Mesoscale Imaging of Cortical Sensorimotor Integration in Huntington’s Disease Mice During Reward-Guided Behaviour

Huntington’s disease (HD) is a neurodegenerative disorder that affects numerous brain functions, yet how altered sensory processing contributes to behavioral and learning deficits remains poorly understood. Previous wide-field mesoscale imaging and electrophysiological recording from anesthetized HD mice revealed that sensory stimulation induced exaggerated, prolonged cortical activity across more brain regions compared to wildtype (WT) littermates. This suggests differences in sensory processing; as such, this study aimed to investigate the cortical activity in a cue-based sensory-guided learning task in a custom-built Raspberry Pi-controlled two-alternative forced choice (2AFC) rig. The rig was designed to enable head-fixed zQ175 knock-in HD mice and WT controls crossed with Thy1-GCaMP6s mice, to perform a cue-based visual discrimination task while mesoscale calcium imaging recorded activity across layer 2/3 of the cortex. Mice that successfully licked the reward spout displayed decreased global cortical activity before the reward presentation, with WT mice showing more spatially localized suppression than HD mice. HD mice exhibited exaggerated cortical responses to visual stimuli and prolonged cortical motor-related activity during licking. While this is an exploratory pilot study with limited sample size, preventing definitive genotype-based comparisons, the custom behavioral system lays the ground-work for future studies into how sensory processing deficits contribute to cognitive impairments in HD. This work provides an important step toward understanding the interplay between cortical circuit dysfunction and behavioral outcomes in HD, offering a novel platform to investigate early sensorimotor integration learning impairments.