Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's...

Huntington's disease (HD) is a progressive, inherited neurodegenerative disorder characterised by motor, cognitive, and neuropsychiatric dysfunction for which several mouse models have been developed. Knock-in models, such as zQ175, retain the genetic context observed in people with HD by introducing CAG repeats into the native huntingtin gene. In this study, we conducted a comprehensive, longitudinal analysis of phenotypic changes in the zQ175 mouse, with a focus on exploring the emergence of complex cognitive processes. Our findings indicate that robust cognitive and motivational deficits precede motor dysfunction in this model, with some apparent sex differences. Specifically, male zQ175 mice were slower to habituate to a novel environment and they showed impaired sensorimotor gating, in comparison to female mice. By 12 weeks old, cognitive deficits were observed in zQ175 mice of both sexes on a Pavlovian classical conditioning task. Reduced motivation to work for reward was identified as early as 27 weeks, while attentional and visuospatial deficits were also detected in the 5-choice serial reaction time task. Implicit learning deficits were identified at 30 weeks. zQ175 mice were hypoactive at ∼24 weeks but became hyperactive by 60 weeks of age. Motor impairments emerged by 24 weeks for females and 48 weeks for males. Thus, we observed a wide range of cognitive deficits (attentional, visuospatial, sensorimotor, instrumental and implicit learning), as well as a gradual progression of motor changes. This detailed phenotypic timeline establishes the face validity of this model insofar as these mice present with complex neuropsychiatric and cognitive impairments that are evident in people with HD.