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Alterations in dopaminergic and glutamatergic systems following cortical cholinergic denervation.
Savage ST, Lundströmer K, Olson L, Mattsson A (2009) Alterations in dopaminergic and glutamatergic systems following cortical cholinergic denervation. Neuroscience 2009 Abstracts 839.14/M21. Society for Neuroscience, Chicago, IL.
Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. We have previously shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (nbm) in adult rats leads to an enhanced sensitivity to both amphetamine and the NMDA receptor antagonist phencyclidine (PCP). The enhanced sensitivity to amphetamine shown as a potentiated dopamine release in nucleus accumbens, along with a marked increase in locomotor activity in response to both amphetamine and PCP, suggested that the disruption of cortical cholinergic activity can lead to disturbances of glutamatergic and dopaminergic transmission. To further evaluate the consequences of cortical cholinergic denervation on the dopamine and glutamate systems, we are conducting an in depth in situ hybridization and immunohistochemistry analysis of nbm 192 IgG-saporin lesioned rats. Preliminary data from these investigations show an enhancement of expression levels of TH and DAT mRNA in the VTA and substantia nigra of the cholinergically denervated rats. The data suggests that cortical levels of NMDAR1 mRNA are not altered in the lesioned animals. However, preliminary data indicate that the induction of c-fos mRNA expression in cortex following PCP administration is reduced in denervated animals as compared to sham lesioned controls. These data may suggest hypofunction of NMDA receptors as a consequence of loss of cholinergic innervations. To evaluate the behavioral consequences of cortical cholinergic denervation, we are employing three behavioral paradigms (Locomotor and Rearing behavior, Social Interaction, and the Novel Object Recognition (NOR) task) under normal and drug challenged conditions. Preliminary social interaction studies have found that the saporin lesioned rats spend a significantly less amount of time interacting with each other as compared to control sham operated rats. We are currently investigating how this impairment is effected under drug challenge. Furthermore, we have found that the degree of lesion affects the performance to the novel object recognition task under saline and drug challenged conditions. Our results from the in situ hybridization and behavioral studies indicate that the loss of cortical acetylcholine can lead to alterations in glutamatergic and dopaminergic signaling. These observations are compatible with a possible role of cholinergic deficits in schizophrenia, and provide a possible link between different hypotheses of the disorder.
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Using visual search to examine cholinergic contributions to feature binding in the rat.
Botly LC, De Rosa E (2009) Using visual search to examine cholinergic contributions to feature binding in the rat. Neuroscience 2009 Abstracts 873.26/EE13. Society for Neuroscience, Chicago, IL.
Summary: According to the feature integration theory of attention, feature binding is an attention-dependent process whereby the different features of an object are simultaneously integrated to form a unified whole. Using a rat digging paradigm that was faithful to this theory of attention, we have previously demonstrated that acetylcholine is critical to the attention-dependent processes required for both crossmodal and intramodal feature binding. Moreover, we demonstrated that cholinergic cells in brain regions that have been implicated in human feature binding, specifically frontal and parietal cortices, supported feature binding in rats. We have now translated the gold-standard test of human feature binding, visual search (VS), for rats. In the present study, sixteen male Long-Evans rats were trained to perform VS using touchscreen-equipped operant chambers and black-and-white shapes. Testing sessions comprised Feature-Search (no feature binding required) and Conjunctive-Search (feature binding required) trials using set sizes of four, six, and eight stimuli. Following acquisition of the VS task, eight rats received bilateral 192 IgG-Saporin immunotoxic lesions of the nucleus basalis magnocellularis (NBM) of the basal forebrain to reduce cholinergic afferentation of the neocortex. Importantly, there was no significant effect of lesion on accuracy for selecting the target stimulus. As expected, relative to sham-lesioned rats, NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive-Search but not Feature-Search trials; thus reflecting a less efficient VS. These data confirm that cholinergic contributions from the NBM support feature binding using a rat analog of the VS paradigm.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Effect of aging and prefrontal cholinergic deafferentation on working memory for familiar and novel odors.
Carter ES, Newman LA, Mcgaughy J (2009) Effect of aging and prefrontal cholinergic deafferentation on working memory for familiar and novel odors. Neuroscience 2009 Abstracts 879.14/EE124. Society for Neuroscience, Chicago, IL.
Summary: Aging is associated with cholinergic fiber loss in the entorhinal cortex (EC). Previous research has shown that acetylcholine (ACh) in this region mediates memory for novel information (Schon et al., 2005), and cholinergic lesions of the EC in young rats impair memory for novel, but not familiar, stimuli at an odor delayed non-match to sample task (DNMS; McGaughy et al., 2005). Currently, we tested whether age-related cholinergic fiber loss in the medial EC of male rats would be sufficient to produce impairments in memory for novel information during the DNMS task. Half of the aged animals were subjected to cholinergic depletion of medial, prefrontal cortex (pACh-lx) including both prelimbic and anterior cingulate cortex prior to the onset of testing. We hypothesized that this previous damage would result in impairments in memory for familiar items and would prevent improvements in memory shown after repeated exposure to novel items. Additionally the effects of increasing the delay between sample and choice portions of the test and memory for list of items were assessed. The pACh-lx animals were not impaired relative to sham-lx animals at memory for familiar information when there was a minimal delay between the sample and choice. However if a 15 minute delay was introduced between the sample and choice phase, pACh-lx rats performed more poorly than sham-lx rats. This suggests that ACh in the medial, prefrontal cortex is necessary for maintaining representations of familiar stimuli over a delay period. Aged rats showed accuracy impairments during sessions that required encoding of novel samples relative to their own performance at sessions requiring encoding of familiar samples. This impairment was greater on trials that required rats to discriminate the novel sample from a familiar non-match than on trials where all stimuli were novel. Though the extent of cholinergic fiber loss in EC due to aging was highly similar to that produced by infusion of the 192 IgG saporin to the EC of young rats, the severity of the cognitive impairments due to aging was not as great as that produced by lesioning. These data suggest that impact of damage to the cholinergic fibers of EC may vary based on whether the deterioration is gradual or has an acute onset.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Damage to nucleus basalis magnocellularis (nBM) cholinergic target areas produce different effects on the acquisition of learning set.
Bailey AM, Enos J, Medley V (2009) Damage to nucleus basalis magnocellularis (nBM) cholinergic target areas produce different effects on the acquisition of learning set. Neuroscience 2009 Abstracts 879.15/EE125. Society for Neuroscience, Chicago, IL.
Summary: Lesions to the nucleus basalis magnocellularis (nBM) using either quisqualic acid or 192 IgG-saporin produce differing effects on the acquisition of learning set. Specifically, quisqualic acid lesions produce severe and long lasting impairments but 192 IgG-saporin lesions produce transient effects on learning set acquisition. One possible explanation for acquisition differences involves altered neuronal activity in the cholinergic target areas of the nBM. We examined two main cholinergic targets of the nBM, namely the amygdala and the prefrontal cortex (PFC). Rats with either NMDA (20 µg/µl) lesions to the basolateral amygdala (n=10) or NMDA (20 µg/µl) lesions to the anterior cingulate PFC (n=6) were tested on an olfactory learning set formation task as well as operant delayed non-matching to-position (DNMTP) and open field activity. The rats with amygdala lesions were additionally tested on a fear conditioning task. Lesions to the PFC significantly impaired acquisition of learning set as measured by chance performance on Trial 2 (M = 56.17%, SD = 7.47). Rats with PFC lesions did not differ from sham animals on the DNMTP task (p > .05) or in activity counts in an open field (p > .05). However, rats with NMDA lesions to the amygdala were significantly higher than chance (50% correct) on Trial 2 (p .05) or percentage correct on the DNMTP task (p > .05). NMDA lesions to the amygdala did, however, significantly decrease time spent freezing to an aversive CS+ in the fear conditioning task (p < .05). In total, the results imply that learning set acquisition differences following either quisqualic acid or 192 IgG-saporin lesions to the nBM are not likely due to damage to the cholinergic projection to the amygdala but may be associated with altered PFC activity.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain.
Thomsen MS, Hay-Schmidt A, Hansen HH, Mikkelsen JD (2009) Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain. Neuroscience 2009 Abstracts 646.2/V14. Society for Neuroscience, Chicago, IL.
Summary: α7 nicotinic acetylcholine receptor (nAChR) agonists are novel drugs candidates for the treatment of cognitive deficits in schizophrenia, which have shown pro-cognitive effects in clinical trials. Selective α7 nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and shell of the nucleus accumbens (ACCshell) in rats, regions which are important for cognitive function. However, the neural substrates involved in these effects remain elusive. Using retrograde tracing from the mPFC with Cholera Toxin B and immunoreactivity of the immediate-early gene c-Fos, a marker of neuronal activation, we identify the horizontal limb of the diagonal band of broca (HDB) in the basal forebrain as an important site of α7 nAChR activation. Approximately 26% of the cortically projecting neurons in the HDB are activated by acute administration of SSR180711 (10 mg/kg), and the neurons activated by SSR180711 in the HDB are cholinergic. Selective depletion of these cholinergic neurons with 192 IgG-Saporin abolishes the SSR180711-induced activation of the mPFC, but not the ACCshell, demonstrating their critical importance for α7 nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area (VTA) with 6-OHDA abolishes the SSR180711-induced activation of the ACCshell, but not the mPFC or HDB. These results indicate that two distinct neural pathways are activated by SSR180711, involving HDB-to-mPFC and VTA-to-ACCshell projections, respectively. The basal forebrain and mPFC are important for attentional function, and may subserve the pro-cognitive effects of α7 nAChR agonists, whereas activation of the ACCshell is implicated in beneficial effects on the positive symptoms of schizophrenia.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Contributions of the medial prefrontal cortex to negative occasion setting
Macleod JE, Ackerman CM, Bucci DJ (2009) Contributions of the medial prefrontal cortex to negative occasion setting. Neuroscience 2009 Abstracts 477.2/FF61. Society for Neuroscience, Chicago, IL.
Summary: The medial prefrontal cortex of rats has a role in many aspects of cognitive function, and especially forms of inhibitory learning. Recent research has revealed heterogeneous functions of the prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex in modulating response inhibition. In a recent study, we tested the effects of separate neurotoxic lesions of the PL or IL in a serial feature negative discrimination paradigm (negative occasion setting). Rats received daily training sessions consisting of 16 trials: on 4 trials in each session, a tone was presented and followed by food reward; on the remaining trials, the tone was preceded by a visual stimulus and not reinforced. Our results indicate that PL but not IL is necessary for learning the discrimination. A second study was conducted to investigate the effects of these lesions on rats that were first extensively trained in this task. We found that rats that had been trained for 30 days prior to receiving PL or IL lesions were still able to perform the task as well as controls. Therefore, PL lesions disrupt acquisition but not performance of a serial feature negative discrimination. This same task has been used in our laboratory to investigate the effects of nicotine on learning. We have shown that nicotine-treated rats exhibit greater discrimination between the two trial types as evidenced by less frequent responding during non-reinforced trials, and learn the discrimination in fewer sessions than control rats. In addition, rats receiving nicotine showed an increase in rearing behavior during the presentation of the light, suggesting nicotine enhanced attention to the visual stimulus. One possible critical site of action for nicotine’s effects is the medial prefrontal cortex. Research in other laboratories utilizing other training procedures suggest that cholinergic activity in the medial prefrontal cortex is critical for attending to behaviorally relevant stimuli, and have implicated the rat PL in visual attention as well as inhibiting prepotent, goal oriented responses. We investigated the contribution of the cholinergic PL to learning the serial feature negative discrimination task by training rats that had received infusions of 192-IgG-saporin into PL to remove cholinergic input from the basal forebrain. No differences between control and lesion rats were observed. Taken together, the results suggest that PL is necessary for acquisition of a serial feature negative discrimination, although the basal forebrain cholinergic input into this region is not required to sufficiently learn the task.
Related Products: 192-IgG-SAP (Cat. #IT-01)
The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment.
Lima T-Z, Blanco MM, Bueno MA, Dos Santos Junior JG, Bargieri DY, Mello LE (2009) The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment. Neuroscience 2009 Abstracts 139.26/D36. Society for Neuroscience, Chicago, IL.
Summary: A substantial loss of cholinergic innervation in the hippocampus and cerebral cortex is universally accepted as a typical feature of Alzheimer’s disease (AD). Cholinergic deafferentation is an often, but not a constant phenomenon in AD and its contribution to the progression of disease is not completely understood. The present work was aimed to evaluate the effect of cholinergic deafferentation on cognitive decline and on Amyloid-b (A_) metabolism and how this outcome is modulated by lithium. To this end rats were subjected to neonatal intracerebroventricular injection of 192 IgG-saporin (an immunotoxin selective to cholinergic neurons). Three months after surgery animals were evaluated in Morris Water Maze (MWM) and then entered a three months long lithium (LiCl) or control treatment. At the end of treatment, animals were once again tested in MWM and their cerebral cortical A_ levels were measured. We found that working memory impairment arises earlier and it is also more severe than reference memory related deficits. The cognitive performance was only slightly influenced by LiCl treatment. Furthermore we found that the cholinergic denervation produced by neonatal IgG-sap infusion did not modify A_ levels or its aggregation state. Moreover lithium increased the levels of A_1-42 despite decreasing the amount of A_1-40, an effect that is dependent of cholinergic integrity. These data suggest that the contribution of cholinergic deafferentation, which occurs over the progression of disease, to the amyloigenesis is likely to be modest in AD brain. In addition the effects of lithium treatment presented here imply in avoiding its use as prophylactic propose for AD and in AD cases without marked cholinergic degeneration.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Role of the medial septum on navigational strategy and shifting between strategies: Effects of selective cholinergic and GABAergic lesions.
Janke KL, Fazelinik S, Roland JJ, Servatius RJ, Servatius RJ, Servatius RJ, Pang K (2009) Role of the medial septum on navigational strategy and shifting between strategies: Effects of selective cholinergic and GABAergic lesions. Neuroscience 2009 Abstracts 283.5/EE134. Society for Neuroscience, Chicago, IL.
Summary: Cholinergic and GABAergic neurons are major components of the septohippocampal pathway, and comparisons between the two neuronal populations are important for understanding the function of medial septum-vertical limb of the diagonal band (MSDB). Recently, we have been investigating the importance of MSDB neurons in cognitive flexibility. Cognitive flexibility is commonly examined in reversal of stimulus-reward associations and attention set shifting. The present studies examine whether selective lesions of cholinergic or GABAergic MSDB neurons impair shifting between egocentric and allocentric navigation strategies. Sprague Dawley rats were administered saline, GAT1-saporin or 192-IgG saporin into the MSDB to produce no damage, selective GABAergic damage or selective cholinergic damage, respectively. Lesion verification will be performed using immunocytochemistry at the end of the studies. In a plus maze, rats started in one of two arms opposite each other (i.e., north and south arms) randomized across trials. On any single trial, the arm opposite the starting arm was blocked forming a T-maze. Rats have a choice of entering one of the remaining 2 arms (east or west arms) for food reinforcement. During the acquisition phase of the first study, rats were reinforced to enter a particular arm (east or west: allocentric response) regardless of their starting location. After they reached criteria (10 consecutive correct choices), the goal location was either reversed (east to west) or shifted to an egocentric response strategy (left or right turn). Animals that received either GAT-1-saporin (.26 ug/ul) or 192-IgG saporin (.217ug/ul) lesion reached criteria faster than saline treated rats. No significant effects of either lesion were observed on spatial reversal or strategy shifts. However, qualitative assessment of the damage suggests that GAT1-saporin may have produced an incomplete lesion. Therefore, a second study using GAT1-saporin at .325 ug/ul was conducted. For this study, half of the rats were trained on an egocentric strategy and the other rats are reinforced for an allocentric response. When rats reached criteria, half of each group was trained in a reversal learning or strategy shift. Preliminary data show that rats treated with GAT1-saporin or saline learned the initial egocentric or allocentric strategy at a similar rate. However, animals were faster to reach criteria in the allocentric condition than the egocentric condition. Reversal learning and strategy shifting in the second study is currently being assessed. The results of this study will provide important insight into the role of the MSDB in learning and cognitive flexibility.
Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)
Selective cholinergic and GABAergic lesions of the medial septum slows acquisition of the classically conditioned eyeblink response in rats.
Roland JJ, Janke KL, Gluck MA, Beck KD, Pang KCH, Servatius RJ (2009) Selective cholinergic and GABAergic lesions of the medial septum slows acquisition of the classically conditioned eyeblink response in rats. Neuroscience 2009 Abstracts 283.6/EE135. Society for Neuroscience, Chicago, IL.
Summary: Both human and animal studies have demonstrated that the hippocampus is not essential for the acquisition of delay eyeblink conditioning. However, nonselective medial septal damage, in both rabbits and humans, impaired acquisition of delayed eyeblink conditioning, as well as latent inhibition of eyeblink conditioning. The medial septum provides a major cholinergic and GABAergic afferent projection to the hippocampus, and the effects of medial septal damage is widely believed to occur through its connections to the hippocampus. Cholinergic muscarinic antagonists impaired delay eyeblink conditioning when administered systemically or directly into the hippocampus. Computational models also predicted the lack of effects on delay conditioning or latent inhibition of eyeblink conditioning caused by interference of the cholinergic septohippocampal system Recent studies have suggested that the GABAergic septohippocampal system may be a major site of action for scopolamine. Therefore, the current study examined the effect of selective cholinergic or GABAergic medial septal lesions on the classically conditioned eyeblink response. Adult male Sprague-Dawley rats received either a sham, cholinergic (192-IgG saporin) or GABAergic (GAT1-saporin) lesion in the MS/DB. Two weeks later, all animals were implanted with stimulating and recording electrodes in the periorbital muscle. Following recovery, all animals received three consecutive days of delay eyeblink conditioning. Each daily session consisted of 100 paired CS-US (conditional stimulus – unconditioned stimulus) trials with an average intertrial interval (ITI) of 30 seconds. The CS was a 500ms tone which co-terminated with the US, a 10ms, 10V periorbital stimulation. Our preliminary results shows that both cholinergic and GABAergic lesions impaired acquisition of delayed eyeblink conditioning, as compared to the sham-lesioned group. However, after three days of training all three treatment groups reached the same asymptotic performance. Future studies will assess the effects of combined cholinergic and GABAergic lesions and the effects of these septal lesions on latent inhibition of the conditioned eyeblink response.
Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)
Role of cholinergic NBM neurons in timing and divided attention.
Mcauley J, Stewart AL, Pang KCH (2009) Role of cholinergic NBM neurons in timing and divided attention. Neuroscience 2009 Abstracts 95.12/EE81. Society for Neuroscience, Chicago, IL.
Summary: The nucleus basalis magnocellularis (NBM) provides cholinergic and GABAergic innervation to the neocortex. In previous studies, non-selective lesions of the NBM using ibotenic acid impaired interval timing and divided attention. Rats with NBM damage produced rightward shifts in peak times, demonstrating overproduction (underestimation) of time. Additionally, NBM damage impaired the ability to divide attention when timing two intervals simultaneously. Damage of the frontal cortex produced similar impairments in timing and divided attention as NBM damage, suggesting the NBM projections to frontal cortex were critical. Currently, the NBM neurons responsible for modulating timing and attention are unknown. The present study will determine the importance of cholinergic NBM neurons in timing and attention using the selective immunotoxin 192-IgG saporin (192-SAP). Sixteen Sprague Dawley rats were first trained on a peak-interval (PI) procedure using fixed-intervals of 12 s and 24 s paired with light and tone stimuli, respectively. During this phase, only one stimulus was presented during a trial (focused attention). Following the initial phase of training, rats were trained on a divided attention version of the peak-interval procedure, in which 2 stimuli were presented simultaneously in a trial and rats timed both intervals in parallel. Rats were administered 192-SAP into the NBM (n = 10) or given SHAM surgeries (n = 6). Following surgery, 192-SAP rats produced a leftward shift in timing with increased variability compared to SHAM rats. These changes in timing were observed in both focused and divided attention conditions, but the effects were larger in divided attention conditions than in focused attention conditions. Results implicate the cholinergic NBM neurons in the modulation of interval timing and divided attention. Current work is verifying the selectivity and efficacy of the 192-SAP administration. Additional studies will examine the role of GABAergic NBM neurons in interval timing and divided attention.
Related Products: 192-IgG-SAP (Cat. #IT-01)