UCSF

Huntington disease (HD) is a genetic neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and neuropsychiatric symptoms. Assessing early motor skill deficits in HD mouse models is challenging with traditional behavioral tasks. This study uses a home cage-based lever-pulling task, PiPaw2.0, to evaluate motor learning in 6-7 months-old zQ175 knock-in HD mice in a more naturalistic environment. In this task, mice learn to pull a lever for a water reward, with the requirement to hold the lever within a specific goal range for a required hold time. As the mice improved, the required hold time increased, thereby gradually increasing the task demands. Both wild type (WT) and zQ175 mice initially showed similar task engagement, but zQ175 mice had significant deficits in adapting to increasing hold time. The WT mice refined their strategies over time, shifting from random to more precise lever pulls, while zQ175 mice failed to make this adjustment, maintaining erratic performance. Additionally, in group-housing WT mouse lever performance benefited from peer interactions, an effect absent in zQ175 mice. Post-task neural assessments revealed that WT mice developed experience-mediated synaptic plasticity in the left striatum (contralateral to lever-pulling paw), while zQ175 mice showed no significant changes, consistent with known corticostriatal plasticity impairments in HD mouse models. In conclusion, our findings demonstrate the effectiveness of group-housed, home cage-based assessments for evaluating motor learning and adaptation in HD mouse models. This study provides insights into the motor control and adaptive learning deficits in HD, emphasizing the value of automated home cage systems in advancing neurodegenerative disease research and highlighting the importance of peer influences on performance.