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PubMed2005

Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice.

Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (ie physostigmine-0.03, 0.10, or 0.30 mg/kg; donepezil-0.10, 0.30, or 1.00 mg/kg; or galantamine-0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that AChE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia.

Animals↗
PubMed2003

Moderate doses of ethanol partially reverse avoidance learning deficits in high-alcohol-drinking rats.

We previously reported that ethanol-naive high-alcohol-drinking (HAD1 and HAD2) rats exhibited selective deficits in active avoidance learning, as compared to low-alcohol-drinking (LAD1 and LAD2) rats, in a signaled bar-pressing task [Alcohol. Clin. Exp. Res. 24 (2000) 1778]. In the current study, we used appetitive and aversive learning tasks to assess whether administration of ethanol influences approach and avoidance learning in HAD and LAD rats. Rats were administered 0.0, 0.5, 1.0, or 1.5 g ethanol/kg body weight during appetitive and aversive conditioning sessions. We found that ethanol impaired acquisition of the appetitive conditioned response in a dose-dependent manner in both HAD and LAD rats, with 1.5 g/kg ethanol producing the greatest deficits. Notably, moderate doses of ethanol (0.5 and 1.0 g/kg) partially reversed avoidance learning deficits in HAD rats, but only when appetitive conditioning preceded aversive conditioning. The highest dose (1.5 g/kg EtOH) abolished avoidance responding altogether in HAD rats. Avoidance responding in LAD rats was not affected by any dose of ethanol. These results are consistent with previous studies suggesting that alcohol preference may be associated with increased fear or anxiety, but the conditions under which ethanol produces a reduction of fear and anxiety in HAD rats appear to be relatively complex.

Alcohol Drinking↗
PubMed2006

Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood.

The neural cell adhesion molecule (NCAM) has been implicated in regulating synaptic plasticity mechanisms as well as memory consolidation processes. Attachment of polysialic acid to NCAM (PSA-NCAM) has been reported to down-regulate its adhesive forces, a process hypothesized to be implicated in synapse selection after learning experiences. PSA-NCAM has been critically implicated in hippocampus-related synaptic plasticity and memory storage, but information about its functional role in other brain areas remains scarce. Here, we studied mice deficient for polysialyltransferase-1 (ST8SialV/PST-1), an enzyme which attaches PSA to NCAM during postnatal development and adulthood, and whose deficiency results in a drastic reduction of PSA-NCAM expression throughout the brain in adulthood. Mice were tested for their performance in the water maze and auditory fear conditioning (AFC). We report that ST8SiaIV knockout mice were impaired in spatial as well as reversal learning in the water maze. On the other hand, AFC was intact and ST8SiaIV mice exhibited no impairments in the acquisition or retention of cued fear memories. Spatial orientation learning and reversal learning require complex integration of spatial information and response selection involving the hippocampus and prefrontal cortex, whereas cued fear conditioning is an associative type of emotional memory that highly depends on amygdala function. Therefore, our results indicate that PSA-NCAM contributes differentially to learning processes that differ in the nature of the neural computations involved, which probably reflects a differential role of this molecule in different brain regions.

Amygdala↗
PubMed1985

Serial ablations of the telencephalon and avoidance learning by goldfish (Carassius auratus).

Simultaneous bilateral ablation of the teleost telencephalon was confirmed to dramatically impair the retention, extinction, and "reversal learning" of a preoperatively learned instrumental avoidance response in a shuttle box. The focus of the experiment was on whether two-stage serial unilateral ablations of the teleost telencephalon would ameliorate the effects seen following one-stage bilateral ablation and whether such amelioration would be a function of the fish's experiences between the staged ablations. The degree of retention, relearning, and extinction of the avoidance response was not modulated by the serial ablation procedure whether or not there was interoperation retraining experience. However, reversal learning, in which the previous warning signal became the safety signal and the previous safety signal became the new warning signal, was less impaired following serial ablations than following single-stage bilateral ablation. These results are contrasted with those from experiments with mammalian subjects.

Animals↗
PubMed2005

Learning and memory as a function of age in Down syndrome: a study using animal-based tasks.

Individuals with Down syndrome (DS) are at a high risk for developing Alzheimer disease (AD) after the age 40; however, low levels of intellectual functioning, coupled with impaired language ability, confound the detection of AD. Comparative neuropsychological tests developed in animal models of aging and cognition do not require intact language function and can be useful for detecting changes in cognition. Experimental paradigms used to detect age-dependent cognitive deficits in animal models were applied in the present study to measure cognitive function in a group of 20 adults with DS ranging in age from 22 to 58 years. Object discrimination, reversal learning, and spatial and object memory were administered using a modified Wisconsin General Testing Apparatus and reinforcement (penny rewards). When considering age as the only clinical variable to parallel the animal studies, age was significantly correlated with performance on object memory and marginally related to performance on reversal learning and spatial memory. However, when evaluating multiple clinical variables including age, a measure of intellectual ability (FSIQ), scores on the Dementia Questionnaire for Persons with Mental Retardation (DMR), and gender using regression analysis, scores on the DMR were the best predictors of errors of reversal learning, whereas FSIQ was the best predictor of performance on object memory. These results suggest that while age may be related to performance on learning and memory tasks, other clinical variables may be stronger predictors of performance in adults with DS. These changes may reflect prefrontal and medial temporal lobe dysfunction that is associated with the development of AD pathology in DS.

Adult↗
PubMed1991

Comparison of the effects of acute and chronic ibotenic and quisqualic acid nucleus basalis lesioning.

The present study examines the effects of acute (1 month recovery) and chronic (8 month recovery) bilateral quisqualic (quis) and ibotenic (ibo) acid nucleus basalis (NB) lesioning on the activity of cholinergic neurons and on passive avoidance (PA) and water-maze (WM) performance. Our data demonstrate that A: The activity of choline acetyltransferase (ChAT) in cortical tissue and the number of ChAT positive neurons in the NB were decreased 1 and 8 months after quis or ibo NB lesioning. B: Ibo NB lesioning produced a greater nonspecific subcortical cell loss than quis NB lesioning. C: PA retention was impaired by acute and chronic quis and ibo NB lesioning. D: Acute ibo NB lesioning impaired acquisition and reversal learning in WM performance whereas chronic ibo NB lesioning impaired only reversal WM learning. Acute and chronic quis NB lesioning impaired reversal WM learning. The present results suggest that NB cholinergic neurons do not recover spontaneously from excitotoxin-induced damage and that they may be importantly involved in inhibitory avoidance and spatial reversal learning performance.

Animals↗
PubMed2006

Rhesus monkeys with orbital prefrontal cortex lesions can learn to inhibit prepotent responses in the reversed reward contingency task.

Monkeys with lesions of the orbital prefrontal cortex (PFo) are impaired on behavioral tasks that require the ability to respond flexibly to changes in reward contingency (e.g., object reversal learning and extinction). These and related findings in rodents and humans have led to the suggestion that PFo is critical for the inhibitory control needed to overcome prepotent responses. To test this idea, we trained rhesus monkeys with PFo lesions and unoperated controls on acquisition of the reversed reward contingency task. In this task, selecting the smaller of 2 food quantities (1 half peanut [1P]) leads to receipt of the larger quantity (4 half peanuts [4P]) and vice versa. Choice of a larger quantity of food is a reliable prepotent response, and, accordingly, all monkeys initially selected 4P rather than one. With experience, however, all monkeys learned to select 1P in order to receive 4. Surprisingly, monkeys with PFo lesions learned as quickly as unoperated controls. Thus, PFo lesions do not yield a deficit in all tests that require the inhibition of a prepotent response.

Animals↗
PubMed1992

Effects of bifemelane on discrimination learning of serotonergic-dysfunction rats.

To investigate the effect of bifemelane hydrochloride on learning achievements of serotonin-deficient rats, animals were fed with tryptophan-deficient diets and operant type discrimination learning tests were performed. In general, serotonin-deficient rats show hyperactivity. In this study, total number of responses in reverse learning experiments was lower in rats that received 50 mg/kg bifemelane compared to the other serotonin-deficient groups. The ratio of correct responses to the total number of responses revealed low learning achievements in the control and low-dose groups, whereas the ratio in the high-dose group was nearly the same as in normal rats in the final few sessions of both the primary and reverse learning experiments. Throughout this study, the high-dose group showed a better improvement in learning achievement than the low-dose group. Therefore, bifemelane has certain effects on learning achievement from a) the functional activation of the serotonergic nervous system and b) changes in neurotransmitter levels in the brain (e.g., acetylcholine, noradrenaline) and overall energy metabolism.

Animals↗
PubMed1983

Temporal correlates of discrimination learning.

The relationship between human temporal behavior and learning was investigated by means of an experimental design which measured temporal behavior using the methods of reproduction and production as possible correlates for a complex-form of discrimination-reversal learning. The results indicated that the method of reproduction is a temporal correlate of original learning and that the method of production is a temporal correlate of reversal learning. The theoretical explanations proposed for these results employed the mechanisms of conditioning, extinction, and stimulus generalization, the intervening variables of excitation and inhibition and the Pavlovian levels of behavioral organization of the first and second signalling systems.

Adult↗
PubMedDate not supplied

Role of monkey hippocampus in recognition of food and nonfood.

To investigate the role of the hippocampal formation (HF) in feeding behavior, single neuron activity in the monkey HF was recorded during performance of an operant task that included food/nonfood discrimination, drinking, and active avoidance. Of 837 neurons recorded in the HF, 155 responded to the sight of one or more objects. Of these, 82 responded to the sight of different objects with different response magnitudes, and some of these 82 responded predominantly to food-related (rewarding) objects or nonfood, aversive objects. The magnitude of response of neurons that responded predominantly to food was not necessarily correlated with the order of animal's preference for those kinds of food. For some neurons that responded predominantly to food or nonfood, effects of extinction or reversal learning on the neuronal responses were tested, and most of the neurons tested maintained their original responsiveness even after behavioral extinction or reversal learning was accomplished. The results suggest that these HF neurons may be involved in preservation of past information concerning food or nonfood.

Animals↗
PubMed2004

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers.

RATIONALE: Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort. OBJECTIVES: The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied. METHODS: Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3-4 h after taking the CP mixture. RESULTS: The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found. CONCLUSIONS: The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.

Adult↗
PubMedDate not supplied

Recovery of memory in chicks after disruption during learning: the reversibility of amnesia induced by protein synthesis inhibitors.

Protein synthesis inhibitors given during learning are known to disrupt memory in various animal species in several models of learning. However, there are suggestions that amnesia induced by protein synthesis inhibitors is not permanent--memory can be recovered by a reminder procedure, i.e., by presenting the animal with one of the components of the external environment which was part of the learning situation. The aim of the present work was to determine the existence of the reminder phenomenon in a well-studied model of single-session training to passive avoidance in chicks. Cycloheximide and anisomycin were used to induce amnesia. Reminder was performed using the aversive taste of methylanthranilate 24 h after training, and testing was conducted 48 h after training. The results obtained provide evidence that memory disrupted by protein synthesis inhibitors in chicks can be recovered by the reminder procedure.

Amnesia↗
PubMed2006

Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains.

Three defining clinical symptoms of autism are aberrant reciprocal social interactions, deficits in social communication, and repetitive behaviors, including motor stereotypies and insistence on sameness. We developed a set of behavioral tasks designed to model components of these core symptoms in mice. Male mice from 10 inbred strains were characterized in assays for sociability, preference for social novelty, and reversal of the spatial location of the reinforcer in T-maze and Morris water maze tasks. Six strains, C57BL/6J, C57L/J, DBA/2J, FVB/NJ, C3H/HeJ, and AKR/J, showed significant levels of sociability, while A/J, BALB/cByJ, BTBR T(+)tf/J, and 129S1/SvImJ mice did not. C57BL/6J, C57L/J, DBA/2J, FVB/NJ, BALB/cByJ, and BTBR T(+)tf/J showed significant preference for social novelty, while C3H/HeJ, AKR/J, A/J, and 129S1/SvImJ did not. Normal scores on relevant control measures confirmed general health and physical abilities in all strains, ruling out artifactual explanations for social deficits. Elevated plus maze scores confirmed high anxiety-like behaviors in A/J, BALB/cByJ, and 129S1/SvImJ, which could underlie components of their low social approach. Strains that showed high levels of performance on acquisition of a T-maze task were also able to reach criterion for reversal learning. On the Morris water maze task, DBA/2J, AKR/J, BTBR T(+)tf/J, and 129S1/SvImJ failed to show significant quadrant preference during the reversal probe trial. These results highlight a dissociation between social task performance and reversal learning. BTBR T(+)tf/J is a particularly interesting strain, displaying both low social approach and resistance to change in routine on the water maze, consistent with an autism-like phenotype. Our multitask strategy for modeling symptoms of autism will be useful for investigating targeted and random gene mutations, QTLs, and microarray analyses.

Animals↗
PubMed2006

Dopamine and noradrenaline efflux in the medial prefrontal cortex during serial reversals and extinction of instrumental goal-directed behavior.

The prefrontal cortex (PFC) of the rat supports cognitive flexibility, the ability to spontaneously adapt goal-directed behavior in response to radically changing situational demands. We have shown previously that transient inactivation of the rat medial PFC (mPFC) impairs initial reversal learning in a spatial 2-lever discrimination task. Given the importance of dopamine (DA) for PFC function, we studied DA (and noradrenaline [NA]) efflux in the mPFC during reversal learning. We observed a higher and more extended increase in DA efflux in rats performing the first reversal compared with controls performing the previously acquired discrimination. The results of an additional experiment suggest that such a difference between the reversal- and control-induced DA increases was absent during a third reversal. During the extinction session, DA efflux did not increase from basal levels. Increases in NA efflux were less than in DA and did not differ between control and any condition. We conclude that prefrontal DA activity is increased during execution of instrumental discrimination tasks and that this increase is amplified during the acquisition of a first, but not of later reversals. These data corroborate our previous findings and indicate that DA is critically involved in this form of cognitive flexibility.

Animals↗
PubMed1987

Selective memory impairment by phencyclidine in rats.

Phencyclidine (PCP) users sometimes report lack of recall of events occurring while they are under the influence of the drug. The present experiment was designed to test whether rats remember information learned after PCP administration. Rats were trained to choose one arm of a T-maze to obtain a food reward. The following day they were injected with either PCP (1 mg/kg) or vehicle and trained to choose the opposite arm for a reward (reversal learning). A third group of rats received neither injections nor training on the second day. On the third day, all rats were tested for their preference of maze arms. Rats who had been injected with saline before reversal learning chose the arm rewarded during the reversal, while rats receiving PCP on the second day chose randomly. The rats which did not learn the reversal chose the arm learned on day 1. These results indicate that while PCP did not interfere with the rats ability to learn, it interfered with long-term storage of information.

Animals↗
PubMed2005

The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP). Importantly, NF1 causes learning disabilities and attention deficits. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia. We report that lovastatin decreased the enhanced brain p21Ras-MAPK activity of the nf1+/- mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.

Analysis of Variance↗
PubMed2005

Low dose quetiapine reverses deficits in contextual and cued fear conditioning in rats with excitotoxin-induced hippocampal neuropathy.

Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.

Animals↗