the balance between central adrenergic and cholinergic systems may be important for normal learning and memory, while the alterations of these systems may play a critical role in cognitive deficits of AD. To better understand this situation specific cholinotoxin, 192-IgG-saporin, was intraventricularly (ivc) injected to produce a selective loss of cholinergic cells in rat basal forebrain nuclei, cholinergically denervating hippocampal (HCD) and cortical areas (CCD). This effect was confirmed by significant decrease in choline acetyltransferase activity in all groups and brain structures.192-IgG-saporin injection was followed by a treatment with α1-adrenergic antagonist prazosin to determine the effect on hippocampal and cortical muscarinic acetylcholine receptors (mAChR) and norepinephrine (NE) level. Prazosin (0.5 & 2 mg/kg ip) produced decreases in NE levels of HSI and CSI and induced no significant increase in mAChR affinity in HSI and CSI groups in dorsal hippocampus,anterior and entorhinal cortex. Injected at the dose of 2 mg/kg it increased mAChR density in CSI of both cortical areas. The present results began to define the interaction between adrenergic and cholinergic systems, as α1 antagonist treatment affects mAChR,a potential therapeutic target in AD.

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Poster: Selective cholinergic denervation inhibits expression of long-term potentiation in the adult but not infant rat hippocampus.

Motooka Y, Kondoh T, Nomura T, Tamaki N, Nishizaki T (2001) Poster: Selective cholinergic denervation inhibits expression of long-term potentiation in the adult but not infant rat hippocampus. Neuroscience 2001 Abstracts 599.7. Society for Neuroscience, San Diego, CA.

Summary: The present study assessed the role of the cholinergic systems on the expression of perforant path long-term potentiation (LTP) in rat hippocampal slices from the infant and adult brain. To denervate the cholinergic systems, 192 1gG-saporin was injected into the lateral ventricle of the infant (2 weeks old) and adult (6 weeks old) rat brain. There, choline acetyltransferase immunoreactive fibers were little detectable two weeks and two months after injection for both the groups. For the infant rats, perforant path LTP was not affected by selective cholinergic denervation; the probability of LTP development was 0.83 (5/six slices) and 0.78 (7/nine slices) at 2 weeks and 2 months later in 192 IgG-saporin-treated slices, as compared with 0.83 at each period in control saline-treated slices. In contrast, the expression of the LTP was blocked by selective cholinergic denervation for the adult rats; the probability of LTP development was 0 (0/ten slices) and 0.38 (3/eight slices) at 2 weeks and 2 months later in 192 IgG-saporin-treated slices, as compared with 0.8 (8/ten slices) and 0.83 (5/six slices) at each period in control saline-treated slices. The results of the present study thus suggest that the cholinergic systems play a crucial role in the expression of LTP in the adult brain and that the denervated systems in the infant brain could be compensated by the sprouting of non-cholinergic fibers.

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Sound sequence discrimination requires cholinergic inputs and suppression of M-currents in the rat auditory cortex.

Kudoh M, Seki K, Watanabe S, Shibuki K (2001) Sound sequence discrimination requires cholinergic inputs and suppression of M-currents in the rat auditory cortex. Neuroscience 2001 Abstracts 621.2. Society for Neuroscience, San Diego, CA.

Summary: Synaptic potentiation after sequential heterosynaptic stimulation is dependent on the stimulus sequence in the auditory cortex. Atropine or antagonists of M1 receptors block this sequence dependence. However, it is rescued by linopirdine, an inhibitor of M-currents, even in the presence of atropine. In the present study, we investigated the role of cholinergic inputs and the resulting suppression of M-currents in sound sequence discrimination. Rats were trained to discriminate sequence of two sounds. Licking a spout during sound presentation of a particular sequence was rewarded with water. The sounds of the rewarded or unrewarded sequence were randomly presented in a trial, which was repeated every one minute for 12 hours in 4 days. The percentage of the trials with a licking response to sounds was calculated separately for the rewarded and unrewarded sequence. Test performance, estimated from the difference, was significantly increased in the 4 days. Atropine (10 mg/Kg, i.p.) suppressed the increase of test performance. A cholinergic immunotoxin, 192IgG-saporin, was injected into the auditory cortex (62-400 ng/1µl) 1 week before the test. Sound sequence discrimination, but not discrimination between the two sounds, was significantly suppressed in these rats. Linopirdine (5 mg/Kg, i.p.) rescued the test performance of sound sequence discrimination in the rats injected with 192IgG-saporin. These results suggest that sound sequence discrimination requires cholinergic inputs and the resulting suppression of M-currents in the auditory cortex.

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Effects of 192-saporin lesion of the basal forebrain on sleep homeostasis and adenosine receptor (A1) mRNA levels.

Greco MA, Salin-Pascual R, Gerashchenko D, Blanco-Centurion C, Shiromani PJ (2001) Effects of 192-saporin lesion of the basal forebrain on sleep homeostasis and adenosine receptor (A1) mRNA levels. Neuroscience 2001 Abstracts 523.12. Society for Neuroscience, San Diego, CA.

Summary: Adenosine is hypothesized to be a mediator of sleep since adenosine levels in the basal forebrain increase after wakefulness and decrease following sleep. The inhibitory effect of adenosine on wake-active cholinergic neurons is thought to be mediated by the A-1 receptor subtype. We hypothesized that if adenosine inhibition of cholinergic neurons takes place via A-1A receptors on cholinergic neurons, the elimination of cholinergic cells should affect sleep homeostasis. To test this hypothesis, 192-saporin was used to selectively lesion basal forebrain cholinergic cells. 48h baseline sleep was recorded from male Sprague Dawley rats. Subsequently, the rats were kept awake for 12h and 24h recovery sleep was recorded. 192-saporin (4 ug) was then administered ICV. The rats were again continuously recorded for 3 weeks after the injection, a 12h prolonged waking period and during a 24h recovery sleep period. Brain sections processed for visualization of A1 mRNA and/or immunohistochemistry revealed that both ChAT- and parvalbumin-positive cells contained A-1A mRNA. 192-SAP eliminated ChAT immunoreactive cells in the basal forebrain. There were no differences in sleep-wakefulness up to 3 weeks after drug administration, a finding consistent with previous reports. In addition, there were no changes in recovery sleep following prolonged waking in lesioned rats. These results indicate that the cholinergic basal forebrain groups are not the primary mediators of wakefulness or of sleep homeostasis. We suggest that the effects of adenosine are mediated via binding to non-cholinergic neurons.

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Basal forebrain cholinergic system: Cortical activation, sleep/waking EEG and evoked potentials.

Shafi R, Berntson GG, Sarter M, Saurer T, Spino M (2001) Basal forebrain cholinergic system: Cortical activation, sleep/waking EEG and evoked potentials. Neuroscience 2001 Abstracts 533.16. Society for Neuroscience, San Diego, CA.

Summary: The role of the basal forebrain cholinergic system in cognitive functions such as arousal, attention and memory has been well documented. The purpose of the present study was to further elucidate the role of the basal forebrain in regulating cortical states and processes that may underlie these functions. Selective lesions of the cholinergic neurons of the basal forebrain were made using the immunotoxin 192 IgG-saporin, which selectively targets the p75 receptor on cholinergic neurons. The effects of these lesions on sleep structure and EEG activity and on afferent priming of cortical reactivity was evaluated. Specifically, we monitored behavioral activity and sleep states and examined the frequency distribution of power distribution in EEG frequency bands during these states. In separate sessions, we also recorded cerebral event-related potentials to auditory stimuli (100 ms, 1 K Hz at 60, 70 and 80 db) after intraperitoneal administration of saline or epinephrine (0.5 mg/kg, which we have previously found to result in priming or enhancement of the auditory evoked response). Compared to controls, lesioned animals showed a reduction in spontaneous activity, reduced power in higher frequency (primarily gamma) EEG bands during both sleep and waking, and altered sleep structure. In addition, lesioned animals displayed lower amplitude auditory evoked potentials and a loss of epinephrine-priming of the evoked response. Results support the view that the basal forebrain cholinergic system may play an important role in cortical activation and the regulation of sleep/waking states, as well as in cortical processing and its enhancement by visceral priming.

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Low dose 192 IgG-saporin selectively destroys basal forebrain cholinergic neurons and impairs acquisition of a spatial memory task.

Zambon NJ, Nagle R, Pokala V, Gibbs RB, Johnson DA (2001) Low dose 192 IgG-saporin selectively destroys basal forebrain cholinergic neurons and impairs acquisition of a spatial memory task. Neuroscience 2001 Abstracts 534.13. Society for Neuroscience, San Diego, CA.

Summary: We previously showed that a high dose (1 μg) of the selective cholinergic immunotoxin 192 IgG-saporin (SAP), injected into the medial septum (MS) of Sprague-Dawley rats, impeded acquisition of a delayed matching-to-position (DMP) spatial memory task, whereas injections of ibotenate (5 μg in 1 μL) did not. The present study examined the effects of lower doses of SAP (0.22 and 0.45 μg in 1 μl) on DMP acquisition. Animals received either SAP or vehicle injected directly into the MS. Two weeks later, animals were food deprived and trained to the DMP task. Rats received 8 trial pairs/day until they reached a criterion of 15/16 correct choices. Seven days later, post-criteria testing for retention was performed. Brain tissues were analyzed for choline acetyltransferase (ChAT) activity, or were processed for immunohistochemical detection of ChAT and parvalbumin. Control rats required significantly fewer days (13.1) to reach criterion than rats that received 0.22 (22.0 days) or 0.45 (20.1 days) μg SAP. There was no effect of SAP treatment on post-criteria testing. Injections of SAP produced marked depletion of ChAT-positive cells and ChAT activity, but no apparent depletion of parvalbumin staining in the MS. In contrast, ibotenate injections used in the previous study were shown to produce marked depletion of parvalbumin staining in the MS, but no significant cognitive impairment. The data suggest that selective destruction of cholinergic neurons in the MS significantly impairs acquisition of the DMP task.

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Behavioural and neurochemical changes associated with single and combined acetylcholine and dopamine lesions in neonatal rats.

Sherren N, Pappas BA (2001) Behavioural and neurochemical changes associated with single and combined acetylcholine and dopamine lesions in neonatal rats. Neuroscience 2001 Abstracts 539.5. Society for Neuroscience, San Diego, CA.

Summary: The functional outcomes of neonatal ACh or DA lesions are frequently less severe or qualitatively different from those seen in adult rats, and may be due to compensatory neurochemical changes. Given that these transmitter systems interact in the adult brain and that ACh and DA hypofunction may underlie the cognitive and motor disabilities seen in Rett syndrome, we hypothesized that combined neonatal ACh/DA lesions may produce a profile of neurochemical changes and behavioural impairments which are more severe or distinct from that caused by either lesion alone. Rats were lesioned at postnatal day 7 with 192 IgG-saporin (ACh rats), 6-OHDA with NE receptor blockade (DA rats), or both (ACh/DA rats). Behavioural testing occurred at 4 months of age. In the open field, only ACh/DA rats exhibited locomotor hyperactivity whereas all lesioned groups exhibited reduced exploratory behaviour. Neither DA nor ACh/DA rats were able to solve the Morris water maze, however ACh rats were indistinguishable from controls. 192 IgG-saporin treatment produced a 75% decrease in hippocampal ChAT activity, and cortical decreases of 30%, 70% and 40% in the frontal/cingulate (FC), retrosplenial (RS) and partietotemporal (PT) regions respectively. 6-OHDA treatment produced a 90% decrease in striatal DA levels and a 75% decrease in FC cortex. Interestingly PT DA levels were 68% higher in ACh rats but 47% lower in ACh/DA rats compared to control, while DA rats showed a decrease which was not significantly different from control. Thus sparing of spatial learning ability in ACh rats may be mediated by increases in PT DA levels, whereas combined ACh/DA lesions exacerbate DA loss in this region.

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