Impaired refinement of kinematic variability in Huntington disease mice on an automated home-cage forelimb motor task

Abstract

The effective development of novel therapies in mouse models of neurological disorders relies on behavioural assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioural 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-hours 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 behaviour. Mice improved their performance of this task over one week of testing by reducing inter-trial 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 (<10 minutes) 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, Q175-FDN HD mice were unable to modulate the variability of their movements in order 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 wildtype mice; however, no such changes were observed in Q175-FDN mice. This behavioural screening platform should prove useful for preclinical drug trials towards improved treatments in HD and other neurological disorders.Significance StatementIn order to develop effective therapies for neurological disorders such as Huntington disease (HD), it’s important to be able to accurately and reliably assess the behaviour of mouse models of these conditions. Moreover, these behavioural assessments should provide an accurate readout of underlying neuronal dysfunction and/or degeneration. In this paper, we employed an automated behavioural testing system to assess motor learning in mice within their home-cage. Using this system, we were able to study motor abnormalities in HD mice with an unprecedented level of detail, and identified a specific behavioural deficit associated with an underlying impairment in striatal neuronal plasticity. These results validate the usefulness of this system for assessing behaviour in mouse models of HD and other neurological disorders.

Early Changes in Striatal Activity and Motor Kinematics in a Huntington's Disease Mouse Model

“…By 6 to 7 months, the YAC128 mice showed severe kinematic deficits, including increased paw slip frequency, reduced paw height, and increased variability accompanied by a marked deficit in latency to fall. Impaired motor refinement has been shown in HD models for other tasks, including research from our group showing that 10‐ to 11‐month‐old Q175/FDN HD mice were impaired at learning a forelimb lever‐pulling task 31 . Our manifest YAC128 mice performed worse than expected, 7,8 which could be attributed to the added difficulty of performing the task while tethered by a fiber‐optic patch cord.…”

“…Impaired motor refinement has been shown in HD models for other tasks, including research from our group showing that 10-to 11-month-old Q175/FDN HD mice were impaired at learning a forelimb leverpulling task. 31 Our manifest YAC128 mice performed worse than expected, 7,8 which could be attributed to the added difficulty of performing the task while showing periods of active behavior (green), grooming behavior (blue), and the other periods are rest behavior. Bottom left: Percentage of time spent in the active, grooming, or rest behavior for premanifest and manifest YAC128 and WT littermates (behavior, P < 0.0001).…”

Longitudinal assessment of water-reaching reveals altered cortical activity and fine motor coordination defects in a Huntington Disease model

“…Mice were tested as previously described (Woodard et al, 2021). Briefly, mice were tested for 4 consecutive days on the rotarod (Ugo Basille) accelerated from 5 to 40 RPM over a total time period of 300 s. Mice received 3 trials per day with a 2 hr inter-trial interval (ITI).…”

“…In clinical settings, impairments in reaching and/or skilled hand movements have been observed in HD patients (Klein et al, 2011). Skilled forelimb movement learning and performance also has been examined in HD mice using automated home-cage lever pulling systems (Woodard et al, 2017(Woodard et al, , 2021, demonstrating that HD motor learning deficits are related to impaired striatal neuronal plasticity (Woodard et al, 2021). Given reaching towards a target and manipulating objects is commonly used in our daily lives and the general 'reach-to-grasp' features of forelimb movements has been shown to be similar between humans and rodents (Galiñanes et al, 2018), preclinical behavioral assessment of skilled forelimb reaching tasks could improve our understanding of HD movement defects.…”