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S. OAKESHOTT, F. BALCI, R. PORT, J. SUTPHEN, J. BERGER, J. WATSON-JOHNSON, A. M. FARRAR, S. RAMBOZ, L. PARK, D. HOWLAND, D. BRUNNER

Background: In addition to other symptom domains, Huntington’s disease (HD) is also characterized by cognitive disturbances that substantially diminish quality of life for both patients and caregivers. Accordingly, increasing emphasis has been placed on the evaluation of cognitive dysfunction in mouse models of HD, with a number of cognitive assays revealing deficits in the inhibition of inappropriate responding. Objective: The present studies characterized cognitive performance in mouse models of HD using the peak interval timing/response inhibition task. Methods: R6/2 CAG 240 (peak training at 11 weeks of age), zQ175 knock in (KI) HET (peak training at 27 weeks of age) and BAC HD (peak training at 48 weeks of age), as well as respective age-matched wild type (WT) control mice, were trained on the peak interval task (20 s interval) in which response rates during unreinforced peak trials were examined. zQ175 and BAC HD mice were further trained on a version of the task in which a second lever was introduced and reinforced on a FI45 schedule to assess performance on a second interval as well as with both 20 s and 45 s peak trials in the same session. Results: Both R6/2 and zQ175 mice were impaired in their ability to terminate ongoing responding following the interval at which reinforcement was expected. Introduction of a 45 s interval in R6/2 CAG 240 and zQ175 KI HET mice resulted in similar findings, with both mouse lines learning to respond maximally at the 45 s interval, and R6/2 CAG 240 and zQ175 KI HET mice exhibiting impairment in their ability to stop responding after passage of the trained interval. Performance on the more difficult dual peak task in zQ175 KI HET mice resulted in similar findings, with no exaggeration of genotypic differences. In contrast to R6/2 CAG 240 and zQ175 KI HET mice, BAC HD mice showed no deficit in any phase of the task. Conclusion: Our results indicate that two different HD mouse models have a similar deficit in response inhibition when tested on the peak interval task, although this deficit was not apparent in the BAC HD mouse line. These findings will be discussed in the context of consistent data from other cognitive assays measuring deficits in response inhibition.