Water-Reaching Platform for Longitudinal Assessment of Cortical Activity and Fine Motor Coordination Defects in a Huntington Disease Mouse Model

Abstract

Huntington Disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod and beam walking, less is known about forelimb deficits. We develop a high-throughput alternating reward/non-reward water-reaching task and training protocol conducted daily over ~2 months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wildtype littermate mice, starting at ~5.5 months. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as wildtype mice, take longer to learn the alternating event sequence as evident by impulsive (non-cued) reaches and initially display reduced cortical activity associated with successful reaches. At this age gross motor defects determined by tapered beam assessment were not apparent. Although wildtype mice displayed no significant changes in cortical activity and reaching trajectory throughout the testing period, HD mice exhibited an increase in cortical activity - especially in the secondary motor and retrosplenial cortices - over time, as well as longer and more variable reaching trajectories by ~7 months. HD mice also experienced a progressive reduction in successful performance. Tapered beam and rotarod tests as well as reduced DARPP-32 expression (striatal medium spiny neuron marker) after water-reaching assessment confirmed HD pathology. The water-reaching task can be used to inform on a daily basis, HD and other movement disorder onset and manifestation, therapeutic intervention windows, and test drug efficacy.