sfn2002

Helm KA, Ziegler DR, Gallagher M (2002) Habituation and dexamethasone (DEX) suppression of the stress response following selective lesions of cholinergic input to hippocampus in rats. Neuroscience 2002 Abstracts 370.1. Society for Neuroscience, Orlando, FL.

Summary: Hippocampal neurons have been identified as targets for glucocorticoids that exert inhibitory control over hypothalamic-pituitary-adrenocortical (HPA) axis activity. Prior research has shown that selective removal of cholinergic input to the hippocampus reduces mRNA expression for low-affinity glucocorticoid receptors, while leaving unaffected both mineralocorticoid receptor mRNA and basal levels of circulating corticosterone (CORT). The current study investigated the possibility that loss of cholinergic support from cells in the basal forebrain alters the CORT response to stress. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of 30 min restraint stress. Blood samples taken before, during and after stress on Day 1 revealed a prolonged elevation of CORT in response to acute stress in cholinergic lesioned rats. After 5 days of chronic stress, however, both groups significantly habituated to the stressor, as indicated by similarly low CORT profiles throughout both the response and recovery period. Against this similar background, rats were administered a Dexamethasone (DEX) challenge on Day 6, and DEX-induced suppression of endogenous CORT before, during and after stress was attenuated in lesioned rats. These results indicate a mechanism whereby loss of cholinergic function (e.g. in aging and Alzheimer’s Dementia) may compromise the dynamic range of sensitivity to glucocorticoid mediated stress pathways in the brain.

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

Ohara PT, Boudah A, Jasmin L (2002) Long-term effects on pain behavior of decreased spinal noradrenaline in neuropathic rats. Neuroscience 2002 Abstracts 351.22. Society for Neuroscience, Orlando, FL.

Summary: We sought to determine if a permanent reduction in the noradrenergic (NA) input to the spinal cord in adult rats would alter the pain behavior associated with nerve injury. Selective NA denervation of the lumbo-sacral cord was achieved by intrathecal injection of anti-dopamine beta-hydroxylase antibodies conjugated to the toxin saporin in 12 female rats. Spinal NA denervation was confirmed histologically in all animals. Saline injected rats served as controls. Two weeks after toxin or saline treatment, a unilateral peripheral neuropathy was induced by tight ligation of the left L5 spinal nerve in both groups. Unexpectedly, the same degree of mechanical hyperalgesia was present in the neuropathic paw of rats in both the toxin and saline treated groups. Rats lacking NA spinal afferents, however, were less responsive to the antinoiceptive effects of morphine administered systemically or intracerebroventricularly. Also, toxin treated rats did not display opioid dependant stress analgesia. Finally, toxin treated rats were more responsive to the antinociceptive effect of the NK1 antagonist CP 96,345 but not to its enantiomer CP 96,344. From these results we conclude that the permanent loss of spinal NA does not alter neuropathic pain behavior, possibly because of compensatory changes in the CNS. The decreased response to opioids is consistent with the previous suggestions of an interaction between noradrenergic and opioidergic systems in producing analgesia. The increased response to NK1 antagonists shows that NA tonically inhibits substance.

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Yoder RM, Pang KCH (2002) Effects of gabaergic or cholinergic medial septal lesions on anxiety. Neuroscience 2002 Abstracts 378.1. Society for Neuroscience, Orlando, FL.

Summary: The hippocampus (HPC) is a structure important for spatial learning and memory. GABAergic and cholinergic neurons in the medial septal area (MSA) provide the two major projections to HPC. Complete destruction of HPC or MSA impairs spatial memory. MSA lesions have an anxiolytic effect, and rats with MSA damage appear be more exploratory. Spatial learning and memory may therefore be influenced by anxiety information reaching HPC through MSA. The present study assessed the effects of MSA GABAergic or cholinergic lesions on anxiety in the elevated plus maze and open-field task. Control rats received intraseptal saline; GABAergic lesions were induced by intraseptal domoic acid; cholinergic lesions were induced by intraseptal 192 IgG-saporin. An elevated plus maze was constructed with 2 open arms and 2 closed arms. Following habituation, each rat was placed in the center of the maze, then observed for 5 minutes. Time spent in the open vs. closed arms and number of entries into open vs. closed arms were compared between groups. The open-field task utilized a square arena with center and outer sections delineated on the floor. Following habituation, each rat was placed into the outer section, then observed for 5 minutes, during which the number of line crossings and amount of time spent in center vs. outer sections were calculated for comparison between groups. In both tasks, frequency of freezing, rearing, head dips, stretched-attend posture, grooming, and defecation was also compared between groups. Results of the present study may help elucidate the role of MSA in the effects of anxiety on learning and memory.

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

Wright KM, Yoder RM, Pang KCH (2002) Spatial strategies in rats with cholinergic or GABAergic lesions of the medial septum. Neuroscience 2002 Abstracts 378.2. Society for Neuroscience, Orlando, FL.

Summary: The major projection neurons of the septohippocampal (SH) system are GABAergic and cholinergic. When both populations of neurons are damaged together, deficits in learning and memory occur. However, when only one population is damaged, spatial memory in the water maze and radial arm maze is intact. The present study evaluated whether spatial strategies differed between rats with either GABAergic or cholinergic septal lesions. Domoic acid or 192 IgG saporin (sap) was injected into the medial septum (MS) to damage GABAergic or cholinergic neurons, respectively. Spatial strategies were examined on the plus maze and water maze. In the plus maze, rats were started from a single arm and trained to enter a goal arm containing both the reward and an intra-maze cue. Probe trials assessed whether the rats used place, response or cue strategies. During a probe trial, the starting location and the intra-maze cue were moved from that during training. In the water maze, animals were trained for 9 days in 3-day cycles. The first two days of the cycle used a visible platform and the third day of training was performed with a submerged platform. A single probe trial was conducted on day 10. On the probe trial, the first quadrant visited determined whether rats were using cue, place, or response strategies. Preliminary results show that rats treated with domoic acid use the place strategy on all probe trials in the plus maze, but do not use a consistent strategy in the water maze. Sap-treated animals also use mainly a place strategy. The results of this study may help determine the role of MS neurons in spatial strategy selection.

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

Butt AE, Hamilton DA, Duerkop MS, King DD, Gibbs RB, Sutherland RJ (2002) Spatial memory impairments in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis. Neuroscience 2002 Abstracts 378.5. Society for Neuroscience, Orlando, FL.

Summary: In three experiments we test the hypothesis that the nucleus basalis magnocellularis (NBM) is involved in spatial learning and memory. Rats received 192 IgG-saporin lesions of the NBM or sham surgeries prior to testing in the Morris water maze task. In Exp. 1, rats were trained to find a hidden platform, receiving 4 trials per day. In Exp. 2, rats were trained with the hidden platform located in one position on the first 3 trials and in a second position on the 4th trial each day. In Exp. 3, rats were trained in a novel environment with the hidden platform located in a new position every 2 days. In Exp. 1, the NBM lesion group showed longer mean latencies to locate the platform than controls on the first several days of testing. Group differences were greatest on the earlier trials within the 4-trial blocks, with performance in the NBM lesion group recovering to control levels on later trials. In Exp. 2, performance in the NBM lesion group was again impaired, with greater group differences occurring on earlier trials within the 4-trial blocks. In Exp. 3, performance during the first block of trials for the different platform locations did not differ between groups, whereas performance on the 1st trial within the second block of trials was impaired in the NBM lesion group. Analysis of AChE staining and assay of ChAT activity confirm the selectivity of the lesions to the cortically-projecting neurons of the NBM and the sparing of cholinergic medial septal projections to hippocampus. Data suggest that NBM lesions interfere with consolidation of memory for spatial locations.

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

Janisiewicz AM, Rodefer JS, Baxter MG (2002) Visual-spatial conditional discrimination learning in rats with lesions of cholinergic medial septal/diagonal band neurons. Neuroscience 2002 Abstracts 378.6. Society for Neuroscience, Orlando, FL.

Summary: Loss of cholinergic neurons in the medial septum/vertical limb of the diagonal band (MS/VDB) seems to impair visual-spatial conditional learning tasks, in which the location of a correct spatial response is signaled by a visual cue. We examined visual-spatial conditional learning in several automated touchscreen tasks in male Long-Evans rats with selective lesions of MS/VDB cholinergic neurons produced by 192 IgG-saporin. One group of rats was first trained on a simple visual discrimination followed by two visual-spatial conditional tasks. In the first conditional task the rat responded to the left or right member of a pair of identical visual stimuli depending on which stimulus pair was displayed. In the second conditional task one of two centrally-displayed stimuli directed the rat to respond to an illuminated panel on the left or right, depending on which visual stimulus was displayed centrally. MS/VDB-lesioned rats were unimpaired on the simple visual discrimination and the first conditional task, but were severely impaired relative to controls on the second conditional task. However, in a second group of rats trained only on the second conditional task, MS/VDB-lesioned rats were superior to controls, who performed poorly. The different results between the two cohorts appear to reflect transfer effects present in the control rats that are absent in the MS/VDB-lesioned rats. These findings suggest that conditional learning deficits following MS/VDB cholinergic lesions may depend on the particular strategy used to solve the conditional task, which may in turn be influenced by the animal’s testing history.

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

Frick KM, Kim JJ, Baxter MG (2002) Effect of 192-IgG saporin lesions of the entire basal forebrain on emotional and spatial learning. Neuroscience 2002 Abstracts 379.1. Society for Neuroscience, Orlando, FL.

Summary: Scopolamine administration studies suggest that acetylcholine appears to be important for acquisition of contextual fear conditioning (FC), but its involvement in consolidation of fear remains a matter of debate. We examined the role of the basal forebrain cholinergic system in emotional learning and memory by testing male Sprague-Dawley rats with 192 IgG-saporin lesions of basal forebrain cholinergic neurons in contextual and tone FC. Lesions were made either 7 days before (n=10) or one day after (n=10) FC and targeted all basal forebrain nuclei; sham-operated rats (n=5 per condition) served as a comparison. Spatial learning in a one-day water maze task provided a comparison for effects of the lesions on FC. Pretraining lesions had no effect on freezing to tone or context. Posttraining lesions produced a mild impairment in freezing to context, but had no effect on freezing to tone. Both groups were impaired in production of 22 kHz ultrasonic vocalization (USV) associated with fear. Performance on water maze training trials was surprisingly impaired in lesioned rats, although this impairment did not interact with training block and probe trial performance was unimpaired, suggesting that it did not reflect a learning impairment. Radioenzymatic assays of choline acetyltransferase activity in neocortex and hippocampus revealed substantial (>80%) decreases in cholinergic input. These data suggest that conditioned fear-induced USV is more sensitive to the loss of basal forebrain cholinergic neurons than conditioned fear-induced freezing.

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

Nattie EE, Li A, Richerson G, Lappi D (2002) Specific killing of rat medullary raphe 5-HT neurons by a serotonin transporter antibody-saporin conjugate reduces the ventilatory response to increased CO2 during sleep and wakefulness. Neuroscience 2002 Abstracts 221.3. Society for Neuroscience, Orlando, FL.

Summary: CO2 increases the firing rate of medullary raphe 5-HT neurons in vitro (Richerson et al., Respir. Physiol. 129: 175-190, 2001) and focal CO2 dialysis in the medullary raphe increases ventilation in the sleeping rat (Nattie and Li, J. Appl. Physiol. 90: 1247-1257, 2001). To examine in vivo the relative importance of these 5-HT neurons in chemoreception we used an antibody to the external ring of the serotonin tranport protein (SERT)(SFN abstract #814.9, 2001) conjugated to the cell toxin saporin (SAP). Rat medullary raphe neurons (P0) in culture assayed by TPOH immunoreactivity were killed by 10 and 5 nM SERT-SAP with peak effects at 4 and 7 days, respectively. Non-serotonergic neurons were unaffected. In adult rats after measurement of baseline ventilatory values, we placed EEG/EMG electrodes and injected the SERT-SAP conjugate (1 uM) into the medullary raphe (two adjacent 100 nl injections). There was substantial loss of TPOH but not NK1R immunoreactivity measured at 14 days. There was no effect on ventilation during air breathing awake or asleep. Ventilation during 7% CO2 was significantly decreased in sleep (P < 0.001; repeated measures ANOVA) at days 1, 3, 7, and 14 (-13 to -15%; P < 0.05; Tukey post-hoc test) and in wakefulness (P < 0.01; repeated measures ANOVA) at days 1, 3, 7, and 14 (-10 to -16%; P < 0.05; Tukey post-hoc test). Medullary raphe serotonergic neurons in the rat play an important role in the ventilatory response to systemic hypercapnia during sleep and wakefulness.

Related Products: Anti-SERT-SAP (Cat. #IT-23)

Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Lack of capsaicin (CAP)-evoked sensitization following SP-SAP treatment is not attributed to decreased CAP-evoked exciataion. Neuroscience 2002 Abstracts 351.24. Society for Neuroscience, Orlando, FL.

Summary: The depletion of SPR+ neurons in the spinal cord by substance P-saporin conjugate (SP-SAP) prevents the development of central sensitization, induced by capsaicin (CAP). SP-SAP treatment causes a dramatic decrease in CAP-evoked excitation of remaining nociceptive neurons. The lack of central sensitization after SP-SAP may be due to the decreased excitation of these neurons by CAP. We therefore compared excitation and sensitization following intraplantar injection of different doses of CAP (10 and 100 μg) in rats pretreated intrathecally with vehicle (VEH) or SP-SAP. Injection of 10μg or 100 μg CAP evoked activation and sensitization of nociceptive neurons in VEH-treated rats. Mean responses to von Frey stimuli doubled and heat threshold decreased by about 6˚ C. In SP-SAP rats, 10 μg CAP evoked excitation that was <60% of control whereas 100 μg CAP evoked excitation that was similar to control values. However, sensitization failed to occur following either dose of CAP. In addition, we examined whether effects of SP-SAP was mediated by descending modulation. Transsection of the dorsolateral funiculus increased spontaneous activity of nociceptive neurons in rats pretreated with VEH, but not with SP-SAP. Our data show that the development of central sensitization is dependent on neurons that possess the SPR, and that these neurons appear to be part of a supraspinal loop that modulates descending tonic inhibition.

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Bradley QR, Borowski TB, de Lacalle S (2002) The effects of 17ß-estradiol on odor discrimination of ovariectomized and intact young and aged rats following unilateral lesions of the nucleus of the horizontal diagonal band of broca (HDB). Neuroscience 2002 Abstracts 385.3. Society for Neuroscience, Orlando, FL.

Summary: Estradiol exerts beneficial effects on cognitive performance. The present study was designed to investigate the effect of estradiol on learning and memory following the destruction of cholinergic neurons of the HDB, a basal forebrain region that exhibits significant neuronal loss during aging and may underlie the cognitive deficits associated with Alzheimers disease. Young (3 months old) and aged (20 months old) ovariectomized and gonadally intact Fisher 344 female rats were given unilateral lesions of the HDB with the cholinergic immunotoxin 192 IgG-saporin (.075mg/ml). Starting one week after surgery rats were tested on an odor discrimination task whereby rats were trained to associate a food reward buried within a scented cup of sand relative to a dissimilar scented cup of sand that contained no reward. Following stable levels of acquisition and retention, subjects were exposed to a reversal procedure where the previously unrewarded cup was now baited. Odor discrimination acquisition, retention and reversal were assessed before and after one month of 17β-estradiol exposure or placebo. Analysis of learning curves revealed that young rats performed better than the aged animals independent of estradiol treatment during the reversal component of the task. However, within each age group 17β-estradiol treatment facilitated performance in ovariectomized rats relative to placebo controls. These findings shed new light on the cognitive enhancing properties of estradiol in age-related cholinergic neurodegenerative disorders.

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