Water-Reaching Platform for Longitudinal Assessment of Cortical Activity and Fine Motor Coordination Defects in a Huntington Disease Mouse Model.
Yundi WangMarja D SepersDongsheng XiaoLynn A RaymondTimothy H MurphyPublished in: eNeuro (2023)
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/nonreward water-reaching task and training protocol conducted daily over approximately two months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wild-type (WT) 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 wild-type mice, take longer to learn the alternating event sequence as evident by impulsive (noncued) 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 wild-type 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 approximately seven 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 (MSN) 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. Significance Statement The movement disorder, Huntington disease (HD), has been extensively studied in preclinical settings using mouse models of disease examining gross motor and balance defects. Little however, is known regarding forelimb deficits and underlying cortical circuit changes. Using a high-throughput alternating reward/nonreward water-reaching task, we characterized early event sequence defects as evident by impulsive reaches and reduced cortical activity associated with successful reaches in HD mice aged ∼5.5 months. Progressive forelimb movement defects first become apparent at ∼6.5 months of age with corresponding increases in cortical activity associated with reaching observed over time. The water-reaching task can be used to inform on a daily basis HD disease onset and progression, therapeutic intervention windows and test drug efficacy.
Keyphrases
- wild type
- mouse model
- high throughput
- high fat diet induced
- randomized controlled trial
- multiple sclerosis
- traumatic brain injury
- computed tomography
- magnetic resonance imaging
- poor prognosis
- physical activity
- depressive symptoms
- multidrug resistant
- emergency department
- magnetic resonance
- mesenchymal stem cells
- oxidative stress
- working memory
- parkinson disease
- children with cerebral palsy