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Swimming navigation and structural variations of the infrapyramidal mossy fibers in the hippocampus of the mouse.

The extent of the infrapyramidal mossy fiber projection in CA3 (IIP-MF) at the midseptotemporal level correlates negatively with two-way avoidance learning and positively with performance in the radial maze, both tasks known to be sensitive to hippocampal lesions. If hippocampal structural variations are causing behavioral variations, one must predict positive correlations between the extent of the IIP-MF and performance in swimming navigation. Thus, the authors studied learning and reversal learning of swimming navigation in mice in which the size of the IIP-MF had been randomized by means of systematic crosses and in 2 mouse strains known for differential infrapyramidal projections (C57BL/6 and DBA/2). In 19 random-bred mice (9 male, 10 female), the extent of the IIP-MF showed negative correlations with swimming time after platform reversal (day 4: r = -0.50, P < .03; day 5 r = -0.73, P < .001), but none during acquisition of the task. In addition, statistical analysis suggested an influence of asymmetrically distributed mossy fiber projections during reversal learning. The strain comparison between 18 DBA/2 and 16 C57BL/6 male mice confirmed these results: no strain difference during days 1-3, and a significantly faster swimming time in the strain C57BL/6 (with large IIP-MF) at day 5 (second day of reversal), associated with significantly more crossings of the former platform location during the early phases of reversal learning. This latter measure was also negatively correlated with asymmetry of the IIP-MF in both strains. Finally, variations of the IIP-MF were correlated partially with adjustment of swimming speed that appeared to depend on size and asymmetry of CA4 as well. Thus, natural variations in the size of the IIP-MF distribution, and, perhaps, of CA4, appear to linearly influence processes directly involved in complex spatial learning.

Animals↗

Changes in functional connectivity in orbitofrontal cortex and basolateral amygdala during learning and reversal training.

Interconnections between orbitofrontal cortex (OFC) and basolateral amygdala (ABL) are critical for encoding and using associative information about the motivational significance of stimuli. Previously, we reported that neurons in OFC and ABL fired selectively to cues during odor discrimination learning and reversal training. Here we conducted an analysis of correlated firing in the cell pairs recorded in the previous study. Correlated firing during the intertrial intervals was compared across task phases during different phases of acquisition and reversal learning. Changes in correlated activity during initial learning and subsequent accurate performance on the discrimination problems closely resembled the changes in odor selectivity in OFC and ABL reported earlier. Increased correlated firing was most pronounced in OFC during accurate go, no-go performance in the postcriterion phase of performance, whereas correlated firing in ABL increased primarily during an earlier phase of learning. In contrast, findings during subsequent reversal training diverged from our earlier report in which odor selectivity diminished in OFC and reversed in ABL. When the reinforcement contingencies of the odors were reversed after the rat had learned the original associations, correlated firing further increased significantly in OFC but remained stable in ABL. This evidence that associative encoding increments with reversal learning in OFC suggests that the original associations, although not expressed as stimulus driven activity, may be maintained within the network as new associations are acquired.

Amygdala↗

Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility.

OBJECTIVE: The catechol O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and behavioral phenotypes in schizophrenia. Whether COMT genotype is beneficial may depend on phenotype definition. The authors examined the effects of COMT genotype on a task that distinguishes imitation from reversal learning. They hypothesized that the Val and Met alleles would be associated with deficits in imitation learning and reversal learning, respectively. METHOD: Twenty-six patients with schizophrenia and schizoaffective disorder completed a task requiring alternation between imitation and reversal rules. RESULTS: Met homozygotes showed better acquisition of the imitation rule but greater deficit shifting from imitation to reversal. Val homozygotes had poorer imitation performance and slower reaction times. CONCLUSIONS: The Met allele, by increasing tonic dopamine, may promote cognitive stability but limit cognitive flexibility.

Adult↗

[Effect of dunce and amnesiac genes on signal learning in Drosophila melanogaster: experiments with odors].

The behavior of normal Drosophila and of X-linked olfactory conditioning mutants, dunce and amnesiac, was analyzed using an olfactory search task. Normal (C-S) flies quickly learn and remember which of two odors signals the presence of food and they are capable of retaining this information for at last eight hours. Both dunce and amnesiac mutants are able to learn, whereas mutant dunce do not reach the learning level of wild type C-S flies. Also dunce flies require more than one learning trial for sizeable learning effect. Reversal learning experiments showed that normal C-S flies and amnesiac are able to switch to a new food signal in response to a new experience, while the dunce mutation inhibits the acquisition of new information in reversal learning experiments.

Animals↗

Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency.

The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other approximately 19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).

Animals↗

Prevention of soman-induced cognitive deficits by pretreatment with human butyrylcholinesterase in rats.

This study examined the ability of pretreatment with human serum butyrylcholinesterase (HuBChE) to prevent soman-induced cognitive impairments. Behavioral testing was carried out using the Morris water maze task evaluating learning, memory, and reversal learning processes. Pretreatment with HuBChE significantly prevented the memory and reversal learning impairments induced by soman. A small deficiency in performance was observed only during part of the learning period in HuBChE-treated rats after administration of soman. Results support the contention that pretreatment alone with HuBChE is sufficient to increase survival and to prevent impairment in cognitive functioning following exposure to soman.

Animals↗

Patterns of cognitive decline in aged rhesus monkeys.

Although cognitive decline has been well established as a consequence of aging in non-human primate models, the prevalence or frequency of impairment for specific age ranges has not been described. The first aim of this study was to estimate prevalence of cognitive impairment on each of the six tests of cognitive performance by comparing the performance of early-aged (19-23 years old), advanced-aged (24-28 years old), and oldest-aged (29+ years old) monkeys to that of young adults (< 15 years old). The second aim was to derive a single overall measure of cognitive performance to help classify behavioral function in our aged monkeys. Accordingly, we obtained performance measures for these age groups on six behavioral measures: (1) acquisition of the delayed non-matching-to-sample task (DNMS); (2) performance of the DNMS with a delay of 120 sec; (3) the spatial condition of the delayed recognition span test (DRST); (4) the color condition of the DRST; (5) spatial reversal learning; and (6) object reversal learning. Early-aged monkeys displayed prevalence rates of impairment significantly greater than zero on all tasks except the DRST-color. The highest prevalence of impairment was observed in this age group in a task measuring spatial memory (DRST). Significant trends toward progressively higher impairment rates in advanced-aged and oldest-aged monkeys were observed for DNMS-acquisition, DRST-color and spatial reversal learning tasks. A linear transformation of standardized scores on the six cognitive tests was derived by means of principal components analysis (PCA). The first PCA (PCA1) included data from 30 monkeys with available data on all six measures, and yielded a composite measure which declined linearly with increasing age (r = -0.74). A second PCA (PCA2) was performed on data from 53 monkeys for which three test scores (DNMS-acquisition, DNMS-120s delay, and DRST-spatial condition) were available. The composite score derived from this analysis was highly correlated (r = 0.93) with the composite score from PCA1, suggesting that a score based on only three tests may provide an adequate classification of global cognitive ability.

Aging↗

Low-dose challenge by the NMDA receptor antagonist dizocilpine exacerbates the spatial learning deficit in entorhinal cortex-lesioned rats.

We investigated the effects of a bilateral quinolinic acid lesion of the medial entorhinal cortex (EC) on acquisition of a spatial learning task. During reversal of the same task, we challenged the animals by the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801). Training took postoperatively place in an eight-arm radial maze in which four of eight arms were baited. In the acquisition phase (ten blocks of five trials) of the test, EC-lesioned animals showed a working (WM) and a reference memory (RM) deficit. The WM deficit was prominent at the beginning and fully compensated at the end of the acquisition phase. The RM deficit became more evident during the course of the experiment. In the reversal learning phase (seven blocks of five trials), the formerly unbaited arms were baited and half of the control and lesioned animals were challenged by a low dose of dizocilpine (0.04 mg/kg i.p.) before training. Only lesioned and additionally dizocilpine-treated animals showed a WM deficit that was again compensated and a RM deficit that was stronger at the end of the test. In summary, quinolinic acid lesion of the medial EC induces both WM and RM deficits in rats. The WM deficit is rapidly compensated. Enhancement of these deficits by challenge with dizocilpine in the reversal learning phase suggests that the NMDA receptor system was rendered more sensitive by this type of lesion.

Animals↗

Learning performance varies with brain weight in heterogeneous mouse lines.

Three lines of unselected heterogeneous stocks of mice were tested for learning and activity in active avoidance acquisition and extinction, water-maze discrimination learning and reversal learning, operant discrimination, and passive avoidance acquisition tasks. Ambulation in the open field was also measured. Small to moderate correlations (absolute values of .17 to .42) between brain weight and learning measures were obtained for all tasks except passive avoidance. A moderate correlation between brain weight and activity was found only in the open field (r = .39). Partialing out differences in operant level and body weight and learning performance. When ambulation in the open field was partialed out, however, all correlations between brain weight and learning performance decreased. Previous research has suggested a positive relation between brain weight and learning scores across mammalian orders and species. The results reported here extend this relation to within-species variation in brain size. The results also emphasize the limitations of estimating genetic associations between brain and behavior from comparisons between small numbers of inbred strains or selected lines.

Animals↗

Effects of lateral suprasylvian visual cortex lesions on visual localization, discrimination, and attention in cats.

Experiments were carried out to begin to define the behavioral functions of the lateral suprasylvian (LS) visual area of the cat's cortex. Behavioral tasks were chosen for analysis on the basis of previous suggestions in the literature concerning possible functions of LS cortex and its afferent pathways. These tasks included the ability of cats to orient the head and eyes to a stimulus presented in particular locations in the visual field, the ability to learn successive reversals of a two-choice visual pattern discrimination, and the ability to maintain or shift attention between relevant or irrelevant visual form and brightness cues. Eight cats were trained on each of these tasks. Four of the cats then received bilateral lesions of LS cortex, including the AMLS and PMLS regions, and the remaining 4 cats were used to assess normal retention. The LS cortex lesions had no significant effect upon performance of any of the behaviors tested. Thus, this region of cortex appears to play no essential role in simple brightness, form, and pattern discrimination performance, visual reversal learning, maintaining and shifting visual attention, or orienting the head and eyes to stimuli in the visual field. These results are discussed in relation to previous lesion studies involving large regions of the cat's extrastriate cortex and studies in other species. Possible functions of LS cortex, based upon recent electrophysiological studies, are suggested.

Animals↗

Effects of laterality and sex on cognitive strategy in a water maze place learning task and modification by nicotine and nitric oxide synthase inhibition in rats.

The aim of the present study was to investigate sex differences in learning strategies and to elucidate the mechanisms, which may underlie these differences. In two separate experiments, rats were presented with different strategies that could be employed to learn the position of a platform in a water maze (WM); furthermore, rats received treatments that could influence these strategies. In the first experiment, we demonstrated that the response-learning paradigm can be applied to the WM and can be compared with visually cued learning and reversal learning. Naïve rats of either sex could acquire this protocol relatively easily. On the probe trial, where the rats are presented with a choice between using response versus visually cued learning, initially response learning was preferred, however, during these experiments, laterality emerged as a significant factor and rats trained to turn right had difficulty in reversing the learned pattern to find the platform. The second part of our study evaluated the effects of nicotine and nitric oxide synthase (NOS) inhibition on the aforementioned parameters. Drug treatments impaired acquisition compared to saline treatments and the effect was more pronounced with NOS inhibition. During the probe trial, while NOS inhibition enhanced the right-side bias in both sexes, nicotine treatment had the same effect only in males. In conclusion, naïve rats can acquire place learning using visible cues or response learning; however, there is a right side bias in both sexes and the laterality effect is more pronounced in male rats. In drug-treated animals, while NOS inhibition enhances laterality (right bias) in both sexes similarly, nicotine modifies the cognitive strategy in a sexually dimorphic manner by augmenting the right bias only in male rats.

Animals↗

Experimental evidence for spatial learning in cuttlefish (Sepia officinalis).

Laboratory mazes were used to study spatial-learning capabilities in cuttlefish (Sepia offcinalis), using escape for reinforcement. In preliminary observations, cuttlefish in an artificial pond moved actively around the environment and appeared to learn about features of their environment. In laboratory experiments, cuttlefish exited a simple alley maze more quickly with experience and retained the learned information. Similar improvement was not found in open-field mazes or T mazes, perhaps because of motor problems. Cuttlefish learned to exit a maze that required them to find openings in a vertical wall. The wall maze was modified to an arena, and simultaneous discrimination learning and reversal learning were demonstrated. These experiments indicate that cuttlefish improve performance over serial reversals of a simultaneous, visual-spatial discrimination problem.

Animals↗

Ischemic tolerance to memory impairment associated with hippocampal neuronal damage after transient cerebral ischemia in rats.

When rats were trained preoperatively with a three-panel runway task and were then exposed to 10-min ischemia by the method of 4-vessel occlusion, they showed no increase in the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), having normal retention of memory performance learned before the ischemic insult. Next, we investigated the abilities of ischemic rats to acquire the three-panel runway task and to learn a subsequent reversal task, where the correct panel-gate locations were changed. Rats with 5-min ischemia exhibited performance as good as that of control rats, but rats exposed to 10- and 20-min ischemia showed more errors than control rats during 10 acquisition sessions and 5 subsequent reversal sessions, each of which (consisting of 6 trials) was given once a day. Marked neuronal degeneration was observed in the hippocampal CA1 sector from the rats with 10- and 20-min ischemia. Exposure to sublethal 5-min ischemia followed by 10-min ischemia at a 2-h interval had no effect on either the memory impairment during acquisition and reversal tests or the hippocampal CA1 damage. When rats were exposed to 5-min ischemia 2 days before lethal 10-min ischemia, they showed acquisition and subsequent reversal learning as good as that of control rats. Preconditioning with sublethal 5-min ischemia followed by 2 days of reperfusion also prevented the neuronal destruction of the hippocampal CA1 sector induced by 10-min ischemia. These findings suggest that postischemic hippocampal CA1 neuronal damage does not affect retention of spatial memory acquired before ischemia, but produces a significant impairment of acquisition and subsequent reversal learning. The present results also demonstrate that preconditioning with sublethal ischemia can develop tolerance to subsequent lethal ischemia to prevent the learning impairment related to the hippocampal CA1 neuronal damage.

Analysis of Variance↗

Involvement of the dorsomedial striatum in behavioral flexibility: role of muscarinic cholinergic receptors.

The present experiments determined whether temporary inactivation or blockade of muscarinic cholinergic receptors in the dorsomedial striatum affects acquisition or reversal learning of a response discrimination. Testing occurred in a modified cross-maze across two consecutive sessions. In the acquisition phase, a rat learned to make a turn to the left or to the right for 10 consecutive correct choices. In the reversal learning phase, a rat learned to turn in the opposite direction as required during acquisition for 10 consecutive correct choices. Experiment 1 investigated the effects of the local anesthetic, 2% bupivacaine, infused into the dorsomedial striatum on acquisition and reversal learning. Experiment 2 examined the effects of the muscarinic cholinergic antagonist, scopolamine injected into the dorsomedial striatum on acquisition and reversal learning. Bupivacaine infusions did not impair acquisition, but did impair reversal learning of the response discrimination. Analysis of the errors indicated that the deficit was not due to perseveration of the previously learned strategy, but to an inability to learn the new strategy. Bilateral injections of scopolamine, 1 or 8 microg/side, did not affect acquisition. Infusions of scopolamine at 8 microg, but not 1 microg, produced a reversal learning deficit. The scopolamine-induced deficit resulted from an inability to learn the new strategy. The results suggest that the dorsomedial striatum is important for behavioral flexibility and that activation of muscarinic cholinergic receptors in this region may facilitate the learning of situationally adaptive response patterns.

Acetylcholine↗

Hippocampal mossy fibers and swimming navigation in mice: correlations with size and left-right asymmetries.

Individual differences in the extent of the infrapyramidal mossy fiber projection (IIP-MF) correlate with performance in tasks sensitive to hippocampal lesions, notably two-way avoidance, radial maze learning, and swimming navigation. Previous studies of swimming navigation suggested that the capacity of reversal learning and measures of directionality might also be related to asymmetries in the distribution of the IIP-MF. In order to verify these findings, the authors crossed the Collins High- and Low-lateralized mice (known to differ in mossy fiber morphology and brain asymmetries) and obtained a F2-generation characterized by strong individual differences in these traits. Twenty-three (13 females, 10 males) mice were tested during 3 days for acquisition of swimming navigation (16 trials) toward a central platform, and during two days (12 trials) for their capacity of reversal learning toward a shifted platform. Morphometry of Timm-stained hippocampi revealed several, partially independent correlations: Larger IIP-MF projections were associated with prolonged crossing over the former platform position during the entire reversal learning; larger IIP-MF projections on the left were correlated with more precise crossing of the former platform position during the first 45 seconds of reversal learning; both extent and asymmetry of IIP-MF correlated positively with overnight improvement of reversal learning; the size of the entire mossy fiber projection (CA4, suprapyramidal and IIP-MF) correlated positively with the time spent in the platform quadrant and measures of initial orientation during acquisition of the task; and the mice showed an ipsilateral turning bias (spin) toward the side with the larger mossy fiber projection. The authors conclude that an intact hippocampus mediates differential processes underlying swimming navigation, and that left and right subfields may have differential functions.

Animals↗

Postnatal high-peak blood ethanol concentration and external cue-based discrimination learning and reversal in the preweanling rat: comparison with memory-based discrimination learning.

Postnatal exposure to ethanol that produces high-peak blood ethanol concentrations (HP-BEC) in artificially reared infant rats affects hippocampal neuroanatomy and discrimination learning based on memorial cues from a patterned (single) alternation (PA) schedule in preweanling rats (P. L. Greene, J. L. Diaz-Granados, & A. Amsel, 1992). In the present experiments, discrimination by preweanling rats exposed to ethanol in the same way was tested with nonmemorial, external cues. In this external cue-based discrimination and in its reversal, ethanol-exposed rats were not different from normal or artificially reared controls whether the cues were presented in a PA or random manner, although there was some evidence that the memorial cues from the PA schedule contributed to learning a discrimination based on external cues, suggesting that the deficit reported earlier in ethanol-exposed rats is a memorial deficit and not a general discrimination deficit.

Animals↗