Department of Psychiatry, Kinsmen Laboratory of Neurological Research, Detwiller Pavilion, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
eNeuro. 2023 Jan 9;10(1). doi: 10.1523/ENEURO.0452-22.2022. Print 2023 Jan.
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 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.
亨廷顿病（HD）是由 CAG 重复序列的显性遗传扩展引起的，导致特征性运动功能障碍。尽管在多种 HD 小鼠模型中已经使用旋转棒和平衡木行走等任务广泛地描述了粗大运动缺陷，但对前肢缺陷的了解较少。我们开发了一种高通量的交替奖励/非奖励水接触任务和训练方案，每天进行约两个月，以同时监测 GCaMP 活动中的前肢损伤和中尺度皮质变化，比较雌性 zQ175（HD）和野生型（WT）同窝小鼠，从大约 5.5 个月开始。水接触任务的行为分析表明，HD 小鼠尽管像野生型小鼠一样熟练地学习水接触任务，但学习交替事件序列的速度较慢，表现为冲动（无提示）的接触，并且最初显示与成功接触相关的皮质活动减少。在这个年龄，通过锥形梁评估确定的粗大运动缺陷并不明显。尽管野生型小鼠在整个测试期间的皮质活动和接触轨迹没有明显变化，但 HD 小鼠随着时间的推移表现出皮质活动的增加，特别是在次级运动和后扣带回皮质中，并且大约七个月后，接触轨迹变长且更可变。HD 小鼠也经历了成功表现的逐渐减少。锥形梁和旋转棒测试以及水接触评估后 DARPP-32 表达减少（纹状体中间神经元标志物）证实了 HD 病理学。水接触任务可以每天使用，告知 HD 和其他运动障碍的发病和表现、治疗干预窗口，并测试药物疗效。
