43 entries found for : sfn2006
Impaired cortical plasticity after early hypoxia–ischemia
Failor SW, Evans MM, Cang J, Stryker MP, McQuillen PS (2006) Impaired cortical plasticity after early hypoxia–ischemia. Neuroscience 2006 Abstracts 717.14. Society for Neuroscience, Atlanta, GA.
Summary: Background: Unique forms of structural plasticity occur in sensory cortex during critical periods in the developing brain. Recovery from neonatal hypoxic-ischemic brain injury may involve plasticity mechanisms. Objective: To investigate the effect of hypoxic-ischemic injury on plasticity, we examined quantifiable forms of use-dependent structural thalamocortical plasticity in somatosensory and visual cortex following early cerebral hypoxia-ischemia (HI) within a rodent model. Methods: Plasticity in primary somatosensory cortex (S1) was induced by lesion of whisker pad row C on selective days during the first postnatal week with or without preceding hypoxia-ischemia (HI, Vannucci model). The whisker barrel map was visualized with cytochrome oxidase staining and 5-HT immunohistochemistry and quantified by measuring the ratio of D-row to C-row areas in tangential sections. Plasticity in primary visual cortex (V1) was induced by 4-day monocular deprivation (MD) beginning at postnatal day (PND) 28. Ocular dominance was quantified using intrinsic signal optical imaging and expressed as an index of the response to right or left eye stimulation, with or without MD and/or preceding early HI. Changes in markers of inhibitory neurons, extracellular matrix and myelin-associated molecules following HI are correlated with plasticity measurements. Results: S1 plasticity following neonatal HI is attenuated throughout the critical period (PND 1-3). S1 plasticity is significantly decreased (P<0.01, all ages) by an average of 66%. HI does not affect timing of the critical period for S1 plasticity. Following MD, the ocular dominance index (ODI) decreases from 0.14 +/- 0.12 (mean +/- SD, n=9) to -0.16 +/- 0.18 (n=5). Following neonatal HI, this ODI shift is attenuated (n=2). Similar respective effects following MD are observed using a selective immunotoxin (192-saporin) to destroy subplate neurons underlying visual cortex (n=6). Conclusions: Neonatal cerebral hypoxia-ischemia impairs structural plasticity in primary somatosensory and visual cortex. Similar results following selective immunoablation of subplate neurons, taken together with prior observations of selective subplate neuron death following neonatal HI, suggests a role for subplate neurons in structural plasticity during critical periods in sensory cortex.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Hernandez-Martinez H, Arias-Carrion O, Drucker-Colin R, Murillo-Rodriguez E (2006) Transplant of hypocretin neurons into the lateral hypothalamus of rats with lesions of the hypocretin neurons. Neuroscience 2006 Abstracts 719.2. Society for Neuroscience, Atlanta, GA.
Summary: Narcolepsy, a disabling neurological disorder is characterized by excessive daytime sleepiness, sleeps attacks, sleep fragmentation, and cataplexy. This sleep disorder has been linked to a loss of neurons containing the neuropeptide hypocretin (HCRT). Our group has developed an experimental model to induce narcolepsy in rats. The bilateral administration of the neurotoxin hypocretin-2-saporin (HCRT2-SAP) into the lateral hypothalamus (LH) of rats destroys the HCRT neurons. Therefore, the loss of HCRT neurons leads to developing narcolepsy. In order to replace the HCRT lost neurons by HCRT2-SAP, a suspension of cells from the posterior hypothalamus of 3-5 days old rat pups were stained with GFP and injected into the LH of lesioned rats. Animals were sacrificed 21 days after transplant, and cryostat-cut coronal sections of the LH sections were examined for presence of HCRT-immunofluorescence neurons. Preliminary data shows that HCRT transplanted neurons into the LH of lesioned rats were present at the target area 21 days after implant. These somata were similar in size and appearance to adult rat HCRT-immunoreactive neurons. Our results indicate that HCRT neurons obtained from rat pups can be grafted into a host brain and graft survives during 21 days. Importantly, our study addresses the possibility to replace HCRT neurons in narcolepsy in order to reverse this disease.
Related Products: Orexin-B-SAP (Cat. #IT-20)
McGaughy JA (2006) The effects of a norepinephrine reuptake blocker, atomoxotine, on an attentional set shifting impairment caused by prefrontal lesions. Neuroscience 2006 Abstracts 749.17. Society for Neuroscience, Atlanta, GA.
Summary: There is substantial evidence to support the role of norepineprhine (NE) in selective attention. The NE system is hypothesized to maintain task-related attentional focus and allow shifts of attention (Aston-Jones and Cohen, 2005). These unique attentional functions correlate with changes in the firing patterns in locus coeruleus. Previous work in our lab has shown that NE lesions of the medial prefrontal cortex produces robust impairments in the ability of rats to perform an attentional set-shift, though acquisition of the attentional set and reinforcement reversal learning were spared. The current study assesses the effectiveness of atomoxotine, a NE reuptake blocker, in remediating these deficits. This drug is currently used in the treatment of attention deficit disorder and may restore balance to the noradrenergic system of the frontal cortex in these patients. Male, Long-Evans rats received lesions of the medial wall of the prefrontal cortex using dopamine beta-hydroxylase saporin (DBH-SAP) to produce selective noradrenergic deafferentation. The performance of DBH-SAP rats was compared to sham-lesioned (SHAM) rats in a test of attentional set-shifting after intraperitoneal injections of atomoxotine (0.0, 0.1,0.3, 0.9 mg/kg) 15 minutes prior to the test of attentional set-shifting. During the attentional set shifting task (Birrell and Brown 1999), rats were exposed to complex stimuli (texturized, scented pots filled with digging media). Initially rats were reinforced for focusing attention on one stimulus dimension, e.g. scent, during the tests of complex discriminations and reinforcement reversals. In tests of attentional set-shifting, subjects were required to inhibit attention to the previously reinforced dimension e.g. scent and learn that a new dimension e.g. texture predicted reinforcement.These results confirm that NE deafferentation of prefrontal cortex impairs the ability of rats to shift attention from the initially reinforced dimension to another dimension, e.g. when texture not odor now predicts reinforcement. Low doses of atomoxotine ameliorate the set-shifting impairments of DBH-SAP rats but hindered the performance of SHAM rats. These data suggest that shifts of attentional set require an optimal level of release of NE in the frontal cortex with both high and low levels of NE causing impairments in these abilities.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Northrop LE, Erskine MS (2006) Noradrenergic nuclei involved in sensory input during mating project to the ventromedial hypothalamus and are involved in mating-induced pseudopregnancy in female rats. Neuroscience 2006 Abstracts 661.23. Society for Neuroscience, Atlanta, GA.
Summary: The ventrolateral region of the ventromedial hypothalamus (VMHvl) is known to control female sexual receptivity through the activity of ovarian steroids in the female rat. These receptors are thought to aide in the steroid-dependent facilitation of the lordosis posture. Besides harboring estrogen and progesterone receptors, dense numbers of noradrenergic receptors are also present in the VMHvl. Previous research has shown that norepinephrine is released in significant amounts within the VMHvl after a female receives vaginocervical stimulation (VCS). At the time of mating, the vaginocervical sensory input travels from the brainstem, through the ventral noradrenergic bundle (VNAB), and finally to the VMH. Sufficient amounts of VCS are necessary for inducing twice daily prolactin surges, which are required for the initiation of pseudopregnancy (PSP). To distinguish whether these cells play a role in mating-induced PSP, they were selectively lesioned using the immunotoxin anti-dopamine-β-hydroxylase-saporin (DBH-SAP) 10 days prior to mating. Females were given bilateral VMHvl infusions of either 60ng/0.6µl of DBH-SAP or 2ng/0.6µl of IGG-SAP (non-specific control). Ten days following infusion on proestrous, females received one of two treatments: no VCS (home cage), or a sufficient amount of VCS (15 intromissions from males) to induce PSP. PSP was measured using vaginal smears and serum PRL concentrations. The next witnessed proestrous day after mating, females were mated again with the same type of stimulus as previously administered and perfused 90 min later. The brainstems were cut in 30µm sections, and ICC was used to visualize DBH and FOS immunoreactivity (IR). FOS-IR and DBH-IR cells were counted in the A2 and A1 cell regions, components of the VNAB. DBH-SAP infused females that received 15I showed 50% induction of PSP whereas IGG-SAP (15I) females showed 100% induction of PSP. None of the home cage rats became PSP . VMHvl DBH-SAP infusions significantly decreased DBH/FOS-IR expression in A2 and A1 nuclei, as well as decreased expression in DBH-IR in A2 nuclei compared to IGG-SAP infused females. Our results show that A1 and A2 noradrenergic cells which innervate the VMHvl are required for initiation of P/PSP.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Lu J, Yoshida K, Fuller PM, Saper CB (2006) Absence of a systemic febrile response to PGE2 and LPS following targeted saporin lesions of the rostral raphe pallidus. Neuroscience 2006 Abstracts 662.18. Society for Neuroscience, Atlanta, GA.
Summary: Anatomical studies have indicated that the rostral raphe pallidus (RPa) medullary area contains sympathetic premotor neurons that may be required for the fever responses triggered by prostaglandin E2 (PGE2) and lipopolysaccharide (LPS) administration. For example, stimulation of this region increases sympathetic activity to brown adipose tissue (BAT) and arteries of the tail, the two primary thermoregulator effector organ in the rat. In addition, neurons in this region are activated by cold exposure and central administration of PGE2. To better understand the role of the RPa in the systemic febrile response to endogenous and exogenous pyrogenic mediators, we performed targeted orexin-saporin lesions of the RPa. Following lesions of the RPa, the amplitude of core body temperature (Tb), as compared with pre-lesion measurements and controls, was significantly increased (p<0.001). Mean Tb did not differ between groups, however. In addition, fever responses to both i.p. LPS and i.c.v. PGE2 were completely blocked in the RPa lesioned rats. Importantly, following LPS administration, the RPa lesioned animals demonstrated the same pattern of Fos expression in the preoptic area as compared to intact controls, suggesting normal activation of the pyrogen-reception system. These observations establish a critical role for the RPa nucleus in the systemic fever response to the pyrogenic mediators LPS and PGE2.
Related Products: Orexin-B-SAP (Cat. #IT-20)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Neuroprotective effects of testosterone in two models of spinal motoneuron injury
Sengelaub DR, Osborne MC, Little CM, Huyck KD, Verhovshek T (2006) Neuroprotective effects of testosterone in two models of spinal motoneuron injury. Neuroscience 2006 Abstracts 683.12. Society for Neuroscience, Atlanta, GA.
Summary: Following induced death or axotomy of spinal motoneurons remaining motoneurons atrophy, but this atrophy can be reversed or prevented by treatment with testosterone (T). For example, partial depletion of motoneurons from the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB) induces dendritic atrophy in remaining motoneurons, and this atrophy is prevented by treatment with T. To test whether T has similar effects in more typical motoneurons, we examined potential neuroprotective effects in motoneurons innervating muscles of the quadriceps. Motoneurons innervating the vastus medialis muscle were selectively killed by intramuscular injection of cholera toxin conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing T or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Compared to intact control males, partial motoneuron depletion resulted in decreased dendritic length (70%) and soma size (13%) in remaining quadriceps motoneurons, but as in the SNB, this atrophy was attenuated by T treatment. In a second model, brain-derived neurotrophic factor (BDNF) and T have a combinatorial effect in the maintenance of motoneurons after axotomy in that dendritic morphology is supported by BDNF treatment, but only in the presence of T. Using immunohistochemical methods, we examined the regulation of the expression of the BDNF receptor, trkB, by T. In both the highly androgen-sensitive motoneurons of the SNB and the more typical quadriceps motoneurons, the expression of trkB receptors was regulated by the presence of T. Motoneurons of castrated animals deprived of T show reduced expression of trkB receptors compared to motoneurons of intact animals or castrated animals given T replacement. This finding suggests that maintenance of trkB receptors with T may be necessary to permit the trophic effects of BDNF in supporting dendritic morphology after axotomy. Together, these findings suggest that T regulates neuroprotective effects through a variety of mechanisms, not only in highly androgen-sensitive motoneurons, but in more typical motoneuron populations as well.
Related Products: CTB-SAP (Cat. #IT-14)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Wong YM, Webber MJ, Dickenson AH, Hunt SP (2006) Molecular changes in the dorsal horn that maintain inflammatory hyperalgesia are similar to those generated during long-term potentiation. Neuroscience 2006 Abstracts 642.17. Society for Neuroscience, Atlanta, GA.
Summary: The generation of LTP in deep dorsal horn neurons by noxious stimulation may be one mechanism whereby acute pain transforms into a chronic pain state. Spinal LTP requires the activation of a subset of superficial dorsal horn neurons that express the neurokinin-1 receptor (NK1-R) and are crucial for the initiation and maintenance of chronic pain states. These neurons participate in local spinal sensory processing and are the origin of a spino-bulbo-spinal loop that drives descending spinal facilitation. Spinal LTP is correlated with increased neuronal expression of the transcription factor zif268 in the superficial dorsal horn. Here, we examined if inflammatory pain states required LTP-like changes in gene expression that are dependent upon an intact lamina I pathway. We also asked if changing levels of zif268 regulated the glucocorticoid receptor (GR) gene, a downstream target of zif268. NK1 expressing neurons in lamina I of the lumbar spinal cord were selectively ablated using SP-SAP applied intrathecally. 28d later, rats were injected with Complete Freunds’ Adjuvant (CFA) (50%, 100μl) 2h prior to perfusion with 4% paraformaldehyde. Using immunohistochemistry, we found that while levels of c-fos immunoreactivity were unchanged by lamina I ablation, the levels of zif268 had decreased by 36% (p<0.05) compared to controls. We therefore treated rats intrathecally with zif268 antisense or missense oligonucleotides (0.16μg/μl/h) via implanted osmotic mini pumps and assessed the behavioural effects of zif268 ‘knockdown’ on inflammatory hyperalgesia. Animals were perfused 4 days after CFA inflammation and protein levels of zif268 and GR were assessed by immunohistochemistry. Antisense, but not missense zif268 treatment, reduced the levels of zif268 by 37% and reduced behavioural allodynia by 40%, but only at days 2-4 post CFA. Levels of GR were also reduced by 30% following zif268 antisense treatment. We therefore applied antisense and missense GR probes intrathecally.This reduced the inflammatory hyperalgesia score by 38% but again only on days 2-4. These results suggest the zif268 gene is essential for the maintenance but not the induction of inflammatory pain states and that zif268 can regulate GR in the spinal cord.
Related Products: SP-SAP (Cat. #IT-07)
Role of spinal cord µ-opioid receptor expressing dorsal horn neurons in morphine analgesia
Kline IV RH, Wiley RG (2006) Role of spinal cord µ-opioid receptor expressing dorsal horn neurons in morphine analgesia. Neuroscience 2006 Abstracts 643.19. Society for Neuroscience, Atlanta, GA.
Summary: The role of spinal cord μ-opioid receptor expressing dorsal horn neurons in morphine analgesia is not clearly understood. Using lumbar intrathecal (i.t.) injections of the targeted toxin dermorphin-saporin to selectively destroy these cells, we sought to determine the effect of this lesion on the antinociceptive activity of systemic and i.t. morphine on the hotplate test. We examined the antinociceptive effects of morphine across a range of stimulus intensities (44, 47 & 52oC) in order to assess responses mediated by C or Aδ thermal nociceptors. Experiment 1 (systemic morphine): Sixteen Sprague Dawley male rats were injected with 500ng dermorphin-saporin i.t. or PBS and hotplate testing resumed one week after injections. Baseline hotplate responses were monitored for three weeks after which systemic morphine dose response curves (0, 2.5, 5, &10 mg/kg s.c.) were performed. Experiment 2 (spinal intrathecal morphine): Twelve Long Evans female rats were surgically implanted with indwelling lumbar i.t. catheters (8.5cm), underwent baseline hotplate testing for 7 days, had i.t. morphine dose response curves (0, 0.01, 0.1, & 1 μg) performed at 44 & 52oC seven days before and eight days after dermorphin-saporin injections. The dependent measures for the hotplate test were: 1) latencies to the first lick or guard response (all temperatures) and 2) the cumulative durations and amounts of licking and guarding events (44 and 47oC). Loss of lamina II MOR-expressing dorsal horn neurons after dermorphin-saporin was confirmed in spinal cord sections from each rat stained for MOR1 and MOR1C using standard immunoperoxidase techniques on adjacent 40 μm sections from the L4 spinal segment. Baseline responses to noxious heat did not decrease after i.t. dermorphin-saporin. The antinociceptive activity of systemic morphine was attenuated in dermorphin-saporin treated rats at 44 & 47oC; this effect was least striking on the 52oC hotplate and greatest on the 44oC hotplate. The dermorphin-saporin-induced lesion reduced the antinociceptive effects of intrathecal morphine more than systemic morphine. Based on the above findings are others not included here, we conclude that dorsal horn MOR expressing neurons are necessary for morphine to exert its maximum antinociceptive and analgesic effects.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Orexin transmission is required for food-related increases in cortical acetylcholine release
Frederick-Duus D, Fadel J (2006) Orexin transmission is required for food-related increases in cortical acetylcholine release. Neuroscience 2006 Abstracts 369.23. Society for Neuroscience, Atlanta, GA.
Summary: The hypothalamic orexin/hypocretin neuropeptides (OxA and OxB) are crucial modulators of state-dependent behavior including the regulation of arousal in response to homeostatic challenges. Orexins provide a moderately dense innervation of cholinergic portions of the basal forebrain, including the ventral pallidum/substantia innominata and nucleus basalis magnocellularis. OxA administration in this area also produces robust increases in cortical acetylcholine (ACh) release. Here, we used in vivo microdialysis to test the hypothesis that orexin transmission is required for the increase in cortical ACh release resulting from presentation of stimuli related to palatable food. Rats were mildly food-deprived and trained to associate sudden darkness in the testing room with presentation of sweetened cereal. Stimulated cortical ACh release in these animals was blocked by orexin B-saporin (OxB-SAP) lesions of the perifornical hypothalamus at doses that produced 75-80% loss of orexin neurons, but minimal loss of other neuronal phenotypes in this area. In intact animals, pretreatment with the orexin 1 receptor (Ox1R) antagonist SB334867 similarly abolished food cue-elicited increases in cortical ACh release, indicating the specific involvement of OxA in this phenomenon. Neither OxB-SAP nor SB334867 reduced affected basal ACh release. Finally, in old rats (28-30 months), double-label immunohistochemistry revealed a reduction in orexin-immunoreactive fibers near cholinergic somata and dendrites in the basal forebrain regions, consistent with the deficits in stimulated ACh release seen with old animals in this paradigm. Collectively, these data suggest that phasic orexin activation of the basal forebrain cholinergic system may bias attentional resources toward stimuli related to underlying homeostatic challenges, thus coordinating the processing of interoceptive and exteroceptive cues. Age-related deficits in these capacities may have an orexinergic basis.
Related Products: Orexin-B-SAP (Cat. #IT-20)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Likhtik E, Apergis-Schoute J, Pare D (2006) A selective lesioning method to probe the role of intercalated (ITC) amygdala neurons in the extinction of classically conditioned fear responses. Neuroscience 2006 Abstracts 370.19. Society for Neuroscience, Atlanta, GA.
Summary: The acquisition of conditioned fear responses (CRs) is thought to involve the potentiation of synapses conveying information about the conditioned stimulus (CS) to the basolateral (BLA) amygdala. Expression of CRs would depend on transfer of potentiated CS inputs by the BLA to the central amygdala (CE). In contrast, the mechanisms of extinction remain controversial. It was proposed that ITC neurons, which receive BLA inputs and generate feedforward inhibition in CE, are in a key position to mediate extinction. In this view, potentiation of BLA inputs to ITC cells during extinction training, would dampen the impact of CS-related BLA activity on CE neurons, inhibiting CRs. However, this idea is difficult to test because ITC cells occur in small, lateromedially dispersed clusters, making conventional lesioning methods inadequate. The present study aimed to find an effective way of eliminating ITC cells, taking advantage of the fact that, compared to the rest of the amygdala, they exhibit strong immunoreactivity for mu opioid receptors (muORs). First, we performed electron microscopic observations to determine whether muORs are expressed by ITC cells vs. afferents to ITC cells. This test revealed that muORs are concentrated in the postsynaptic membrane density of asymmetric synapses found on ITC cells. Next, we tested whether it is possible to obtain selective ITC lesions by injecting the toxin saporin conjugated to the mu opioid agonist dermorphin (DER-SAP) in the proximity of ITC cells. Thus, rats received intra-amygdaloid pressure injections of DER-SAP in one hemisphere and of vehicle on the contralateral side. Seven days later, the animals were perfused and the tissue processed to reveal muOR. DER-SAP injections produced a marked reduction in muOR immunoreactivity at the BLA-CE border, where ITC cells are usually located. Thus, selective lesioning of ITC cells can be achieved using this method. We are currently testing the impact of such ITC lesions on extinction learning.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
McKay LC, Feldman JL (2006) Unilateral ablation of neurokinin-1 receptor-expressing (NK1R) neurons within the preBötzinger complex (preBötC) in adult rats disrupts breathing during sleep but not during wakefulness. Neuroscience 2006 Abstracts 455.4. Society for Neuroscience, Atlanta, GA.
Summary: In adult rats, as the number of ablated preBötC NK1R neurons increases, breathing becomes increasingly disrupted during sleep(1), eventually resulting in an ataxic breathing pattern during wakefulness when cell loss is >80%(1,2). Here we determine whether ablation of fewer preBötC NKIR neurons leads to sleep-disordered breathing (SDB), while breathing during wakefulness remains stable. Adult male Sprague Dawley rats (n=8) were anesthetized (100mg/kg Ketamine, 10mg/kg Xylazine i.p.) and instrumented to record diaphragmatic, abdominal and neck EMG, ECG, and EEG. Fourteen days post-implantation a second surgery was performed to stereotaxically inject unilaterally into the preBötC, the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons. Rats were kept on a 12-hour light/dark cycle and monitored within a plethysmograph from day 1 post-injection until they were sacrificed (days 21-50). Post-unilateral SP-SAP injection, respiratory pattern remained normal during wakefulness and sleep until ~day 9. At this point, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered. The disruptions in breathing pattern were characterised by an increase in frequency of apneas and hypopnea (~4-6/hour of sleep vs <3 pre-injection control; p<0.05). Rats that were monitored up to 50 days post-SP-SAP injection continued to have SDB, while breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP injected rats, an ataxic breathing pattern did not develop during wakefulness(1,2). Histological analysis of the ventrolateral medulla confirmed that only NKIR neurons within the preBötC on one side of the medulla were ablated (~300 preBötC NK1R neurons/side in the adult rat). Unilateral SP-SAP injection results in SDB, while breathing during resting wakefulness appears normal. Over time, breathing during sleep does not improve. We have previously proposed that in the elderly and in individuals who suffer from various neurodegenerative diseases, gradual loss of preBötC NK1R neurons may explain why SDB is highly prevalent in these populations. We further speculate that SDB can go unnoticed because breathing during wakefulness is relatively stable.
Related Products: SP-SAP (Cat. #IT-07)
Effect of running on neurogenesis in cholinergic lesioned mice
Ho N, Han S, Dawe GS (2006) Effect of running on neurogenesis in cholinergic lesioned mice. Neuroscience 2006 Abstracts 318.5. Society for Neuroscience, Atlanta, GA.
Summary: Neurogenesis occurs mainly in two regions of the adult rodent brain, the dentate gyrus of the hippocampus and the subventricular zone. There are many factors which regulate neurogenesis, but voluntary exercise has consistently been shown to enhance neurogenesis. Exercise has been reported to specifically stimulate neural cell proliferation in the hippocampus but not the olfactory bulb. One of the major sources of afferents to the hippocampus are the septohippocampal projections, in which axons from the medial septum and diagonal band of Broca (MSDB) project to the hippocampus. Major components of the septohippocampal pathway that act as ‘pacemakers’ for hippocampal theta rhythm, which increases in conjunction with the voluntary running, are the cholinergic and GABAergic projections rising from cells in the MSDB. This present study investigates the effect of a partial cholinergic lesion in the basal forebrain and MSDB of mice, a partial model of the neurodegeneration that occurs in Alzheimer’s disease, on neural cell proliferation and neurogenesis. Murine p75-SAP, a conjugate of a p75 antibody that targets selectively cholinergic cells and cytotoxic saporin, was injected into the ventricles of female adult Swiss mice. After recovery from surgery mice were then administered bromodeoxyuridine (BrdU). BrdU immunopositive cells were quantified 24 hours and 4 weeks to assess for neural cell proliferation and survival of newly generated cells. Partial cholinergic denervation led to a decrease in the survival of new born cells in the dentate gyrus. We compared the effects of voluntary running for a period of 12 days in non-lesioned and lesioned mice under similar experimental conditions. Running resulted in an increase in neural cell proliferation for both the non-lesioned and lesioned groups. Running led to a marked increase in cell proliferation in lesioned mice compared to the controls, and also enhanced neurogenesis, as determined by the colocalization of BrdU and the neuronal nuclei marker NeuN in cells within the dentate gyrus. The present study suggests that voluntary running may have a positive effect on neurogenesis in neurodegenerative models in rodents. Further work needs to be done to elucidate the underlying mechanisms of exercise-induced neurogenesis.
Related Products: mu p75-SAP (Cat. #IT-16)
Li A, Nattie EE (2006) Lesions of neurokinin-1 receptor immunoreactive (NK1R-ir) neurons in the ventral medulla decrease chemoreception and ventilation. Neuroscience 2006 Abstracts 455.5. Society for Neuroscience, Atlanta, GA.
Summary: We injected SSP-saporin, a toxin specific for NK1R-ir neurons, into the cisterna magna in order to lesion a wide aspect of the ventral medulla. NK1R-ir loss after 21 days was 79% in the retrotrapezoid nucleus, 65% in the A5 region, 38% in the medullary raphe and 49% in the pre-Botzinger complex. This resulted in a large reduction in the ventilatory response to 7% CO2 during wakefulness (-61%) and NREM sleep (-57%). The response to 12% O2 was reduced by 35-40% at 8 days but partially recovered by 22 days. We did not measure chemoreception in REM sleep. Ventilation in wakefulness, NREM and REM sleep measured over 4 hrs of air breathing decreased by 12-13% at 21 days compared to baseline values (P< 0.005, one-way repeated measures ANOVA; P< 0.05 post hoc comparison, Dunnett’s test). In REM sleep compared to awake and NREM sleep, the rats breathed with a higher frequency and smaller tidal volume, a pattern that was unaffected by the lesion, and with a greater coefficient of variability, which was further increased by the lesion (71 +/- 4 % vs 34 +/- 6 %). We did not observe any severe rhythm disturbances. We attribute the effect of these lesions, which are greatest in the ventral medullary regions including the retrotrapezoid nucleus and the medullary raphe, to loss of tonic chemoreceptor input. This input seems to have equal weight in wakefulness and in NREM and REM sleep and it seems to minimize the variability of frequency observed in REM sleep.
Related Products: SSP-SAP (Cat. #IT-11)
Rapp KL, Khan AM, Watts AG (2006) Catecholaminergic afferents are required for hypothalamic parvicellular paraventricular neurons to transduce signals associated with hypoglycemia into p44/42 MAP kinase phosphorylation events. Neuroscience 2006 Abstracts 355.9. Society for Neuroscience, Atlanta, GA.
Summary: Hypoglycemia activates CRH neuroendocrine neurons in the hypothalamic paraventricular nucleus (PVH), thereby rapidly elevating plasma ACTH and corticosterone concentrations. Hindbrain-originating catecholaminergic (CA) neurons projecting to the PVH facilitate ACTH release after insulin-induced hypoglycemia; however, the intracellular signaling mechanisms that CRH neurons use to transduce CA signals into secretogogue function are unknown. We have previously shown that p44 and/or p42 MAP kinases (ERK1/2) are phosphorylated in CRH neurons after 2-deoxy-D-glucose challenge (Endoc. v145:351, 2004). We now ask: Are hindbrain-originating CA projections to the PVH essential for ERK1/2 phosphorylation in response to insulin-induced hypoglycemia? Male Sprague-Dawley rats received acute bilateral PVH microinjections of either saporin toxin conjugated (DSAP) to an antiserum against dopamine beta hydroxylase (DBH) or conjugated to a non-targeted mouse IgG (control mIgG-SAP), were fitted with jugular catheters, and allowed to recover. On the day of testing, plasma glucose was measured just before the onset of hypoglycemia (induced via insulin bolus [2U/kg, i.v.]) and then 10 and 30 min thereafter. Rats were then anesthetized and transcardially perfused. Brain tissue processed for dual immunofluorescence using antibodies raised against DBH and phospho-ERK1/2 was visualized by confocal microscopy. Baseline plasma glucose levels did not differ significantly between groups (5.66 ± 0.26 mM), but were significantly reduced in each group when compared to baseline after 10 (1.48 ± 0.12 mM) and 30 (1.92 ± 0.12 mM) minutes. DSAP rats displayed marked loss of DBH immunostaining in the PVH relative to controls, with concomitant loss of phospho-ERK1/2 immunostaining within the parvicellular PVH. Further analysis was performed to address the effect of DSAP on DBH staining and ERK1/2 recruitment in the hindbrain and arcuate nucleus. Our results confirm that phosphorylation of ERK1/2 in parvicellular PVH after insulin-induced hypoglycemia requires intact CA afferent innervation. These data contribute to our understanding of how intracellular signaling is regulated in parvicellular PVH neurons. They also underscore an emerging importance of CA afferents for mediating neuroendocrine responses to systemic alterations in glucose.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Glucoprivation enhances dopamine-beta-hydroxylase gene expression in hindbrain catecholamine cells
Li A, Ritter S (2006) Glucoprivation enhances dopamine-beta-hydroxylase gene expression in hindbrain catecholamine cells. Neuroscience 2006 Abstracts 359.12. Society for Neuroscience, Atlanta, GA.
Summary: Hindbrain catecholaminergic neurons are key participants in systemic glucoregulation. Using in situ hybridization, we investigated the effects of glucoprivation on gene expression of dopamine-beta-hydroxylase (DBH), a key enzyme for catecholamines synthesis, to further define the catecholamine subpopulation activated by glucoprivation. Glucoprivation induced by systemic injection of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG, 250 mg/kg body weight) increased total DBH mRNA expression in caudal ventrolateral medullary cell groups (namely, A1, the A1/C1 overlap, and middle C1) from 6 - 49 times control levels. In retrofacial C1, A5 and A7 no enhancement was observed. In the dorsomedial medulla, DBH mRNA hybridization signal was modestly increased (tripled) in cell group A2, but not in the area postrema. Furthermore, a previous hypothalamic microinjection of the retrogradely transported immunotoxin, anti-DBH-saporin, profoundly reduced DBH-positive cells in hindbrain, and abolished the 2DG-stimulated increases of DBH mRNA expression in the caudal ventrolateral medulla and A2 regions. The strong glucoprivation-induced enhancement of DBH gene expression in particular cell populations is consistent with the demonstrated importance of catecholaminergic neurons for glucoregulation and provides further evidence for functional specialization within the catecholamine cell population.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Farias P, Valdes J, Riveros M, Torrealba F (2006) The tuberomammillary nucleus is a key component of the arousal system for the appetitive phase of feeding. Neuroscience 2006 Abstracts 361.24. Society for Neuroscience, Atlanta, GA.
Summary: The histaminergic neurons from the tuberomammilary nucleus (TMN) are important in maintaining a high level of arousal or increased sensory alertness. We have seen TMN activation (assessed by Fos-ir) in three different motivated behaviors: feeding, drinking and sexual. The aim of this work is to prove that TMN neurons are essential to promote the arousal during the appetitive phase of feeding. We evaluated the effect of TMN lesion performed with the neurotoxin-saporin coupled to orexin-B on locomotor activity and on thermal responses during food presentation to hungry rats as well as changes in Fos-ir of arousal nuclei and subcortical regions involved in thermal responses. Rats were implanted with telemetric transponders to measure locomotor activity and body core temperature. The brains were processed for Fos-ir, and counterstained with appropriate antibodies to identify ascending arousal system (AAS) nuclei. Histaminergic neurons in the TMN were identified by adenosine deaminase (ADA)-ir. The lesions significantly decreased the number of ADA ir/mm2. The larger lesion (<54% surviving neurons) produced a significant decreased in locomotion and temperature responses to food enticing, compared to intact rats or rats with smaller lesion. Larger lesion abolished the increase in Fos-ir of the AAS nuclei (except the locus coeruleus), and the increase in Fos-ir in thermoregulatory nuclei observed in intact rats. The activation of the orexin neurons of the lateral hypothalamic area and the increase in locomotor activity during food presentation were correlated with the activation of the dorsal TMN. The increased Fos-ir in locus coeruleus and dorsal raphe, and the increase in body core temperature were correlated with the activation of the ventral TMN. In conclusion the TMN neurons seems to act as a “master switch” since they are necessary to initiate the increased arousal that characterizes motivated behaviors, and they likely engage other arousal nuclei as well as thermoregulatory nuclei during the appetitive phase of feeding.
Related Products: Orexin-B-SAP (Cat. #IT-20)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2006) Ascending and descending pathways support fentanyl-induced pain hypersensitivity with and without a surgical incision. Neuroscience 2006 Abstracts 248.10. Society for Neuroscience, Atlanta, GA.
Summary: Acutely administered the analgesic opioid fentanyl has been shown to enhance mechanical hypersensitivity in a model of surgical pain induced by hindpaw incision in the rat. Recent evidence showed the importance of descending pathways originating from the rostral ventromedial medulla (RVM) in opioid-induced hyperalgesia after sustained morphine administration. Such hyperalgesia is also associated with numerous neurochemical changes in primary afferent fibers and spinal dorsal horn, such as increased spinal dynorphin expression. These changes may activate ascending pathways, mediated in part by NK-1 neurotransmission. Here, we examined the roles of ascending and descending pathways in sensory hypersensitivity after acute fentanyl administration. Male Sprague-Dawley rats received 4 fentanyl (4x100 μg/kg, s.c.) or saline injections administered at 15 min intervals. Some animals also received an incision in the plantar hindpaw. Thermal hyperalgesia and tactile allodynia were measured daily. In control rats, fentanyl induced analgesia followed by an immediate and long-lasting hyperalgesia, as previously described. Fentanyl also enhanced pain sensitivity induced by plantar incision. In SP-saporin pretreated rats, fentanyl induced analgesia and a moderate long-lasting hyperalgesia. The SP-saporin pretreatment slightly reduced both hyperalgesia and allodynia in postoperative rats and, to a larger extent, in fentanyl treated rats. Lidocaine injection in the RVM completely reversed fentanyl-induced sensory hypersensitivity and fentanyl enhancement of incision-induced hyperalgesia and allodynia. A slight reduction of incision-induced sensory hypersensitivity was observed after lidocaine injection in rats without fentanyl pretreatment. Spinal dynorphin content increased by 30 ± 7% and 71 ± 33% in fentanyl and fentanyl/incision treated rats, respectively. These data support the crucial role of the descending pathways from the RVM in the fentanyl-induced hyperalgesia and the partial implication of the NK-1 receptor containing ascending pathways.
Related Products: SP-SAP (Cat. #IT-07)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat
Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW (2006) Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Neuroscience 2006 Abstracts 264.4. Society for Neuroscience, Atlanta, GA.
Summary: Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set shifting (Birrell and Brown, 2000, J Nsci, 20:4320-4324). The mPFC receives multiple projections, but norepinephrine (NE) has previously been reported to modulate attention by its action in the mPFC (for review see Dalley et al., 2004, Nsci Biobeh Rev, 28:771-784), including shifting attentional set. Indeed, there is recent evidence that increasing NE in the mPFC by autoreceptor antagonism improves set-shifting performance in rats (Lapiz and Morilak, 2006, Nsci, 137:1039-1049). Furthermore, reduction of prefrontal NE by infusion of anti-DBH-saporin into PFC has been shown to impair attentional set-shifting in rats (Eichenbaum et al., 2003, SfN Abstract 940.7). The main source of noradrenergic input to the mPFC is from locus coerulus via the dorsal noradrenergic bundle (DNAB). This study examined the effect of lesions of the DNAB on the acquisition, maintenance and shifting of attentional set. Eleven male Lister-hooded rats received bilateral DNAB lesions by infusion of 6-hydroxydopamine (4μg in 2μl each side) at (nosebar -2.4mm) AP -6.0mm, ML ±1.0mm, DV -5.0mm (from dura). Twelve control rats received injections of vehicle. Rats learned to dig for bait in bowls then learned two simple discriminations - based on the bowls odor or the digging substrate - to a criterion of six consecutive correct trials. The next day, a series of discriminations tested acquisition of novel discriminations (both intra (ID) and extradimensional (ED)) and reversal learning. Trials to criterion, incorrect trials and dig-latencies were recorded and analysed. At conclusion of testing, brain tissue samples were analysed for NE content by HPLC-ECD. All rats required more trials to reverse previously learned associations, and to learn new discriminations when attentional refocusing was required (ED shift). Rats with DNAB lesions were unimpaired at reversal stages, but were impaired at the ED acquisition stage. Lesioned rats showed reductions of NE levels in mPFC (up to 95% in the infralimbic region, 89% in the prelimbic region and 93% in cingulate area Cg1). These data provide further evidence for the role of NE in attentional set-shifting, and combine with previous data to elucidate the mechanisms by which mPFC mediates attentional set-shifting in the rat.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain
Chauhan NB (2006) Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain. Neuroscience 2006 Abstracts 271.8. Society for Neuroscience, Atlanta, GA.
Summary: Today’s Alzheimer’s disease (AD) research lacks a “complete” model that would represent both plaque and tangle pathology together with correlative memory deficits. Although currently developed transgenic model including APP/PS1/tau mutations do not “truly” represent AD because tangles observed in AD brain are independent of tau mutations. Subtly increased β-amyloid (Aβ) levels either due to familial mutations or sporadic causes, primarily targets pre-tangle cytopathology and degeneration of basal forebrain cholinergic neurons (BFCN) via deranged signaling of glygogen synthase kinase 3-beta (GSK3β)-, protein kinase A (PKA)-, and extracellular signal-regulated kinase (ERK2) of ERK-mitogen-activated protein kinase (MAPK) cascade, leading to reduced phosphorylation of cAMP responsive element binding protein (CREB) that results in synaptic and memory deficits much earlier than the emergence of classic AD-pathology. Thus, subtly elevated Aβ, together with BFCN deficits resulting from Aβ-induced deranged signaling, set up a vicious feedback loop to produce characteristic plaque- and tangle-pathology observed in AD. Based on these facts, we wished to test if selective lesioning of basal fore brain cholinergic neurons during the early stages of amyloid build-up will exacerbate tau phosphorylation and produce tangle-like inclusions in transgenic mice with APP mutations. We produced selective immunotoxic lesions of BFCN by injecting the BFCN-specific cholinergic immunotoxin, which is known to specifically target p75-expressing BFCN and spare p75-expressing cerebellar neurons (Mu-p75-Saporin, Advanced Targeting Systems, #IT-16), intracerebroventricularly (ICV) in TgCRND8 mice harboring Swedish (KM670/671NL) and Indiana (V717F) mutations. This model exhibited tangle-like inclusions, provoked already existing plaque pathology, and worsened already impaired behavioral deficits.
Related Products: mu p75-SAP (Cat. #IT-16)
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Masawaki A, Sugiyo S, Shimoda T, Sakai Y, Watanabe M, Moritani M, Yoshida A, Niwa H, Takemura M (2006) Formalin-induced pain-related responses in rat lacking neurokinin-1 receptor neurons in the trigeminal nucleus caudalis. Neuroscience 2006 Abstracts 50.8. Society for Neuroscience, Atlanta, GA.
Summary: This study examines the effect of intra cisterna magna injection of substance P (SP) conjugated to saporin (SP-Sap; 5µM, 5µl) on formalin-induced pain-related behavior (PRB; face scrubbing behavior ) and c-Fos expression in the trigeminal nucleus caudalis (SpVc). In SP-Sap-treated rats, the numbers of NK-1-immunoreactive neurons in lamina I of the SpVc decreased compared with those in saline- or blank Sap-treated rats. The mean numbers ±SEM of PRB /5 min at the first phase (0-5 min after For injection) were 58.2±19.2 in the SP-Sap-treated rats, 115.6±14.0 in the saline treated rats and 86.9±45.7 in the blank-Sap-treated rats. The numbers at the quiescent period (5-10 min) were 45.2±26.3 in the SP-Sap- treated rats, 93.6±26.5 in the saline treated rats and 69.4±16.3 in the blank-Sap-treated rats. These at the former second phase (10-50 min) were 58.1±22.3 in the SP-Sap-treated rats, 133.6±26.1 in the saline treated rats and 95.8±29.6in the blank-Sap-treated rats. These at the latter second phase (55-90 min) were 7.0±5.6 in the SP-Sap-treated rats,13.7±12.4 in the saline treated rats and 10.4±22.5 in the blank-Sap-treated rats. These results indicate that formalin-induced nociceptive responses in the SP-Sap-treated rats are reduced.
Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)
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.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Orexin lesions block food-related increases in cortical acetylcholine release
Fadel J, Frederick-Duus D, Butts R (2005) Orexin lesions block food-related increases in cortical acetylcholine release. Neuroscience 2005 Abstracts 644.8. Society for Neuroscience, Washington, DC.
Summary: Hypothalamic orexin (hypocretin) neurons influence and coordinate arousal, state-dependent behavior, feeding and metabolic processes. Orexin fibers are seen in close proximity to choline acetyltransferase (ChAT)-positive magnocellular somata in portions of the basal forebrain and intrabasalis administration of orexin A increases cortical acetylcholine (ACh) release, suggesting that orexin inputs to the basal forebrain may be important for biasing attentional resources toward stimuli related to underlying homeostatic challenges. Here, we mildly food-deprived rats and trained them to associate an environmental stimulus (darkness) with presentation of palatable food. Microdialysis in these animals showed that the darkness stimulus, with or without accompanying food presentation, produced a robust increase in cortical ACh release. A subset of animals received unilateral administration of the immunotoxin orexin B-saporin (OxB-SAP; 350 ng/0.5 μl) or vehicle into the lateral hypothalamus and perifornical area. OxB-SAP produced a substantial (70-80%) ipsilateral loss of orexin-immunoreactive cells and a corresponding decrease in orexin fiber density in the basal forebrain. OxB-SAP did not alter the number or basal forebrain neurons showing ChAT-immunoreactivity and produced only mild (approximately 15%) loss of melanin-concentrating hormone cells. Basal cortical ACh release was unaffected in lesioned animals, but OxB-SAP lesions abolished increases in cortical ACh release associated with the food-paired stimulus. These data indicate that orexin inputs to the basal forebrain are required for food anticipatory-related increases in cortical ACh release. Orexins appear to be important components of the neural pathways by which interoceptive cues related to homeostasis recruit forebrain attentional systems.
Related Products: Orexin-B-SAP (Cat. #IT-20)