Early Alterations of Motor Learning and Corticostriatal Network Activity in a Huntington's Disease Mouse Model

Huntington's disease (HD) is a neurodegenerative disorder that presents motor, cognitive, and psychiatric symptoms as it progresses. Prior to motor symptoms onset, alterations, and dysfunctions in the corticostriatal projections have been described along with cognitive deficits, but the sequence of early alterations of brain circuits is largely unknown. There is thus a crucial need to identify early alterations that precede symptoms and that could be used as potential early disease markers. Using an HD knock-in mouse model (Hdh^CAG140/+) that recapitulates the human genetic alterations and that shows a late and progressive appearance of anatomical and behavioral deficits, we identified early alterations in the motor learning abilities of young mice, long before any motor coordination dysfunctions. In parallel, ex vivo two-photon calcium recordings revealed that young HD mice have altered basal activity patterns in both the dorsomedial and dorsolateral parts of the striatum. In addition, although wild-type mice display specific reorganization of the activity upon motor training, network alterations present in the basal state of non-trained mice are not affected by motor training of HD mice. Our results thus identify early behavioral deficits and network alterations that could serve as early markers of the disease.