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PubMed2005

Long-lasting impairment of associative learning is correlated with a dysfunction of N-methyl-D-aspartate-extracellular signaling-regulated kinase signaling in mice after withdrawal from repeated administration of phencyclidine.

In humans, the administration of phencyclidine causes schizophrenic-like symptoms that persist for several weeks after withdrawal from phencyclidine use. We demonstrated here that mice pretreated with phencyclidine (10 mg/kg/day s.c. for 14 days) showed an enduring impairment of associative in a Pavlovian fear conditioning 8 days after cessation of phencyclidine treatment. Extracellular signaling-regulated kinase (ERK) was transiently activated in the amygdalae and hippocampi of saline-treated mice after conditioning. In the phencyclidine-treated mice, the basal level of ERK activation was elevated in the hippocampus, whereas the activation was impaired in the amygdala and hippocampus after conditioning. Exogenous N-methyl-D-aspartate (NMDA), glycine, and spermidine-induced ERK activation was not observed in slices of hippocampus and amygdala prepared from phencyclidine-treated mice. Repeated olanzapine (3 mg/kg/day p.o. for 7 days), but not haloperidol (1 mg/kg/day p.o. for 7 days), treatment reversed the impairment of associative learning and of fear conditioning-induced ERK activation in repeated phencyclidine-treated mice. Our findings suggest an involvement of abnormal ERK signaling via NMDA receptors in repeated phencyclidine treatment-induced cognitive dysfunction. Furthermore, our phencyclidine-treated mice would be a useful model for studying the effect of antipsychotics on cognitive dysfunction in schizophrenia.

Amygdala↗

PubMed1979

Reversal of innate aversions: attempts to induce a preference for chili peppers in rats.

Although humans frequently develop preferences for innately unpalatable bitter or irritant substances, such preferences are extremely rare in animals. An attempt was made to understand the nature of this difference by systematic experiments with laboratory rats, with chili pepper as the unpalatable substance. In parallel with major aspects of the human experience with chili pepper, rats were exposed to it as a flavoring in all their food for periods up to 11 mo from birth, without significant preference enhancement. Gradual introduction of chili into the diet also had no effect, nor did a series of poisoning and safety experiences designed to teach the rats that only chili-flavored foods were safe to eat. A sequence of seven pairings of chili-flavored diet with prompt recovery from thiamine deficiency did significantly attenuate the innate aversion and may have induced a chili preference in at least one case. Extensive experience with chili did not reliably make rats much less sensitive to its oral effects. The only reliable way to eliminate chili aversion in rats is to destroy their chemical irritant sense, which was accomplished in one group of rats. It is concluded that in contrast to humans, it is extremely difficult to reverse innate aversions in rats.

Animals↗

PubMed1975

Role of cortex in Pavlovian discrimination learning.

Two totally neodecorticate rabbits and two groups of normal rabbits were trained on a light-tone differentiation using a Pavlovian nictitating membrane response. The significance of the two stimuli involved in the differentiation was then reversed. Excellent initial differentiations were produced by both decorticates and normals, although there was some evidence of a small retardation of conditional response acquisition in the decorticates in this first stage of the experiment. Under reversal conditions the decorticates extinguished responding to the formerly positive conditional stimulus in fewer trials and produced more complete differentiation performances than normal animals. The decorticates, unlike the normal animals, failed to show a reduction in conditional response onset latencies during either differentiation or reversal training.

Acoustic Stimulation↗

PubMed1994

LTP saturation and spatial learning disruption: effects of task variables and saturation levels.

The prediction that "saturation" of LTP/LTE at hippocampal synapses should impair spatial learning was reinvestigated in the light of a more specific consideration of the theory of Hebbian associative networks, which predicts a nonlinear relationship between LTP "saturation" and memory impairment. This nonlinearity may explain the variable results of studies that have addressed the effects of LTP "saturation" on behavior. The extent of LTP "saturation" in fascia dentata produced by the standard chronic LTP stimulation protocol was assessed both electrophysiologically and through the use of an anatomical marker (activation of the immediate-early gene zif268). Both methods point to the conclusion that the standard protocols used to induce LTP do not "saturate" the process at any dorsoventral level, and leave the ventral half of the hippocampus virtually unaffected. LTP-inducing, bilateral perforant path stimulation led to a significant deficit in the reversal of a well-learned spatial response on the Barnes circular platform task as reported previously, yet in the same animals produced no deficit in learning the Morris water task (for which previous results have been conflicting). The behavioral deficit was not a consequence of any after-discharge in the hippocampal EEG. In contrast, administration of maximal electroconvulsive shock led to robust zif268 activation throughout the hippocampus, enhancement of synaptic responses, occlusion of LTP produced by discrete high-frequency stimulation, and spatial learning deficits in the water task. These data provide further support for the involvement of LTP-like synaptic enhancement in spatial learning.

Animals↗

PubMed1989

Does conditional discrimination learning by pigeons necessarily involve hierarchical relationships?

Four experiments demonstrate that when putative conditional and discriminative cues are presented simultaneously in the single reversal procedure, it is not possible to ascribe a uniquely conditional or uniquely discriminative function to either of the cues. In Experiment 1, pigeons were trained to respond to a blue key and not to a red key while the houselight was on; then in a different session they learned the reversal of this discrimination with the houselight off (single reversal). Separate groups were tested for color generalization with houselight conditions alternating in blocks of trials or for houselight intensity generalization with blue and red key colors alternating in blocks of trials. Both test procedures revealed a conditional relationship between houselight and key color conditions. Experiment 2 produced the same result following training in which the key colors were held constant across training sessions while the houselight and no houselight conditions varied within sessions. In Experiment 3, separate groups were trained with the two procedures but were tested with randomly ordered combinations of key colors and houselight intensities. The two groups yielded indistinguishable bidimensional generalization gradients with peaks at both previously reinforced stimulus combinations. In Experiment 4 the subjects were switched from one of these training procedures to the other with no decrement in their discriminative performance. We conclude that for successive discriminations between conditional- and discriminative-stimulus combinations, the notion of a hierarchical relation between conditional and discriminative stimuli must be extended to include a symmetrical relationship or the notion should be abandoned altogether.

Journal Article↗

PubMed2001

Amygdalar efferents initiate auditory thalamic discriminative training-induced neuronal activity.

It is well known that neurons of the medial geniculate (MG) nucleus of the thalamus send axonal projections to the amygdala. It has been proposed that these projections supply information that supports amygdalar associative processes underlying acquisition of acoustically cued conditioning and learning. Here we demonstrate the reverse direction of influence. Temporary inactivation of the amygdala using the GABA(A) receptor agonist muscimol just before the onset of discriminative avoidance conditioning permanently blocked the development of training-induced discriminative neuronal activity in the MG nucleus of rabbits. No discriminative activity developed when the amygdala was inactivated or during later training to criterion without muscimol. Thus, amygdalar processing at the outset of training is necessary for the development of training-induced discriminative activity of neurons in the MG nucleus.

Acoustic Stimulation↗

PubMed2004

Evidencing inhibitory deficits in Alzheimer's disease through interference effects and shifting disabilities in the Stroop test.

To investigate the contribution of inhibitory deficits in the deterioration of executive function abilities in Alzheimer's disease (AD), a modified version of the Stroop test was submitted to 44 AD patients and 44 elderly controls. Half of the subjects performed successively the Interference Stroop task, the two control tasks and the Reverse Stroop task, and half performed the Reverse Stroop task, the control tasks and finally the Interference Stroop task. This experimental design allowed to assess inhibitory deficits by measuring classical interference effects but also by measuring the ability to shift between tasks instructions. Results confirmed AD patients' difficulty in suppressing the automatic response of reading in the Interference Stroop task. Moreover, AD patients presented worsened performances in the Interference task when administered after the Reverse task, and a Reverse Stroop effect was found in the patients revealing their difficulty in suppressing a previously relevant rule in order to learn a new one.

Aged↗

PubMed1975

Successive spatial discrimination reversals in the prairie dog.

Six prairie dogs (Cynomys ludovicianus) were given reversal training on a spatial discrimination reversal task in a Wisconsin General Test Apparatus (WGTA). As with many other species, more errors occurred on the first reversal problem than during acquisition of the original discrimination. However, performance improved over training until each S eventually reversed after a single nonreinforced error. Initial findings indicate that prairie dogs perform at high levels in discrimination learning experiments and could be valuable subjects for psychological research.

Animals↗

PubMed2000

NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation.

The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for week(s) after initial learning. By developing an inducible, reversible, and CA1-specific knockout technique, we could switch N-methyl-D-aspartate (NMDA) receptor function off or on in CA1 during the consolidation period. Our data indicate that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage.

Animals↗

PubMed2004

Cognitive correlates of white matter growth and stress hormones in female squirrel monkey adults.

Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

Adrenocorticotropic Hormone↗

PubMed2006

Holeboard discrimination learning in mice.

We have adapted to mice a holeboard-learning task, which allows simultaneous assessment of spatial working and reference-memory performance. The holeboard apparatus consists of an open-field chamber with a 16-hole floor insert. Across trials, animals have to learn that the same four holes of 16 are always baited. Here, we show that C57BL/6 mice readily acquire this task within 4 days when submitted to six trials per day or within 8 days when submitted to only four trials per day. We also show that C57BL/6, Swiss-Webster, CD-1 and DBA/2 mice acquire this task similarly, despite the fact that some differences could be observed in measures of exploratory activity during habituation and training. Moreover, the muscarinic antagonist scopolamine disrupts learning at doses of 0.1 and 1.0 mg/kg, although the highest dose appeared to have side-effects. Lastly, we found that amyloid precursor protein transgenic mice have a selective disruption in their working-memory performance only during reversal training (i.e. after a change in the configuration of the baited holes). Overall, our data indicate that this spatial learning task is well adapted to mice and will be useful to characterize spatial memory in various genetic or pharmacological mouse models.

Amyloid beta-Protein Precursor↗

PubMed1993

Impaired acquisition of swimming navigation in adult mice exposed prenatally to oxazepam.

Prenatally administered oxazepam (OX) impairs adult radial maze performance in mice, possibly by permanent hippocampal changes. CDI mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Ten males and ten females were exposed to OX on fetal days 12-16 by maternal administration PO of 30 mg/kg/day and fostered at birth to untreated dams, while control mice received vehicle solution. All mice were tested at 8-9 weeks for ability to find a submerged platform in a fixed location (acquisition: 18 trials, 6 trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, 6 trials per day). OX mice showed a slight but significant impairment of swimming navigation during the initial part of training, as indicated by longer swimming paths during the fourth and fifth trial (day 1), an impairment due both to delayed habituation to the novel stressfull condition and acquisition of platform climbing but unrelated to navigational abilities. No treatment-dependent differences were observed in the reversal phase. During reversal, both OX and control females spent significantly more time in swimming across the location of the old platform. Unrelated to navigational performance, females showed a slightly but significantly higher swimming speed than males. Due to the absence of any navigational impairment, data suggest that prenatal exposure to oxazepam exerts long-term influence on adult learning capacities primarily through interaction with brain systems located outside the hippocampus.

Animals↗

PubMed1997

Short-term odor memory: effects of posterior transection of the lateral olfactory tract in the rat.

Rats were trained on a series of novel 2-odor discrimination problems before and after combined unilateral bulbectomy and posterior transection of the contralateral lateral olfactory tract. In postoperative tests, experimental rats performed as well as controls when a short intertrial interval (30 seconds) was used but, in contrast to controls, failed to learn a 2-odor discrimination when the intertrial interval was 10 minutes. When tested on a reversal task, controls showed memory for original learning by making many errors while experimental rats quickly acquired the task. The results suggest that lateral olfactory tract afferents to posterior olfactory cortex may play a significant role in short-term memory for odors.

Animals↗

PubMed2002

A new approach to the formation of equivalence classes in pigeons.

Four pigeons were given simultaneous discrimination training with visual patterns arbitrarily divided into two sets, with the stimuli in one set designated A1, B1, C1, and D1 and those in the other set designated A2, B2, C2, and D2. In sequentially introduced training phases, the pigeons were exposed to a series of reversals to establish AB and then CD equivalences. In subsequent testing sessions, a subset of stimuli from one set served as positive stimuli and those from the other set as negative stimuli on training trials, and transfer of the reinforced relation to other members of the sets was tested with nonreinforced probe trials. The pigeons were trained further on AC and BD equivalences and then were tested for the emergence of untrained AD and BC equivalences. Two of the 4 pigeons exhibited the emergence of one of these untrained equivalences, evidence for the emergence of transitive relations. This finding suggests that the pigeons established three-member functional equivalence classes by incorporating separately trained multiple equivalence relations. Repeated reversal training and probe testing enabled us to explore the formation and expansion of functional equivalence classes in pigeons.

Animals↗

PubMed1997

Effects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat.

The present study tested the effects of electrolytic lesions in two mPFC subregions, the dorsal anterior cingulate area (dACA) and prelimbic cortex, as well as the effects of a larger medial prefrontal cortex (mPFC) lesion which included both subregions, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiments 1 and 4), two-way active avoidance (Experiments 2 and 5) and conditioned emotional response (Experiments 3 and 6). Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the training and reversal stages of the radial maze task similarly to sham rats, indicating that these lesions did not affect animals' capacity to process and remember spatial information. dACA and mPFC lesions produced a transient deficit in the acquisition of the radial maze task, suggestive of an involvement of these regions in mnemonic processes. However, in view of the normal performance of these groups by the end of training and during reversal, this deficit is better interpreted as stemming from a difficulty to learn the memory-based strategy used to solve the task. Only mPFC lesion led to better avoidance performance at the beginning of training and tended to increase response during the presentation of a stimulus previously paired with shock, compared to sham rats. Both effects can be taken as an indication of reduced emotionality following mPFC lesion. The results are discussed in relation to known behavioral functions of the mPFC and the suggested functional specialization within this region.

Animals↗

PubMed1999

Specific cognitive deficits in mild frontal variant frontotemporal dementia.

Eight patients with relatively mild frontal variant frontotemporal dementia (fvFTD) were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, planning, visual discrimination learning/attentional set-shifting and decision-making were employed. Patients with fvFTD were found to have deficits in the visual discrimination learning paradigm specific to the reversal stages. Furthermore, in the decision-making paradigm, patients were found to show genuine risk-taking behaviour with increased deliberation times rather than merely impulsive behaviour. It was especially notable that these patients demonstrated virtually no deficits in other tests that have also been shown to be sensitive to frontal lobe dysfunction, such as the spatial working memory and planning tasks. These results are discussed in relation to the possible underlying neuropathology, the anatomical connectivity and the hypothesized heterogeneous functions of areas of the prefrontal cortex. In particular, given the nature of the cognitive deficits demonstrated by these patients, we postulate that, relatively early in the course of the disease, the ventromedial (or orbitofrontal) cortex is a major locus of dysfunction and that this may relate to the behavioural presentation of these patients clinically described in the individual case histories.

Adult↗

PubMed2004

Memory enhancing activity of Glycyrrhiza glabra in mice.

In the traditional system of medicine, the roots and rhizomes of Glycyrrhiza glabra (family: Leguminosae) have been employed clinically for centuries for their anti-inflammatory, antiulcer, expectorant, antimicrobial and anxiolytic activities. The present study was undertaken to investigate the effects of Glycyrrhiza glabra (popularly known as liquorice) on learning and memory in mice. Elevated plus-maze and passive avoidance paradigm were employed to test learning and memory. Three doses (75, 150 and 300 mg/kg p.o.) of aqueous extract of Glycyrrhiza glabra were administered for 7 successive days in separate groups of animals. The dose of 150 mg/kg of the aqueous extract of liquorice significantly improved learning and memory of mice. Furthermore, this dose significantly reversed the amnesia induced by diazepam (1 mg/kg i.p.) and scopolamine (0.4 mg/kg i.p.). Anti-inflammatory and antioxidant properties of liquorice may be contributing favorably to the memory enhancement effect. Since scopolamine-induced amnesia was reversed by liquorice, it is possible that the beneficial effect on learning and memory was due to facilitation of cholinergic-transmission in mouse brain. However, further studies are necessitated to identify the exact mechanism of action. In the present investigation, Glycyrrhiza glabra has shown promise as a memory enhancing agent in all the laboratory models employed.

Administration, Oral↗

PubMed2006

Effects of a metacognitive intervention on students' approaches to learning and self-efficacy in a first year medical course.

AIM: To determine the influence of metacognitive activities within the PBL tutorial environment on the development of deep learning approach, reduction in surface approach, and enhancement of individual learning self-efficacy. METHOD: Participants were first-year medical students (N = 213). A pre-test, post-test design was implemented with intervention and control cohorts, with intervention students experiencing a program of metacognitive activities within their PBL tutorials of at least 20 weeks duration. All students completed the Medical Course Learning Questionnaire at the commencement, and again at the completion of, the study. The metacognitive intervention itself consisted of reflection on the learning in PBL coupled with peer- and self-assessment. RESULTS: Self-efficacy was significantly reduced for both control and intervention cohorts at the conclusion of the study. A significant reduction in the adoption of deep and strategic learning approach, matched by a corresponding increase in the use of surface learning, was demonstrated for both cohorts. There was a statistically significant association between high self-efficacy and deep learning approach, with older students over-represented in the group of efficacious deep learners. CONCLUSION: Over the course of first-year medical studies, students lose self-efficacy and move away from deep-strategic learning approaches towards more surface approaches. The program of metacognitive activities failed to reverse this trend. The substantial swing towards surface learning raises questions about the perceived capacity of PBL curricula to promote deep approaches to learning in dense curricula, and reinforces the importance of personal and contextual factors, such as study habits, workload and assessment, in determining individual approaches and idiosyncratic responses to learning situations.

Adult↗