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PubMed1985

Spatial learning and memory, maze running strategies and cholinergic mechanisms in two inbred strains of mice.

The acquisition process of the radial maze task was studied in two inbred strains of mice, C57BL/6 and DBA/2. A quantitative and qualitative evaluation of performance was performed and the pretest level of activity was measured. The results showed a significant correlation between activity and performance since the highly active C57BL/6 mice exhibited better performance of the radial maze task than the less active DBA/2 mice. Moreover, for correct trials, strain-dependent maze-running strategies were observed: while both strains displayed about the same percentage of clockwise and spatial strategies, it was observed that among the spatial strategies C57BL/6 used a larger number of different correct solutions. Subsequently, the effect of scopolamine administration on working memory processes was assessed in sequential and discrete trials. A different reactivity of each strain to anti-cholinergic treatment was found in discrete trials since only DBA/2 mice were impaired. The effect of scopolamine is discussed in relation to the different models of information processing involved in learning and memorizing the experimental rule.

Animals↗
PubMed1995

Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats.

The emergence of cognitive deficits in a subgroup of aged rats is associated with increased hypothalamic-pituitary-adrenal axis activity, decreased hippocampal mineralocorticoid and/or glucocorticoid receptor gene expression and neuronal loss. Short-term treatment with antidepressant drugs in young rats increases hippocampal corticosteroid receptor gene expression. In this study, the effects of chronic antidepressant administration on hippocampal mineralocorticoid and glucocorticoid receptor gene expression and spatial memory in young and aged rats were investigated. Young (eight months) and old (22 +/- 1 months) Lister-hooded rats were ranked according to watermaze performance. Matched pairs of rats were treated with amitriptyline (10 mg/kg) or saline daily for nine weeks, then reassessed in the watermaze. Amitriptyline significantly improved spatial memory in the young rats (33% increase in transfer test time) and increased hippocampal mineralocorticoid, but not glucocorticoid receptor messenger RNA expression. By contrast, in aged rats, amitriptyline had no effect on spatial memory or hippocampal corticosteroid receptor gene expression, either in cognitively unimpaired or cognitively-impaired animals. In aged rats, basal plasma corticosterone levels, which were significantly higher than in young animals, correlated negatively with spatial memory, while hippocampal glucocorticoid receptor mRNA expression correlated negatively with plasma corticosterone levels and positively with spatial memory. Amitriptyline had no significant effect on basal morning plasma corticosterone levels in either young or aged rats, but significantly decreased evening corticosterone levels in aged rats. Our data support the notion that corticosterone exerts a concentration-dependent biphasic influence, via selective activation of hippocampal mineralocorticoid and glucocorticoid receptor, on spatial memory. Amitriptyline improves spatial memory in young rats and increases hippocampal mineralocorticoid receptor gene expression. The lack of amitriptyline effect on spatial memory in aged rats may reflect decreased plasticity of both the synaptic processes underlying spatial memory and the regulation of hippocampal mineralocorticoid/glucocorticoid receptor expression, with mineralocorticoid receptors fully occupied due to elevated basal plasma corticosterone levels (in part a consequence of inadequate glucocorticoid receptor function).

Aging↗
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↗
PubMed1990

Spatial learning is affected by transient occlusion of common carotid arteries (2VO): comparison of behavioural and histopathological changes after '2VO' and 'four-vessel-occlusion' in rats.

Place learning in the Morris water maze following transient (24 min) occlusion of the common carotid arteries (2VO), and following permanent occlusion of both vertebral arteries plus transient (20 min) clamping of the carotids (4VO) was investigated in rats 6-9 days after occlusion. Both 2VO and 4VO treatment increased the latency to find the hidden platform during escape trials; spatial bias, tested in a probe trial, was decreased. Histological analysis revealed neural necrosis in the CA1 sector of the hippocampus in 4VO rats but not in 2VO animals. The data suggest that an experimentally induced reduction in cerebral blood flow of 50% (after 2VO) or 95% (after 4VO) produces persistent functional changes even in absence of actual neural damage.

Animals↗
PubMed1989

Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage.

Rats display an acquisition deficit in a circular water maze following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). Experiments were therefore performed to determine if acquisition behavior on this task could predict the degree of cortical cholinergic deafferentation and if the acquisition deficit could be pharmacologically reversed. Performance on acquisition was highly correlated with the lesion-induced reduction in cortical choline acetyltransferase (ChAT) activity. Accuracy of spatial behavior was highly correlated to percentage ChAT depletion (r = 0.75). Neither lesioned rats nor controls displayed a retention deficit after a 9-day interval, nor did either group display a passive-avoidance retention deficit. To test the causal relationship between cholinergic dysfunction and spatial behavior, the central nervous system cholinergic enhancer nerve growth factor (NGF) was intraventricularly infused for 4 weeks. NGF infusion resulted in improved acquisition of the water maze task compared to NBM-lesioned rats receiving vehicle infusion and untreated rats with NBM lesions. These studies indicate that the decrease in cortical ChAT activity is likely to be responsible for the observed acquisition deficit and that pharmacological manipulations can be successfully used to improve behavior following NBM lesions.

Animals↗
PubMed1985

Facilitation of spontaneous and learned spatial behaviours following 6-hydroxydopamine lesions of the lateral septum: a cholinergic hypothesis.

Mice received injections of 6-hydroxydopamine (6-OHDA) in the lateral septum; they were tested for spontaneous alternation, acquisition and reversal of a spatial discrimination in a T-maze. In each of these tasks, performance of 6-OHDA lesioned mice was improved relative to controls. Neurochemical analysis revealed that 6-OHDA lesioned mice exhibited a significant increase in the rate of sodium-dependent high affinity choline uptake in the hippocampus. These results are discussed in relation to current theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behaviour.

Animals↗
PubMed1992

Parenteral domoic acid impairs spatial learning in mice.

The present study is the first to examine the effect of a single intraperitoneal injection of the neuroexcitotoxin domoic acid on learning in mice. Compared to saline controls, animals exposed to domoic acid (2.0 mg/kg) showed significant impairment on the acquisition of the place task in the Morris water maze. Observation of swim paths taken by mice searching for the underwater platform revealed a failure on the part of the domoic acid-exposed mice to select the appropriate problem solving strategies. The results, along with neuroanatomic work done here and elsewhere, suggest that impairment of acquisition and retention of this spatial navigation task by domoic acid, involves a neuropathology that includes not only the hippocampus, but other limbic, and possibly extralimbic brain regions.

Animals↗
PubMed1991

Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring.

Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.

Alcohol Drinking↗
PubMed1981

Recovery of visual-spatial learning and memory in chronic alcoholics.

Administered the Memory-for-Designs Test and a verbal and visuospatial paired associate learning test to separate groups of alcoholics (N = 32) 3 and 11 weeks abstinent from alcohol and to a matched control group (N = 16). Alcoholics were not impaired in verbal learning. Alcoholics 3 weeks abstinent performed significantly less well than controls on all nonverbal tasks and less well than 11-weeks alcoholics on one nonverbal measure. No significant differences were found between 11-week alcoholics and controls. The results suggest that some recovery of function may occur in alcoholics after 10 weeks of abstinence. The data also support the hypothesis of impaired right hemisphere in alcoholics.

Alcoholism↗
PubMed1988

Experience during suckling alters later spatial learning.

These experiments explore the role of preweaning experience in learning during the juvenile period. Pups that had been reared with many nipples available reached criterion on an 8-arm radial maze in a few trials; conversely, pups reared with only a few nipples required 3 times the number of trials to reach criterion (Experiment 1). Pups that had been reared with relatively few nipples available rarely nipple-shifted, while those that had been reared with a particularly high density of nipples shifted more frequently (Expt 2). A rearing procedure was devised that allowed precise experimental control of all phases of the suckling experience (Expt 3). Allowing or preventing a single behavior, nipple-shifting, while holding all other variables constant, was sufficient to affect acquisition of the maze task. In Experiment 4, the specificity of the early experience for later tasks was explored using a variety of nonspatial, lever-pressing operants. Rearing condition did not affect acquisition of a lever-pressing operant or of a visual discrimination task. However, pups reared with a high density of nipples responded at higher rates to a variable interval schedule and were more resistant to extinction. The possibility that strategy, rather than learning ability, was affected by rearing condition was assessed using a 2-arm maze task that was structured to present an optimal strategy of either win-shift or win-stay (Expt 5). The ease with which rats acquired the win-stay task was unaffected by rearing condition; all groups performed at about chance levels. However, pups reared with many nipples more readily acquired the win-shift task.

Animals↗
PubMed1992

Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam.

This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.

Animals↗
PubMed1991

The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine.

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.

Animals↗
PubMed1989

A novel NMDA antagonist, MK-801, impairs performance in a hippocampal-dependent spatial learning task.

N-Methyl-d-aspartate (NMDA) receptors have been implicated with the triggering of long-term potentiation, a currently studied physiological model of learning and memory. The compound (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) has recently been classified as a potent and selective NMDA antagonist acting at the associated ion channel. After determination of the highest intraperitoneal dose of MK-801 at which increases in activity (measured in photocell activity cages and 3-arm maze) were not observed (0.2 mg/kg), rats that had been previously trained to obtain food pellets in an 8-arm radial maze up to criterion were tested with 0.1 and 0.2 mg/kg doses. Dose-related decreases in "efficiency" in the task were found. The present findings support the suggestion that NMDA antagonists cause impairments in "working memory" and also support the status of long-term potentiation as a physiological model of memory.

Animals↗
PubMed1992

Effect of oxiracetam on scopolamine-induced amnesia in the rat in a spatial learning task.

The effects of the nootropic agent 4-hydroxy-2-oxopyrrolidinoacetamide (oxiracetam) on memory and performance impairments induced by scopolamine were evaluated in the Morris water maze task. No effect was seen on the performance of rats when treated with oxiracetam (30 mg/kg, IP) alone. Task performance of scopolamine (0.2 mg/kg, SC)-treated rats was impaired as compared to that of control animals. The behavioral deficits expressed in the task by scopolamine treatment were attenuated by the same dose of oxiracetam.

Animals↗
PubMed1990

The effects of dorsal noradrenergic bundle lesions on spatial learning, locomotor activity, and reaction to novelty.

The dorsal noradrenergic bundle (DNB) of male Wistar rats was lesioned bilaterally using intracerebral injections of 6-hydroxydopamine neurotoxin. Some of the rats were trained in a water maze using an "alternation" strategy, where the two positions of the hidden platform in the pool were changed between successive trials in the daily tests, and other rats in a water maze, where the temperature of the water was lowered to about 11 degrees C. The rats trained in the cold-water maze were also tested in open-field and saccharin neophobia tests. No differences were found between the two groups in learning of water maze tasks or in locomotor activity in the open-field tests. However, the saccharin neophobia test revealed an increased neophobia in the DNB-lesioned rats.

Animals↗
PubMed1990

The effects of forebrain ischaemia on spatial learning.

Rats were subjected to 15 min of forebrain ischaemia using the 4-vessel occlusion method. Following recovery they were trained using place navigation learning in a Morris water maze and forced choice rewarded alternation in a T-maze. Ischaemic rats were impaired in place navigation learning but the deficit was transient and there was no impairment of subsequent transfer test performance. Food-rewarded forced-choice alternation in a T-maze revealed a persistent impairment in ischaemic rats. The behavioural deficits were associated with neuropathological damage in the CA1 cell layer of the dorsal hippocampus with varying degrees of damage in layers CA2, CA3 and CA4. Granule cells in the dentate gyrus were not visibly affected. Variable amounts of lesion damage were found in the dorsolateral striatum. Ischaemic rats are therefore impaired on both place navigation and forced choice rewarded alternation, suggesting that ischaemic brain damage affects reference and working memory processes to different extents. Forced choice alternation may be the more sensitive method of assessing cognitive changes caused by forebrain ischaemia.

Animals↗