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Abstract

Voluntary movement arises from coordinated computations across cortical and subcortical circuits. Huntington’s disease (HD) perturbs these processes early, yet how cortical dynamics and striatal neurotransmission jointly change during action remains unresolved. This thesis integrates automated home-cage behavior, chronic mesoscale cortical imaging, and subcortical fiber photometry to define circuit mechanisms underlying impaired motor refinement in early-manifest zQ175DN knock-in mice (~6–8 months). In Chapter 2, I established an automated, forelimb lever-pull task that required maintaining the lever within a goal range for a required hold time that increased with performance. Wild-type (WT) and zQ175 mice showed comparable initial engagement. However, as task demands increased, zQ175 mice exhibited marked difficulty adapting to longer hold times. WT animals progressively refined their strategy, shifting from variable to precise pulls, while zQ175 mice maintained erratic performance. Ex vivo, experience-dependent plasticity in contralateral dorsolateral striatum (DLS), present in WT, was absent in zQ175, indicating early disruption of motor learning-relevant corticostriatal circuits in HD. Chapter 3 details the development and validation of a chronic, multiscale platform combining widefield Ca²⁺ imaging of dorsal cortex with striatal fiber photometry. The method yielded stable, concurrent measurements over weeks and supported repeated recordings during behavior. Using this platform, in Chapter 4 I examined motor execution in a lever-pull paradigm with home-cage pretraining and head-fixed recordings. In the home cage, WT mice improved over days, while zQ175 mice maintained lower success with minimal improvement. Under head fixation, primary sensorimotor cortex exhibited robust, lever pull-aligned activity in both genotypes, whereas secondary motor cortex (rostral forelimb area, M2/RFA) was selectively under-recruited in zQ175. In dorsal striatum, glutamate transients (fiber photometry) were time-locked with similar peak amplitude and latency across genotypes but decayed more slowly in zQ175. Collectively, these findings define an early-manifest phenotype with preserved movement initiation but impaired refinement under higher accuracy demands. Mechanistically, selective M2/RFA under-recruitment together with prolonged striatal glutamate signaling likely degrade feedback-based control and experience-dependent tuning while sparing basic motor drive. These systems-level insights identify concrete targets for mechanistic dissection and for translational strategies to stabilize network function early in HD.