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PubMed2001

The function of dreaming.

Theories on the function of REM sleep and dreaming, with which it has a contingent relationship, remain diverse. They include facilitation of memory storage, reverse learning, anatomical and functional brain maturation, catecholamine restoration, psychoanalytical (wish fulfilment or otherwise). It is possible that one function is grafted onto another as the personality develops. Given a close relationship between REM sleep and dreaming, and given that the neonate spends 18 hours asleep per day, of which 12 hours are spent in REM sleep, it is logical to look in the neonate for a primary function of dreaming. The two constants in the dreaming process are: 1) the dreamer is always present as first person observer; 2) there is always a topographical setting. Based on the foregoing, it is proposed that a major function of REM sleep is the development and maintenance of a sense of personal identity, through creating a 'being there' environment at regular intervals during prolonged periods of absence from a waking state in topographical surrounds. The infant cannot forget who he/she is. Thus, he/she develops a clear sense of his/her own identity, or the 'I'ness of me', and a sense of his/her separateness from the topographical world. At the same time, by largely forgetting the dreams, he/she is not burdened by the need for an elaborate method of storage of the vicarious and bizarre experiences.

Aging↗
PubMed2005

Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.

Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.

Aging↗
PubMed2005

Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors.

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 microg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

Adrenal Cortex Hormones↗
PubMed1993

Alternating prism exposure causes dual adaptation and generalization to a novel displacement.

In two experiments, we examined the hypothesis that repeatedly adapting and readapting to two mutually conflicting sensory environments fosters the development of a separate adaptation to each situation (dual adaptation) as well as an increased ability to adapt to a novel displacement (adaptive generalization). In the preliminary study, subjects alternated between adapting their visuomotor coordination to 30-diopter prismatic displacement and readapting to normal vision. Dual adaptation was observed by the end of 10 alternation cycles. However, an unconfounded test of adaptive generalization was prevented by an unexpected prism-adaptive shift in preexposure baselines for the dual-adapted subjects. In the primary experiment, the subjects adapted and readapted to opposite 15-diopter displacements for a total of 12 cycles. Both dual adaptation and adaptive generalization to a 30-diopter displacement were obtained. These findings may be understood in terms of serial reversal learning and "learning to learn."

Adaptation, Psychological↗
PubMed1991

Reversal of a drug versus drug discrimination task with different exteroceptive conditions.

The effects of a change of an exteroceptive context (light and dark) on a drug vs. drug discrimination reversal task was investigated. Rats were trained to discriminate between either 1750mg/kg ethanol and 17.5mg/kg pentobarbital (high dose) or 1000mg/kg ethanol and 10.0mg/kg pentobarbital (low dose), using an electrified T-maze procedure. Once the initial acquisition had been acquired (phase I), the response requirements were reversed (phase II). For the experimental groups, this was accompanied by a change in exteroceptive conditions (light became dark and vice versa). For the control groups, the reversal phase was without any change in exteroceptive context. Finally, the animals were tested with saline and the training doses of the drugs, for both exteroceptive conditions. It was found that both original and reversal acquisition occurred faster in the high dose group. This is consistent with previous findings. There were no effects of a changed exteroceptive context on the speed of reversal learning, or on discriminative performance during final testing, in either dose group. A possible explanation is suggested for these findings.

Journal Article↗
PubMed1990

Ontogenic factors in short- and long-term recovery of discriminative behavior in rats after selective brain damage.

Stereotypical behavior or response perseveration dominating early mammalian responding, especially under conditions of aversive motivation, may be radically modified through damage in the prefrontal and hippocampal systems. These observations contribute evidence to the notion that changes in neural circuitry may be supporting behavioral recovery of function after selective brain damage. The extent of behavioral deficits as well as the prognosis for recovery are governed by task-specific variables, usually related to a discriminative element in stimulus control. Conversely, reversion to earlier, stereotypical behavior may be produced in adult rats exposed to damage at points within the same sites. Specific experiments tested weanling and adult rats within tasks that differed in the (1) extent and site of damage, (2) variety of signalling stimuli, (3) complexity of the task requirements, and (4) time since surgery for initiation of training. Experiments on 1-way active avoidance, alternation and reversal learning indicated that performance deficits are attributed to developmental immaturity early in ontogeny, and enhanced neurophysiological growth with age provides a reliable predictor of recovery. However with increasing age, variables related to the subtleties of damage site and task also emerge as salient factors in behavioral deficiencies. Interestingly, the cue properties or information value contained in the conditioned stimulus (CS) and the environmental context provide differential compensation for selected types of injury-induced deficits, and there was some evidence that the utility of environmental signals can be improved over long-term recovery periods. The results support the view that relationships between age at the time of injury and extent of recovery are perhaps best explained within developmentally determined constraints.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

Nefazodone: preclinical pharmacology of a new antidepressant.

Recent pharmacologic studies suggest that nefazodone may possess antidepressant activity. Nefazodone is active in behavioral models predictive of antidepressant potential. It is active in reversing learned helplessness, prevents reserpine-induced ptosis, and enhances response efficiency in the differential reinforcement for low rates of response paradigm. In in vitro studies, nefazodone inhibits the binding of [3H]ketanserin to cortical serotonin2 (5-HT2) binding sites, whereas in vivo, it antagonizes the 5-HT2-mediated quipazine-induced head shake in rats. In ex vivo studies, acute oral administration of nefazodone inhibits cortical serotonin uptake and occupies frontal cortical 5-HT2 receptor binding sites. Chronic administration of nefazodone produces a reduction in 5-HT2-mediated behavior and decreases cortical 5-HT2 receptor binding site density. Further, a chronic high-dose nefazodone regimen significantly potentiates 5-HT1A-mediated behavioral responses in rats. Nefazodone exhibits decreased anticholinergic, alpha-adrenolytic, and sedative activity relative to other antidepressants.

Animals↗
PubMed1979

Operant conditioning of infant monkeys (Macaca fascicularis) for toxicity testing.

A technique has been developed that allows infant monkeys to perform on an operant schedule as soon as they are able to self-feed. Behavior is shaped in small increments through a series of operants; sensory and motor systems as well as performance on schedules using intermittent reinforcement may be tested as early as 3-4 weeks of age. This is accomplished by exposing the infant to the operant situation almost continuously, and allowing the infant to feed only by operantly responding. Infants exposed to lead post-natally differed from controls in pattern of fixed ratio responding, "activity" as measured by pattern of responding over the course of the session, and on a two-choice form discrimination reversal learning set paradigm. This technique allows rapid accumulation of large amounts of data without experimenter intervention.

Animals↗
PubMed1978

Associative symmetry in the PA learning of retarded and nonrerarded children.

Mentally retarded and nonretarded children learned pairs of pictures in a single-function order (A and B terms of each pair were in the same position throughout) or in a double-function order (all items were re-paired and served as A and B terms). Associative symmetry was demonstrated by all groups when the lists were presented single-function; forward asymmetry was demonstrated when the list was presented double-function. When categorized pairs were presented double-function, items that were correctly associated by category produced symmetry; items that were correctly associated but not by category produced forward asymmetry. The possible influence of single vs. multiple associations on associative symmetry was discussed.

Child↗
PubMed1994

A comparative neuropsychological approach to alcoholism and the brain.

Comparative neuropsychology involves the study of brain-behavior relationships by applying experimental paradigms, used extensively in animal laboratories, for testing human clinical populations. Popular paradigms include delayed reaction tasks, discrimination and reversal learning tasks, and matching- and nonmatching-to-sample. Such tasks were perfected on experimental animals having well defined brain lesions, and adapted for the sensory and motor capabilities of human neurological patients. By holding task requirements constant for human and nonhuman primates, analogous measures can be made of neurobehavioral deficits associated with specific brain damage. Human and nonhuman primates solve many so-called animal-learning tasks, in similar ways. Moreover, many tasks, despite their apparent simplicity, already have proven to be sensitive to cognitive impairments after brain damage in humans and nonhumans alike. An important advantage of using paradigms from comparative neuropsychology, in conjunction with standard clinical neuropsychological assessments, is that the simplicity of the tasks makes them manageable for patients with severe cognitive impairments. In addition, since the tasks do not require linguistic strategies for performance, the problems can be solved by patients whose language skills are compromised. An example of the application of comparative neuropsychology to clinical populations is given: patients with a history of long term alcohol abuse were tested on delayed reaction paradigms, and the findings have been useful in clarifying the contribution of damaged frontal cortical-subcortical brains systems to their cognitive impairments.

Alcoholism↗
PubMed1999

Functionally dissociating aspects of event memory: the effects of combined perirhinal and postrhinal cortex lesions on object and place memory in the rat.

Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.

Animals↗
PubMed2006

Anatomy of a decision: striato-orbitofrontal interactions in reinforcement learning, decision making, and reversal.

The authors explore the division of labor between the basal ganglia-dopamine (BG-DA) system and the orbitofrontal cortex (OFC) in decision making. They show that a primitive neural network model of the BG-DA system slowly learns to make decisions on the basis of the relative probability of rewards but is not as sensitive to (a) recency or (b) the value of specific rewards. An augmented model that explores BG-OFC interactions is more successful at estimating the true expected value of decisions and is faster at switching behavior when reinforcement contingencies change. In the augmented model, OFC areas exert top-down control on the BG and premotor areas by representing reinforcement magnitudes in working memory. The model successfully captures patterns of behavior resulting from OFC damage in decision making, reversal learning, and devaluation paradigms and makes additional predictions for the underlying source of these deficits.

Animals↗
PubMed1996

Discrimination learning and multiple reversals in young adult and older monkeys (Macaca arctoides).

Two groups of five young adult an older stumptailed macaques (Macaca arctoides) were tested on a visual discrimination task followed by a reversal upon attainment of criterion; task and reversal were repeated until 20 reversals with the same pair of objects had been completed. Both groups required more trials to learn the first reversal than the original discrimination, with no significant difference between the groups. Older monkeys tended to show more perseverative errors on early reversals, but a striking improvement in their scores across successive blocks of reversals culminated in performances virtually indistinguishable from those of the young group by the end of testing.

Age Factors↗
PubMed1986

Learning sets, discrimination reversal, and hippocampal function.

Impairments of discrimination reversal are commonly found following lesions of the hippocampal system. In a recent experiment, however, acquisition of a reversed discrimination was actually facilitated, rather than impaired, by partial lesions of the fimbria-fornix (FFX), an extrinsic fiber connection to the hippocampus. That experiment differed from most previous reversal experiments in that the discriminative stimuli were olfactory rather than spatial or visual, and 3 discriminations were given prior to the reversal of the third discrimination, rather than a single discrimination. The present experiment was designed to determine the generality of the results obtained in the olfactory experiment. Rats with partial lesions of the FFX and operated controls were tested on a series of 3 Go, No-go spatial discriminations, a reversal of the third discrimination, and 4 subsequent discriminations, in that order. Control rats acquired a learning set in the first 3 discriminations, reaching criterion on the third discrimination in fewer trials than they took on the first discrimination. Their choice accuracy was not significantly affected by the reversal and discrimination performance reached an asymptotic level after the reversal. Rats with FFX lesions also acquired a learning set in the first 3 discriminations, but they consistently took longer than control rats to learn each of the 7 discriminations. These rats were especially impaired on the reversal. These results contrast markedly with those obtained when a similar procedure was used with olfactory discriminations. Identification of the variables responsible for these differences should help distinguish those behaviors that require hippocampal function from those that do not.

Acetylcholinesterase↗
PubMed1980

Malnutrition and behavior: the performance versus learning problem revisited.

At 100 days of age rats, whose dams suffered severe zinc deficiency and/or undernutrition throughout lactation, were tested in two learning tasks. One test was an original discrimination learning task and the other test was a more difficult reverse discrimination learning task. In the reverse learning test, performance differed significantly between rehabilitated malnourished rats and normal rats. Difference in motivation, and not learning ability, was the explanation for the differences in performance between the malnourished and normal rats.

Animals↗
PubMed2000

Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice.

beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.

Age Factors↗