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/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 StatementThe 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.

Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington’s disease mouse model

“…Moreover, only at this age, decreased pericyte count was present in the S1Ctx and a trend of decrease in the CPu at this age. It can be inferred that loss of pericytes in these regions can be a transitory change, coinciding with the phenotypic conversion in this model, that is being compensated for after initial abnormalities occur 26,58 . Interestingly, these regions show consistent hyper(de)activations in QPPs.…”

“…Remarkably, the RspCtx also showed a premature peak of either activation or deactivation in both long QPPs, indicating that there is an asynchronous peak in the BOLD activity that leads to altered time-locked relationships with other regions. A recent study in zQ175DN mice of the same age reported altered mesoscale cortical activity in the RspCtx during a behavioral task where they report that initial behavioral deficits occur at this age, suggesting a potential role of the RspCtx in phenoconversion in this model 58 . The overall diminished DMLN activity at 10 months also led to a breakdown of the LCN DMLN state flux reflected in the lack of presence of the LCN DMLN QPP in the zQ175DN HET group, alongside the decreased occurrence of DMLN.…”

“…This marked decrease in activation in the DMLN QPP was also seen in the reduced occurrence of this pattern in the zQ175DN HET mice.Remarkably, the RspCtx also showed a premature peak of either activation or deactivation in both long QPPs, indicating that there is an asynchronous peak in the BOLD activity that leads to altered time-locked relationships with other regions. A recent study in zQ175DN mice of the same age reported altered mesoscale cortical activity in the RspCtx during a behavioral task where they report that initial behavioral deficits occur at this age, suggesting a potential role of the RspCtx in phenoconversion in this model58 . The overall diminished DMLN activity at 10…”

Cortical network and projection neuron types that articulate serial order in a skilled motor behavior

“…Here, through an unbiased areal screen with PN type resolution, we have identified a dynamic cortical network that correlates with the sequential forelimb and orofacial movements that compose RGD. Compared with most previous wide-field imaging studies in the mouse 39,40,76–79 , two design features of our study enabled mapping this network. First, the 4 driver lines that target major PN types, in addition to the pan-PN Emx1 line, allowed us to resolve PN-characteristic areal activity patterns that were masked in the broad population signal.…”

Wide-field imaging in behaving mice as a tool to study cognitive function

“…Recent studies have used wide-field calcium or voltage imaging to study mesoscale dynamics in mouse models for Huntington disease (HD 88 , 89 ). Sepers et al.…”