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At least 1,423 records · Page 79Linked to original sources
PubMed1988

Visuospatial learning impairment following lesion of the cholinergic projection to the hippocampus.

Ibotenic acid lesions of the vertical limb of the diagonal band of Broca (VDB) in marmosets produced significant depletions in choline acetyltransferase (ChAT) activity and a decrease in acetylcholinesterase (AChE) staining in the hippocampal formation and entorhinal cortex (to which the cholinergic neurones of the VDB project) but not in the neocortex or amygdala. Marmosets with VDB lesions were impaired on acquisition (but not retention) of repeated trial visuospatial tasks. This impairment was ameliorated by pretreatment with the cholinergic agonist pilocarpine indicating (a) that the learning impairment was a consequence of damage to the cholinergic system and (b) that the cholinergic projections exert a modulatory or enabling function on the target areas which can be substituted by a non-impulse-dependent drug action. Unlike marmosets with lesions of the basal nucleus of Meynert (NBM), VDB-lesioned animals were not impaired on learning repeated trial object discrimination and showed no change in general behaviour although they did become hypothermic and mesomorphic. These results are consistent with the suggestion that the hippocampus (perhaps in conjunction with the entorhinal cortex) is concerned primarily with memory for responses but not memory for reward and that lesions of the cholinergic system produce impairments equivalent to the effects of ablation of the terminal areas.

Animals↗
PubMed1988

Serial position curves for item (spatial location) information: role of the dorsal hippocampal formation and medial septum.

Animals were trained on an item recognition memory task for a list of 5 spatial locations. After reaching criterion performance the animals sustained small or medium-size dorsal hippocampal formation lesions, small or large medial septal lesions, or served as sham-operated or cortical controls. Following recovery from surgery, animals were retested for item recognition memory. Sham-operated and cortical control animals showed no deficits in performance. In contrast, animals with small dorsal hippocampal formation or medial septal lesions displayed a deficit for the early items, but had excellent memory for the last item of the list. Animals with medium-size dorsal hippocampal formation or large medial septal lesions displayed a deficit for both early and late items within the list. Because residual short-term memory capacity can be seen only with small hippocampal formation or medial septal lesions, it is suggested that the hippocampal formation and cholinergic input into the hippocampal formation via the medial septum code spatial information within a continuous extended time frame.

Animals↗
PubMed1989

Transplantation of septal cholinergic neurons to the hippocampus improves memory impairments of spatial learning in rats treated with AF64A.

Embryonic septal neurons were transplanted into damaged hippocampus in adult rats which had received lateral ventricular administration of AF64A, a cholinergic neurotoxin. About 3 months after transplantation, the rats with bilateral septal grafts showed significant improvement in the radial maze and T-maze tasks. Many ingrowths of acetylcholinesterase (AChE)-positive fibers originating from the grafts were observed in the hippocampus of the rats which showed good performance in these learning tasks. These results indicate that transplantation of septal cholinergic neurons into the AF64A-treated hippocampus may induce at least partial recovery in learning tasks believed to involve the hippocampus.

Animals↗
PubMed1989

Dietary cis-fatty acids that increase protein F1 phosphorylation enhance spatial memory.

Activation of protein kinase C (PKC) facilitates long-term potentiation (LTP), a model of memory, and increases its substrate protein F1 (aka GAP43) phosphorylation in direct relation to synaptic enhancement. Unsaturated fatty acids (c-FAs) which activate purified PKC, when injected into hippocampus, enhance LTP. To determine if dietary c-FAs could alter memory itself as well as brain PKC substrate (F1) metabolism, rats were maintained for 10 weeks on fatty acid diets enriched in mono-unsaturated oleic acid (OA; 20% olive oil, w/w), or a mono- and di-unsaturated mixture of oleate/linoleate (O/L; 20% corn oil), or a saturated fatty acid diet of laurate/myristate (L/M; 20% hydrogenated coconut oil). The O/L diet group was superior to the OA and L/M groups in spatial memory performance after the first two weeks of acquisition and in later achievement of criterion performance. The O/L diet had a significantly higher hippocampal protein F1 in vitro phosphorylation than in both the OA and L/M in trained and non-trained animals. Significantly, animals that made fewer errors showed higher F1 phosphorylation (r = -0.70). Diet both increases brain PKC substrate phosphorylation and enhances maze learning, confirming the feasibility of enhancing learning and memory by dietary regimens derived from basic neurochemical studies of synaptic plasticity.

Animals↗
PubMed1989

Raphe cells grafted into the hippocampus can ameliorate spatial memory deficits in rats with combined serotonergic/cholinergic deficiencies.

The ability of embryonic raphe cells grafted into the hippocampus to restore spatial learning ability was tested in rats with combined serotonergic/cholinergic deficits. Embryonic raphe cells (E14) were transplanted into the hippocampus of serotonin-depleted rats. Two to 3 months after transplantation, control, lesioned and grafted rats were tested in a spatial memory task (a water maze) with and without the addition of atropine. All 3 groups could negotiate the water maze equally well, in non-drug conditions. The injection of atropine caused a severe disruption of performance only in the serotonin depleted rats. The presence of an active serotonergic graft was examined in the intact rat hippocampus using the serotonin releasing drug fenfluramine (FFA). A pronounced depression of hippocampal EEG was observed in control and grafted but not in lesioned rats 15 min after the injection of FFA. These results suggest the involvement of serotonin in cognitive functions in the rat. Furthermore, it is suggested that an interaction between serotonergic and cholinergic neurotransmission occurs in the hippocampus.

Animals↗
PubMed1990

Effects of combined serotonin depletion and lesions of the nucleus basalis magnocellularis on acquisition of a complex spatial discrimination task in the rat.

The purpose of the present experiment was to determine the effects of lesions of cholinergic neurons originating from the nucleus basalis magnocellularis (NBM), alone or in combination with central serotonin depletion, on learning and memory in rats trained in the Stone 14-unit T-maze--a complex, positively-reinforced spatial discrimination task. Lesion of cholinergic neurons within the NBM was accomplished by bilateral infusion of ibotenic acid. Serotonin depletion was accomplished by the systemic administration of p-chloroamphetamine (PCA). The results show that PCA-induced serotonin depletion enhanced learning. This effect was completely prevented by NBM lesions, despite the fact that NBM lesions alone did not affect the performance of rats in this task. The results of this study support the view that the cholinergic and serotonergic systems may functionally interact in learning and memory processes. The significance of this interaction in the etiology and treatment of dementia should be further investigated.

Analysis of Variance↗
PubMed1990

Chromaffin cell grafts to rat cerebral cortex reverse lesion-induced memory deficits.

Adrenal chromaffin cells were isolated from donor adult rats and transplanted to the cerebral cortex of bilaterally nucleus basalis magnocellularis-lesioned rats. Chromaffin cell grafts to lesioned animals completely reversed the spatial memory deficit seen in lesioned alone animals on a T-maze alternation task. Although chromaffin cell grafts have been used previously to reverse motor abnormalities arising from defective nigro-striatal aminergic transmission, the present report is the first evidence that chromaffin cell transplants can reverse deficits in memory function. Grafts also enhanced cortical acetylcholinesterase staining.

Adrenal Medulla↗
PubMed1990

Muscimol injections in the medial septum impair spatial learning.

These experiments examined the role of GABAergic systems in modulating septohippocampal cholinergic influences on learning. Microinjections of the GABA(A) agonist muscimol (0.5, 1.0 or 5.0 nmol) or physiological saline were administered (0.5 microliters) into the medial septum of rats via chronically implanted cannulae just prior to daily training in the Morris water maze spatial learning task. The animals received 3 training trials on each of 4 days. The escape latencies of rats trained with a submerged escape platform at a fixed location were significantly shorter than those trained with a randomly located platform. Rate of learning of the fixed location was significantly impaired in rats given pretraining muscimol injections in the medial septum at doses (1.0 and 5.0 nmol) that significantly reduced hippocampal high-affinity choline uptake (HACU). Analyses of responses on a probe trial with no pretraining injections and no platform revealed that, in comparison with controls, animals that had received muscimol prior to each training session were likely to swim in the region where the platform had been located. The finding that muscimol-injected rats were subsequently able to learn the task when trained without muscimol injections indicates that the acquisition impairment was not due to a lasting effect of the drug injections. Our results are consistent with the view that the septal GABAergic modulation of the septohippocampal cholinergic pathway is involved in regulating the acquisition of spatial information.

Animals↗
PubMed1992

Chronic cerebrovascular insufficiency induces dementia-like deficits in aged rats.

Young and aged rats were subjected to cerebrovascular insufficiency (CVI) for 3 and 9 weeks. At the end of each time period, local cerebral blood flow (lCBF), spatial memory function, 31P- and 1H-NMR spectroscopy and imaging of the brains were evaluated in vivo. Morphometric counts of CA1 hippocampal neuron damage and staining for glial fibrillary acidic protein (GFAP) were done post-mortem. Results show that after 3 weeks of CVI, cortical and hippocampal lCBF was significantly reduced in young and aged animals respectively. In addition, young and aged rats at 3 weeks following CVI showed spatial memory deficits in the Morris water maze and elevation of 31P-phosphomonoester as measured by non-invasive NMR spectroscopy. At the same time period, in vivo 1H-microimaging (MRI) of brains showed areas of high signal intensity (suggesting local edema) localized asymmetrically to the right hippocampal region in young and aged CVI rats. Morphometry of the hippocampal CA1 sector at post-mortem confirmed the in vivo MRI changes and demonstrated that a significant percentage of the CA1 pyramidal cells were damaged after CVI. Nine weeks after CVI, hippocampal CBF reductions, spatial memory impairment, spectroscopic-microimaging changes and CA1 sector cell damage continued to be observed in the aged animals but were resolved in the young rat brains. In addition, GFAP immunoreaction progressively increased in the hippocampus of aged rats subjected to CVI for 9 weeks. It is concluded that cognitive, metabolic and morphologic damage was significantly more severe and longer lasting in aged than young rat brain after chronic CVI. The deficits observed in this rat model appear to mimic the early pathology reported in Alzheimer's disease and suggest that the present model could provide fundamental clues relative to the etiology and possible management of this dementia.

Aging↗
PubMed1992

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing.

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effects of nicotine on spatial memory deficits in rats with septal lesions.

Impaired septohippocampal function has been implicated in the memory deficits associated with Alzheimer's disease (AD), and septal lesions have been used to model the cognitive deficits associated with AD. In this study, we assessed the effects of systemic administration of nicotine on lesion-induced deficits in the acquisition of a spatial discrimination version of the Morris water maze. Rats with radiofrequency lesions of the medial septum were required to learn which of two visible platforms in a pool of water provided a means of escape. On each of the first 4 days of training, the rats received an injection of (-)nicotine (0, 0.1 or 0.3 mg/kg, i.p.) before training. Nicotine markedly improved the performance of septal rats. This enhanced performance was maintained in rats subsequently tested 1 and 15 days later without additional drug treatment. Septal rats initially trained under nicotine were impaired, however, when the platform locations were reversed and training was conducted under saline. Our findings suggest that nicotinic receptor stimulation might be useful in the treatment of cognitive deficits.

Alzheimer Disease↗
PubMed1992

Regional glucose metabolic changes after learning a complex visuospatial/motor task: a positron emission tomographic study.

Regional cerebral glucose metabolic rate (GMR) quantified with positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) was measured twice in 8 young men performing a complex visuospatial/motor task (the computer game Tetris), before and after practice. After 4-8 weeks of daily practice on Tetris, GMR in cortical surface regions decreased despite a more than 7-fold increase in performance. Subjects who improved their Tetris performance the most after practice showed the largest glucose metabolic decreases after practice in several areas. These results suggest that learning may result in decreased use of extraneous or inefficient brain areas. Changes in regional subcortical glucose metabolic rate with practice may reflect changes in cognitive strategy that are a part of the learning process.

Adult↗
PubMed1992

Muscimol infused into the medial septal area impairs long-term memory but not short-term memory in inhibitory avoidance, water maze place learning and rewarded alternation tasks.

These experiments investigated the effects of injections of muscimol (1 or 5 nmol), administered into the medial septal area prior to training, on memory tested at different retention delays after training in 3 tasks: an inhibitory avoidance task, a one-trial place learning task, and a rewarded alternation task. In all 3 tasks, intraseptal injections of muscimol did not impair memory performance at short retention delays, but impaired memory at the longer retention delays. These findings are consistent with the view that GABAergic regulation of the septohippocampal cholinergic system plays a selective role in the establishment of long-term memory.

Animals↗
PubMed1992

AF102B, a novel M1 agonist, enhanced spatial learning in C57BL/10 mice with a long duration of action.

Orally administered AF102B, a selective muscarinic M1 cholinergic agonist, improved spatial learning in C57BL/10 mice in the Morris water maze. In four experiments in which all drug-treated animals received only one single administration of AF102B, improvement of acquisition depended on two factors: pretreatment time (tp) and dose. When a standard tp of 1 h was used, AF102B exhibited a U-shaped dose-response curve that is characteristic of many nootropic agents: learning was significantly improved by dose levels ranging from 0.1 to 1 mg/kg p.o. When the tp was extended out to as long as 8 days, two new effects emerged: (a) 1 mg/kg, the dose that had been the peak active dose at 1 h, exhibited a biphasic time course of action, being active at 1 h or at all tp intervals from 3 h to 5 days, but not at 1.5 h; (b) 0.03 mg/kg, a dose that had been inactive at a tp of 1 h, was active at all tp intervals from 3 h to 5 days, but not at shorter (1 and 2 h) or longer (6-8 days) tp intervals. In another experiment, animals received 0.03 mg/kg for 1-5 consecutive days: this dose level was active if the tp interval between the last dose and the learning session was 24-120 h, but not if it was only 1 h. Thus AF102B enhanced cognition in mice with a longer duration of action than reported for traditional muscarinic agonists.

Animals↗
PubMed1992

Lesions of the medial septum which produce deficits in working/spatial memory do not impair long-term potentiation in the CA3 region of the rat hippocampus in vivo.

The effects of removing the septohippocampal pathway on the ability to induce long-term potentiation (LTP) in the CA3 region of the hippocampus was examined in vivo in rats. The septal input to the hippocampus was destroyed by electrolytic lesioning of the medial septum (MS). Prior to electrophysiological investigation, working/spatial memory of lesioned and control rats was tested using an 8-arm radial maze task. Maze performance was significantly impaired in animals with MS lesions. LTP inducibility was examined in the commissural fimbrial fibre- and mossy fibre (mf)-CA3 pathways in MS-lesioned and control rats. The pre-tetanus values in MS-lesioned rats tended to be smaller than those in controls, in both pathways. High-frequency stimulation of the commissural fibres resulted in a sustained increase in the orthodromic population spike and EPSP amplitude in both control and MS-lesioned rats. The magnitude of potentiation was similar in both groups. In control rats, high-frequency stimulation of the mf potentiated the amplitude of both the population spike and EPSP; in MS-lesioned rats, the EPSP amplitude alone was significantly increased by mf high-frequency stimulation. Hippocampal acetylcholinesterase (AChE) content was severely reduced bilaterally in MS-lesioned rats with working/spatial memory impairments, indicating that the lesions were effective in destroying the cholinergic septohippocampal input. These findings suggest that, in contrast to working/spatial memory processes, LTP at CA3 synapses is not dependent upon the integrity of the septohippocampal pathway.

Afferent Pathways↗
PubMed1993

Differential effects of benzodiazepine receptor agonists on hippocampal long-term potentiation and spatial learning in the Morris water maze.

The amnesic effect of benzodiazepine drugs has been well documented, though the mechanisms mediating this effect are unknown. Long-term potentiation (LTP) has been proposed as a mechanism by which information is stored in the mammalian central nervous system. This experiment sought to determine if benzodiazepines impair mnemonic processes by blocking LTP. Rats implanted with a stimulating electrode in the perforant path and a recording electrode in the dentate gyrus were given high-frequency stimulation after the administration of either chlordiazepoxide (5 mg/kg), diazepam (5 mg/kg) or CL 218,872 (10 mg/kg). None of these drugs completely blocked the induction of LTP as measured by changes in the magnitude of the population spike amplitude, though CL 218,872 significantly suppressed potentiation over the duration of recording (24 h). Moreover, the potentiation observed in diazepam-treated rats returned to baseline after 24 h. Two weeks after the last recording, the same implanted rats were given their previous drug and dose and then tested for spatial learning ability in the Morris water maze. Each drug resulted in a severe impairment of spatial learning, but had no effect on cue learning. Two days later, in the absence of drugs, the same rats readily acquired a reversed platform location. Together these results suggest that CL 218,872 may impair spatial learning by suppressing LTP in the perforant path but that chlordiazepoxide and diazepam can impair spatial learning in the absence of LTP suppression in this pathway.

Animals↗
PubMed1993

Pharmacological consequences of nicotinergic plus serotonergic manipulations.

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (nicotinic cholinergic agonist: nicotine 0.03, 0.1, 0.3 mg/kg, nicotinic cholinergic antagonist: mecamylamine 7.5 mg/kg) and serotonin neurons (p-chlorophenylalanine (PCPA), 400/kg mg on each of 3 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. Nicotine did not affect PA performance but at the highest dose slightly impaired WM performance. PCPA did not affect WM navigation or PA performance in saline or nicotine-treated rats. Nicotine restored WM and PA performance defect in mecamylamine pretreated rats. PCPA aggravated the WM defect and decreased the WM performance-improving effect of nicotine in mecamylamine pretreated rats. PCPA did not aggravate the PA performance defect of mecamylamine but completely blocked the PA performance-improving effect of nicotine in mecamylamine pretreated rats. These results suggest that serotonergic and nicotinergic cholinergic systems jointly modulate performance in WM and PA tests.

Animals↗
PubMed1993

Galanin fails to alter both acquisition of a two trial per day water maze task and neurochemical markers of cholinergic or serotonergic neurones in adult rats.

The co-existence of galanin with acetylcholine in ventral forebrain neurones combined with evidence that galanin attenuates cholinergic function and is present in senile plaques in Alzheimer's disease all implicate this neuropeptide in the regulation of cognition. This study simultaneously examines the effect of galanin on acquisition in a Morris water maze and post-training markers of cholinergic and serotonergic forebrain neurones thought to be involved in cognition. Synthetic porcine galanin (10(-9) to 10(-6) M) produced dose-related inhibition of atropine sensitive indirectly-evoked contractions of an isolated guinea-pig ileum which was unaffected by naloxone (10(-7) M). This confirmed the bioactivity of synthetic galanin, which reduces acetylcholine, but not opiate, release from the ileal myenteric plexus. Galanin pretreatment (1 or 10 micrograms i.c.v., -15 min) failed to alter acquisition of a Morris water maze task (2 trials per day) in Hooded Lister rats. Following behavioural acquisition, five days of galanin administration did not alter choline acetyltransferase activity, thyrotrophin-releasing hormone-like immunoreactivity or 5-hydroxytryptamine levels or turnover in the frontal cortex, hippocampus or septum, although dopamine levels were significantly elevated in the frontal cortex. These findings suggest that galanin does not affect acquisition in a simple visual-spatial task which taxes reference more than working memory and questions the assumption that a cholinergic mechanism is the major contributor to previously reported cognitive effects of galanin.

Acetylcholine↗