Longitudinal assessment of water-reaching reveals altered cortical activity and fine motor coordination defects in a Huntington Disease model
Bibliographic record
Abstract
Abstract Huntington Disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor and balance defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod, beam walking and gait analysis, little is known about forelimb deficits. Here we use a high-throughput alternating reward/non-reward water-reaching task conducted daily over ∼2 months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wildtype (WT) littermate mice, starting at ∼5.5 months of age. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as WT mice, take longer to learn the alternating event sequence. Although WT 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 ∼7 months of age. HD mice also experienced a progressive reduction in successful performance rates. Tapered beam and rotarod tests before and/or after water-reaching assessment confirmed these early and manifest stages of HD characterized by the absence and presence of failed water-reaching trials, respectively. Reduced DARPP-32 (marker for striatal medium spiny neurons) expression in HD mice further confirmed disease pathology. The water-reaching task can be used to inform HD and potentially other movement disorder onset, 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/non-reward water-reaching task, we characterized early event sequence learning defects 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. These forelimb defects revealed in the water-reaching task are coincident with gross motor defects characterized using the tapered beam and rotarod tasks, demonstrating the suitability of the water-reaching task in phenotyping HD motor deficits.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".