CORTICAL AND STRIATAL CIRCUIT RECRUITMENT DURING A VOLUNTARY MOTOR TASK IN A MOUSE MODEL OF HUNTINGTON'S DISEASE

Voluntary movement requires coordinated corticostriatal signaling, and is affected in Huntington’s Disease (HD). We studied 6-8 month-old zQ175 and WT littermates during a lever-pulling task in automated home-cage and head-fixed contexts. Mice that expressed red calcium indicator jRGECO1a under Thy1 promoter (excitatory neuron-selective, for transcranial widefield cortical Ca²⁺ imaging using an intact-skull cranial window), were also injected with AAV1-iGluSnFR (glutamate sensor) and received an angled optical fiber implant, both targeting dorsal striatum (DS) for photometry. This preparation enabled simultaneous widefield cortical Ca²⁺ imaging and fiber photometry readout of striatal glutamate transients. In the home-cage, zQ175 showed lower success and more overshoot failures in the lever-pull task, indicating impaired refinement of movement and feedback control. Imaging of cortical activity revealed robust primary motor area (Caudal Forelimb Area; CFA) activation in both genotypes after lever-pull onset, but markedly reduced recruitment of secondary motor area (Rostral Forelimb Area;RFA) in zQ175, indicating selective impairment in secondary motor (M2) cortical engagement. Striatal iGluSnFR transients were time-locked with lever-pull and showed similar peak amplitude/latency, but zQ175 showed prolonged decay, consistent with sustained excitatory drive. Whole-cell current clamp recordings of M2 neurons showed no differences in resting potential, rheobase, or frequency-current curves, arguing against altered intrinsic excitability as the basis for reduced RFA/M2 engagement. Collectively, our results point to circuit-level incoordination of corticostriatal signaling in an animal model of HD. Ongoing work will test whether disrupted RFA/M2 connectivity drives abnormal corticostriatal dynamics and if targeted RFA/M2 activation rescues circuit signatures and performance.