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A. KUDWA, J. TORELLO, J. FITZPATRIC, S. MILLER, R. MUSHLIN, L. PARK , D. HOWLAND, S. RAMBOZ, L. MENALLED

The BAC (Bacterial Artificial Chromosome) mouse model of Huntington’s disease expresses the full length human htt transgene and has been well-characterized for its progressively impaired motor function. Cognitive deficits also characterize both human Huntington’s patients and several mouse models of the disease. Much effort has gone into assessing cognitive deficits in the BAC mouse model, but not all studies have revealed robust cognitive deficits in this line. In the present study, we tested 2 independent cohorts of 18-month old BAC mice (FVBNxC57Bl/6) in an operant touchscreen assay. Following an initial period of instrumental training, BAC WT and BAC MT mice were tested for their ability to discriminate 2 complex visual stimuli (discrimination phase), where nosepokes to the correct touchscreen stimulus were rewarded by delivery of a sweetened 14 mg food pellet reward, and nosepokes to the incorrect touchscreen stimulus resulted in a brief blackout period where the screens became inoperative, followed by correction trials until the correct response was made. Following this discrimination phase of testing, the prior contingencies were reversed (reversal phase) and the previously incorrect stimulus became the correct stimulus. In a subsequent third phase of testing (new stimulus phase), 2 novel stimuli were introduced and mice were asked to undergo a second round of discrimination testing with these stimuli. In all cases, mice were expected to reach a criterion of 70% correct choices over multiple days prior to entering the next phase of touchscreen testing. Our results showed that, in two independently-tested cohorts of BAC mice, learning during the discrimination phase was similar between the BAC WT and MT genotypes; however significant deficits were exhibited in both the reversal and new stimulus phases of testing. The relative specificity of this cognitive deficit points to an issue of cognitive inflexibility in the BAC model, which would be consistent with deficits characteristic of Huntington’s Disease in humans. We propose that the touchscreen assay may be a useful test for exploring potential therapeutic effects on impaired cognitive function in this line. This work was funded by the CHDI Foundation.