People with HD have a demonstrated early extra-dimensional set-shifting deficit. In the present study, we use a novel water T-maze set-shifting procedure and demonstrate its validity as a set-shifting task in a mouse model of Huntington's disease. Three groups of YAC128 mice of different ages (27, 69 and 117 weeks) were run on the task, which incorporated six distinct stages in which the mice must learn a rule and then switch to a different rule. The six stages were: directional learning, directional learning reversal, light discrimination, light discrimination reversal, return to place learning and a maze rotation spatial learning test. Rule changes from place learning to light discrimination and back constitute extra-dimensional shifts. The results of the study demonstrate robust light/dark discrimination reversal learning deficits in transgenic mice from 27 weeks of age, and a directional learning to light discrimination extra-dimensional set-shifting deficit from 69 weeks of age. The extra-dimensional shift deficit was confirmed with control trials demonstrating the validity of the deficit and the task. The onset of reversal learning and extra-dimensional shift deficits corresponded with the development of mutant huntingtin N-terminal fragment aggregates in neurons of relevant forebrain regions.
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