LEARNING IMPAIRMENT IN TRANSGENIC MICE WITH CENTRAL OVEREXPRESSION OFCORTICOTROPIN-RELEASING FACTOR

The present studies were designed to test the learning and memory capa cities of transgenic mice with central overexpression of corticotropin -releasing factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the sam e training. In Morris maze resting, control subjects reached the subme rged platform significantly faster (F-(1,F-48)=4.51, P < 0.05) after t hree days of trials, while the performance of transgenic mice was unim proved over the same period. The deficit in Morris maze performance in transgenic mice was reversed when the platform was visible above the surface of the water. Pre-test administration of the benzodiazepine an xiolytic, chlordiazepoxide (10 mg/kg), before acquisition training als o produced a significant (F-(4,F-40)=16.61, P < 0.001) and persistent improvement in Morris maze performance in transgenic mice when compare d to vehicle-treated transgenic litter mates. Finally, there was no ev idence of hippocampal cell loss in transgenic brains. These results su ggest that corticotropin-releasing factor-overexpressing mice exhibit a profound learning deficit without sensory or motor-related impairmen ts, and that memory plasticity can be restored by anxiolytic pre-treat ment. Thus, constitutive overabundance of brain corticotropin-releasin g factor may produce hyperemotionality that interferes with learned be haviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of b rain corticotropin-releasing factor systems. Copyright (C) 1996 IBRO. Published by Elsevier Science Ltd.