Cognitive profile of rats exposed to lactational hyperphenylalaninemia: Correspondence with human mental retardation

Abstract

The present study was designed to provide further information on the enduring cognitive effects of experimental phenylketonuria (PKU) in rats, produced by the administration of alpha-methylphenylalanine and phenylalanine on postnatal days 3-21. These rats evidenced: (1) impaired learning set formation, (2) stimulus perseveration, particularly after an error, and (3) difficulty in utilizing the less salient features of their environment in mastering discrimination problems. In contrast, long-term memory function and the ability to form simple associations did not differ from controls. This pattern of intact and impaired cognitive functions bears remarkable similarity to that of mentally retarded humans and neonatally hyperphenylalaninemic rhesus monkeys, thus affirming the use of rats to study mental retardation. In addition, possible reasons for the mildness of the impairments commonly observed in animal models of severe mental retardation syndromes are discussed. We suggest that transfer of learning paradigms that assess the animal's ability to use information acquired in other problems are more likely to uncover significant cognitive impairments in such models than are procedures that test only the animals' ability to solve a single problem.

Workshop to identify critical windows of exposure for children's health: neurobehavioral work group summary.

“…Task complexity unmasks various learning deficits (78,79). Cumulative learning tasks that require transfer of training experience appear particularly useful in revealing learning deficits.…”

Brain development and assessing the supply of polyunsaturated fatty acid

“…It is difficult to establish conclusive links between the functional and behavioral effects of nutritional insults when many of the methods for testing behavior cannot be clearly or easily related to human functioning (76). Other methods attempt to correlate the appearance of a behavior with the development of specific indices, such as neurotransmitter systems.…”

A mouse model of fragile X syndrome exhibits heightened arousal and/or emotion following errors or reversal of contingencies

“…The learning set task was included to tap transfer of learning, an area of dysfunction commonly seen in mental retardation (MR) syndromes (Campione & Brown, 1984;Campione, Brown, Ferrara, Jones, & Steinberg, 1985). Learning set tasks have previously revealed cognitive impairment in animal models of MR syndromes (Strupp, Bunsey, Levitsky, & Hamberger, 1994;Strupp, Himmelstein, Bunsey, Levitsky, & Kesler, 1990;, notably including disease models for which basic learning tasks had not revealed dysfunction (reviewed in Strupp & Diamond, 1996;). The reversal learning task was hypothesized to reveal dysfunction in the Fmr1 KO mice for three converging reasons: First, reversal learning taps inhibitory control and adaptability to change, capabilities that are impaired in humans with FXS (Kau, Reider, Payne, Meyer, & Freund, 2000;Rogers, Wehner, & Hagerman, 2001).…”