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Branched chain amino acids improve radial-arm maze acquisition and water maze forced-choice learning in rat offspring exposed in utero to hyperphenylalaninemia.

Maternal phenylketonuria results in a high incidence of children born mentally retarded. We showed that the large neutral amino acids valine, isoleucine, and leucine (VIL) ameliorate the effects of intrauterine hyperphenylalaninemia in rats on a test of complex maze learning. To further test the ameliorative effects of VIL on intrauterine CNS development during hyperphenylalaninemia, gravid rats were administered a phenylalanine/p-chlorophenylalanine (index group) supplemented diet with or without VIL added. Controls were given standard diet with or without VIL. All groups were pair-fed to the index group. As adults, the progeny exposed in utero to hyperphenylalaninemia showed characteristic learning impairments in a complex water (Cincinnati) maze on forced and elective-choice phases of the task and deficits in radial-arm maze and Morris maze acquisition, whereas those exposed to hyperphenylalaninemia combined with VIL showed no deficits in the forced-choice phase of Cincinnati maze learning and no evidence of radial-arm maze deficits. However, the improvement was not complete, with no ameliorative effects obtained on the elective-choice phase of the Cincinnati maze or on the Morris hidden platform test. No deficits were seen on phases containing test trials for memory function (Olton and Morris mazes). The acquisition differences occurred in the absence of any effects of VIL on maternal weight gain during gestation, maternal serum amino acid concentrations of phenylalanine or tyrosine, or effects on offspring growth. VIL alone produced no adverse or enhancing effects on learning or memory. Based on these data it was concluded that the VIL supplement continues to show promise as a potential treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.

Amino Acids, Branched-Chain↗

Interlaboratory comparison of behavioral testing.

New requirements by several regulatory agencies for testing the psychotoxic potential of new drugs, chemicals, and environmental contaminants raise unique problems. In order to assess intra- and interlaboratory reliability of behavioral tests a model animal maze learning procedure was designed and run in 3 cooperating laboratories. Uniform procedures were written and identical mazes were constructed. Normal control animals of identical age and sex, but of different strains, were used by the participants. A positive control group of neurologically impaired rats was run by one laboratory. Significant differences in test results among the laboratories were found. Data obtained from the positive control animals (mean errors=28.3) indicated a learning impairment statistically significant compared to the negative control data (mean errors=12.7) from any of the participating laboratories. Based on the results of this study, a reasonable standard of interlaboratory reliability in behavioral testing appears an attainable goal.

Animals↗

Baseline performance and learning rate of procedural and declarative memory tasks: younger versus older adults.

Twenty-five older and 25 younger adults were compared on declarative (i.e., Rey Auditory-Verbal Learning Test and Visual Pair Associations) and procedural (i.e., Tower of Hanoi puzzle and Porteus mazes) learning tasks. A dissociation between learning rate on declarative and procedural tasks was demonstrated for the elderly participants. The younger group showed a steeper learning rate than the older group on the declarative tasks. By contrast, the learning rate of both groups on the procedural tasks did not differ consistently, whether the measure was number of errors/moves or time elapsed (with one exception in which the older group showed a steeper learning rate than the younger group). The younger group's baseline performance was better than that of the older group on all tasks employed in this study. These results reinforce the importance of distinguishing between baseline performance and the rate of learning on procedural learning tasks.

Adult↗

Modulation of learning processes by ionotropic glutamate receptor ligands.

A great body of evidence has been provided for the role of N-methyl-d-aspartate (NMDA) receptors in learning processes, since the pioneering work of Morris et al. (1986) showing impairment of water maze learning and long-term potentiation (LTP) during i.c.v. infusion of the NMDA receptor antagonst 2-amino-5-phosphonovaleric acid (AP5). The existing literature, based on pharmacological studies, suggests the importance of NMDA receptors for the acquisition and/or the initial phase of long-term memory consolidation in many, but not all, learning paradigms. Data on short-term memory are inconsistent, probably due to difficulties in separation of learning deficits from performance. Although it is generally accepted that NMDA receptor antagonists impair learning, more recent data suggest that, under certain conditions, the opposite effect, enhancement of learning, can be obtained. The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in learning, although accepted in LTP, is less well documented. It has been suggested that positive modulation of these receptors could result in cognitive enhancement that might find therapeutic application. The present paper reviews the literature dealing with these issues and discusses possible consequences for the therapy of dementia.

Journal Article↗

Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat.

Prenatal cocaine exposure in humans is associated with a variety of adverse neurobehavioral effects. In the rat, in utero cocaine exposure has been shown to elicit learning impairment during early postnatal development. However, little research has focused on the persistence of these behavioral disruptions. The current study examines the long-term effects of prenatal cocaine exposure on learning performance during young adulthood. Fetal cocaine exposure evoked differential effects in male and female rats on radial-arm maze learning performance. Cocaine-treated females showed significantly impaired choice accuracy during acquisition of radial-arm maze performance when compared to control females. In contrast, cocaine-treated males showed no impairment and in fact showed significantly improved performance on one measure of choice accuracy. For both sexes, this effect was apparent during the final third of acquisition. No evidence was found to suggest altered sensitivity to anticholinergic drugs. While both nicotinic and muscarinic cholinergic antagonists caused significant impairments in memory performance, control and cocaine-exposed rats were effected equally. Single doses of these drugs which caused moderate memory deficits were chosen for use in the current study. The entire dose range should be evaluated to determine the relative sensitivity of cocaine-exposed and control animals to these drugs. The results of this study indicate that there are cognitive effects of prenatal cocaine exposure which persist into adulthood and the sex of the offspring seems to be critical.

Animals↗

The pattern of intact and impaired memory functions in autism.

A battery of tests of auditory and visual memory was used to investigate memory function in 52 high-functioning adolescents and young adults with autism and 40 group-matched normal controls. It was hypothesized that memory dysfunction is present in autism but is not modality specific and is produced by poor utilization of organizing strategies. It was therefore hypothesized that memory impairment in autism would become more prominent as task complexity was increased. The participants with autism performed as well as controls on short-term memory and paired-associate learning tasks, but performed significantly less well than controls on a list learning task. They also performed significantly more poorly on immediate and delayed recall of a story and of a complex geometric figure. On a maze learning task, their performance became progressively worse relative to controls as the complexity of the maze increased. On a series of span tasks, they did not differ from controls on letter span, but did significantly worse on word span and sentences of increasing complexity. These findings indicate a lack of modality specificity and a failure to initiate organizing strategies as evidenced by inefficiency in new learning, poor utilization of contextual cues in story and complex pattern recall, and greater impairment with increasing complexity of the material.

Adolescent↗

Age-related differences in behavior across the life span of the C57BL/6J mouse.

C57Bl/6J mice, representing four divergent age groups (ranging from 3 months to 31 months) were each tested on a number of behavioral procedures, selected to sample a wide spectrum of behaviors. The evaluation demonstrated that, as with other mammalian species, not all behaviors in the mouse are affected by old age. Most severely impaired was retention of a single-trial passive avoidance task, most probably reflecting a deficit in memory ability. One tests of motor function, the most demanding tasks revealed the greatest debilitating effects of age, paralleling the effects of task difficulty previously reported in numerous learning studies. Finally, a deficit in the ability to modify preexisting habits in a T-maze learning situation was observed, corroborating reports of increased perseveration in aged humans and nonhuman primates. The similarity of these results across the life span of the C57 mouse with those previously reported for other aged mammalian species demonstrates that certain common types of behaviors seem to be impaired selectively by increased age across mammalian species and raises the possibility that common neurological etiologies may exist for these behavioral deficits.

Aging↗

Learning in young alcoholics.

A group of young male alcoholics with a mean age of 26.7 years performed less well than matched controls on a test of complex maze learning. The relatively short period of time during which these alcoholics had been drinking to excess (M = 5.7 years) suggests that acquired deficits may appear earlier in the drinking history of many alcoholics than has been previously assumed. Data from the maze was analyzed by modelling each individuals' cumulative error scores with a two-parameter hyperbolic function. The model provided an excellent fit to individual data and group differences were observed in both parameters of the model. It is concluded that curve fitting provides an efficient method for representing individual performance on a multitrial learning task.

Adult↗

Delayed matching-to-sample performance by rats in a new avoidance-motivated maze: response to scopolamine and fimbria-fornix lesions.

A new avoidance-motivated detour-maze in which memory for an immediately preceding sample event could be assessed was evaluated by testing seven 6-month-old male F-344 rats with a delayed matching-to-sample (DMTS) paradigm. Rats first received extensive pretraining with this paradigm over several months and after a minimum of 1,390 choice-trials demonstrated great proficiency in this maze. Studies were then conducted to establish cholinergic and hippocampal involvement in the DMTS task by using drug manipulations (scopolamine and physostigmine), and after lesions to the fimbria-fornix (FF) pathway. A high dose (1.0 mg/kg) of scopolamine but not a low dose (0.3 mg/kg) significantly interfered with choice accuracy as measured by errors and trials to criterion; physostigmine (0.01 and 0.03 mg/kg) had no significant effect; and fimbria lesions significantly disrupted both choice accuracy and runtime performance. Disruption was most pronounced on difficult problems (different paths to the goal). After lesions only, considerable within-trial perseverative errors occurred during the early postlesion weeks on four difficult problems from among the 18 tested. Results were discussed in terms of (a) specificity of this disruption, (b) indications of proactive interference effects, and (c) the movement-related excitation component of maze learning. The present results accord with earlier findings of disruption by scopolamine and FF lesions in a 14-unit T-maze, both mazes having similar performance requirements of shock avoidance and multiple 90-degree turns along the paths to the goal. The present results affirm that this new detour maze provides a viable approach for assessing cognitive performance in a within-subject design and thereby offers new possibilities for testing various aspects of cognitive processing, particularly for aged rodent models, in a complex aversive situation.

Aging↗

Inter-session delay and its effects on performance and retention of spatial learning on a radial maze with mice.

Spatial learning on the radial maze was studied in two inbred strains of mice (C57BL/6 and DBA/2). Five different periods of delay (no delay, 40 min, 2, 8, and 24 h) were inserted between sessions in order to analyze the role of this inter-session delay on training and on retest 1 month later. Results showed that learning profiles and performance levels varied widely with inter-session delay. When the delay was very short (no delay and 40 min), mice of both strains were incapable of learning the task but when the delay was more than or equal to 2 h, the mice succeeded very quickly. The inter-session delay also influenced the performance of mice in the 1-month retention test. C57BL/6 mice obtained good performances in the procedure including a 2-h inter-session delay, while DBA/2 mice obtained good performances with 2- and 8-h delays. These results demonstrate the importance of the procedure in complex spatial learning.

Animals↗

Effects of noradrenergic DSP4 lesion on the effectiveness of pilocarpine in reversing scopolamine-induced amnesia.

We studied the effectiveness of pilocarpine in reversing the scopolamine-induced water maze learning deficit (increase in escape latencies, decrease in spatial bias) in control and DSP4- (a noradrenergic neurotoxin) lesioned rats. The water maze acquisition deficit (escape latency, first spatial bias) induced by scopolamine 0.8 mg/kg was augmented by DSP4 treatment. The water maze performance deficit induced by scopolamine was reversed by pilocarpine 4 mg/kg in both DSP4-lesioned and control rats. A smaller dose of pilocarpine (1 mg/kg) did not reverse scopolamine-induced acquisition deficit in either control or DSP4-lesioned rats. Analysis of the second spatial bias test measured 2 weeks after training revealed that pilocarpine 4 mg/kg reversed scopolamine-induced retention deficit in control and DSP4-lesioned rats. Pilocarpine 1 mg/kg reversed scopolamine-induced retention performance deficit during the second spatial bias test in control but not in DSP4-lesioned rats. The present results suggest that 1) noradrenergic and cholinergic systems may interact in the regulation of spatial acquisition and retention and 2) the effectiveness of cholinergic drugs in reversing scopolamine-induced spatial retention deficit may be affected by noradrenergic lesioning.

Amnesia↗

Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention.

The memory-enhancing potential of D-cycloserine (cycloserine) a partial agonist at the glycine recognition site on the NMDA receptor, was evaluated in mice using a thirst-motivated linear maze learning task. Immediate acute post-training injections (10, 20 and 80 mg/kg) significantly improved retention relative to vehicle-injected controls. Retention was also facilitated if cycloserine (3 and 10 mg/kg but not 20 or 40 mg/kg) was administered 20 min before the retention test. Acquisition of the habit was accelerated if cycloserine (3 mg/kg) was injected 20 min before the training session. Acute post-training injections failed to facilitate retention if mice were pretreated with cycloserine (3 mg/kg) b.i.d. for 15 days before training on the maze. These results indicate that acute cycloserine administration can enhance consolidation and retrieval of memory but that desensitization may occur with chronic exposure to the drug.

Analysis of Variance↗

Tolman and Tryon. Early research on the inheritance of the ability to learn.

Few psychologists today are aware of the seminal role played by learning theorist Edward C. Tolman in the early development of the field of behavior genetics. Tolman was the first to publish a study of selective breeding for maze-learning ability in rats. He continued to foster research in this field by supporting the work of his students, particularly Robert C. Tryon. Tryon carried out the first major long-term study of maze-bright and maze-dull rats. This article focuses on Tolman's early years at Berkeley and the events culminating in the inheritance project, as well as on the evolution of this research under Tryon's direction.

Animals↗

Cerebral embolization leads to memory impairment of several learning tasks in rats.

The effects of cerebral embolization, produced by injecting microspheres into the left internal carotid artery, on passive and active avoidance tasks and water filled multiple T-maze task, were studied in male Wistar rats. The rats with cerebral embolization were markedly impaired acquisition and retention of the one-trial passive avoidance response. The impairment depended on the number of microspheres injected and continued for 2 weeks. The cerebral embolized rats were also impaired acquisition of two-way active avoidance response in a shuttle box. These impairments are not due to decrease in shock sensitivity, because there was no significant change in the flinch-jump threshold. The embolized rats also exhibited a significant disturbance in performance of water filled multiple T-maze learning. These results suggest that rats with cerebral embolization are impaired in three different types of learning tasks, and may be useful as an animal model for the vascular type of dementia.

Animals↗

Effects of forced-choice runway variations on rats' T-maze serial pattern learning.

Rats learned an ordered RNR/RNN serial pattern task in a T-maze where they were shifted to a different runway on Trial 3 only in the RNR series (shift-win/stay-lose group) or only in the RNN series (stay-win/shift-lose group). The shift-win/stay-lose group developed faster speeds on Trial 3 of the RNR than on Trial 3 of the RNN series more easily than the stay-win/shift-lose group. This difference occurred whether all rats were forced onto the same runway on the first two trials (Experiment 1) or onto a different runway on Trial 2 from that on Trial 1 in each series (Experiment 2). Posttraining probe tests revealed that the shift-win/stay-lose group in each experiment relied on the runway shift event in Trial 3 or on the series position to anticipate the second reward within a series. Such reward expectancies were greater when the runway shift occurred in the same series position as during training. These probe tests revealed that the stay-win/shift-lose group relied only on the series position in Experiment 2. Our findings do not support predictions based on an associative predictive validity model. Rather, they reflect rats' predisposition to spontaneously alternate choices in the T-maze, a tendency corresponding to their inherent win-shift foraging strategy. Rats in each group also reduced their speeds less on the nonrewarded Trial 2 when it preceded a rewarded rather than a nonrewarded Trial 3. This effect suggests that rats were able to determine which series contained a second rewarded trial. We discuss the theoretical implications of this Trial 2 speed effect in terms of rats' uncertainty about where this second rewarded trial might occur in the RNR series.

Animals↗

Differential vulnerability of male and female rats to the timing of various perinatal insults.

The results of five experiments showed that exposure to diazepam, hypoxia and monosodium glutamate during the prenatal or early postnatal period of rapid brain development may result in different behavioral consequences depending on the timing of the exposure rather than the nature of the agent. Moreover, male and female offspring may be affected differently by the same agent at different periods of development. Prenatal insults of various kinds impair the later performance of males but not the females in a complex learning task, while postnatal insults seem to affect detrimentally this same behavior in both males and females. The effects of perinatal insults on maze learning and open field activity do not lend themselves to explanation by "feminization" or "masculinization" of behavior caused by interference with prenatal gonadal hormones.

Animals↗

Graft-induced learning impairment despite graft-enhanced cholinergic functions in the hippocampus of rats with septohippocampal lesions.

Effects of aspirative fimbria-fornix lesions and intrahippocampal grafts of fetal septal-diagonal band or hippocampal tissue were examined, in Long Evans female rats, on spontaneous alternation, radial maze learning, hippocampal acetylcholine concentrations and [3H]choline accumulation by hippocampal slices. Septohippocampal damage decreased all of these variables. Septal-diagonal band grafts increased hippocampal acetylcholine levels as well as [3H]choline accumulation of tissue (when incubated for 45 min), but they had no effect on alternation rates and further impaired radial maze performances. No such behavioral and neurochemical effects were observed in rats with hippocampal grafts. Our data suggest that factors other than graft-induced improvement of cholinergic functions in the denervated hippocampus may be involved in the expression of behavioral effects by intrahippocampal acetylcholine-rich grafts.

Acetylcholine↗