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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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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)
Featured Article: Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in Parkinson’s Disease
Kucinski A (2015) Featured Article: Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in Parkinson’s Disease. Targeting Trends 16(1)
Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-ChAT-SAP (Cat. #IT-42)
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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)
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 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)
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)