Impaired Refinement of Kinematic Variability in Huntington Disease Mice on an Automated Home Cage Forelimb Motor Task

The effective development of novel therapies in mouse models of neurologic disorders relies on behavioral assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioral testing system (PiPaw), which integrates an operant lever-pulling task directly into the mouse home cage. This task is accessible to group housed mice 24 h per day, enabling high-throughput longitudinal analysis of forelimb motor learning. Moreover, this design eliminates the need for exposure to novel environments and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behavior. Male mice improved their performance of this task over 1 week of testing by reducing intertrial variability of reward-related kinematic parameters (pull amplitude or peak velocity). In addition, mice displayed short-term improvements in reward rate, and a concomitant decrease in movement variability, over the course of brief bouts of task engagement. We used this system to assess motor learning in mouse models of the inherited neurodegenerative disorder, Huntington disease (HD). Despite having no baseline differences in task performance, male Q175-FDN HD mice were unable to modulate the variability of their movements to increase reward on either short or long timescales. Task training was associated with a decrease in the amplitude of spontaneous excitatory activity recorded from striatal medium spiny neurons in the hemisphere contralateral to the trained forelimb in WT mice; however, no such changes were observed in Q175-FDN mice. This behavioral screening platform should prove useful for preclinical drug trials toward improved treatments in HD and other neurologic disorders.

Automated summary

The development of novel therapies in mouse models of neurologic disorders relies on accurate behavioral assessments. An automated behavioral testing system (PiPaw) was designed to enable high-throughput longitudinal analysis of forelimb motor learning in group housed mice 24 h per day, reducing stressors associated with animal behavior. Male mice improved performance in a lever-pulling task over time, with differences observed in reward-related kinematic parameters and movement variability. This system was used to assess motor learning in mouse models of Huntington disease, with potential for preclinical drug trials in neurologic disorders.