A dystonia mouse model with motor and sequencing deficits paralleling human disease.
A dystonia mouse model with motor and sequencing deficits paralleling human disease.
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DOI：
10.1016/j.bbr.2022.113844
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发表时间：
2022-05-24
影响因子：
2.7
通讯作者：
Leventhal, Daniel K.
中科院分区：
文献类型：
--
作者：
Kernodle, Krista;Bakerian, Allison M.;Cropsey, Allison;Dauer, William T.;Leventhal, Daniel K.
肌张力障碍是一组以不自主扭转运动和姿势为特征的运动障碍。缺乏明确的肌张力障碍行为模型阻碍了对引起该疾病的回路异常的识别。大多数小鼠行为测定都是独立于皮质进行的，但皮质功能障碍与人类肌张力障碍有关。因此，识别肌张力障碍模型非常重要，在该模型中，运动皮层依赖性行为以与人类疾病相关的方式发生改变。本研究的目的是表征最近开发的 DYT1 肌张力障碍 Dlx-CKO 小鼠模型的皮质依赖性行为。小鼠执行两项任务：熟练的伸手和水诱导的梳理。这些测试评估运动学习、灵巧技能和先天运动排序。此外，熟练的伸手动作很大程度上取决于运动皮层，而背侧纹状体对于正常梳理毛发至关重要。与对照小鼠相比，Dlx-CKO 小鼠在熟练到达过程中表现出显着较低的成功率和颗粒接触。尽管 Dlx-CKO 小鼠在熟练的伸手能力方面存在障碍，但仍会调整其伸手策略。通过训练，他们能够更一致地联系目标。 Dlx-CKO 小鼠的梳理行为比对照小鼠更加混乱，非链式梳理比例较高就证明了这一点。然而，当 Dlx-CKO 小鼠参与句法链时，它们的执行方式与对照小鼠类似。这些异常可能为临床前干预试验提供目标，并有助于确定从torsinA功能障碍到运动表型的生理路径。
The dystonias are a group of movement disorders characterized by involuntary twisting movements and postures. A lack of well characterized behavioral models of dystonia has impeded identification of circuit abnormalities giving rise to the disease. Most mouse behavioral assays are implemented independently of cortex, but cortical dysfunction is implicated in human dystonia. It is therefore important to identify dystonia models in which motor cortex-dependent behaviors are altered in ways relevant to human disease. The goal of this study was to characterize a cortically-dependent behavior in the recently-developed Dlx-CKO mouse model of DYT1 dystonia. Mice performed two tasks: skilled reaching and water-elicited grooming. These tests assess motor learning, dexterous skill, and innate motor sequencing. Furthermore, skilled reaching depends strongly on motor cortex, while dorsal striatum is critical for normal grooming. Dlx-CKO mice exhibited significantly lower success rates and pellet contacts compared to control mice during skilled reaching. Despite the skilled reaching impairments, Dlx-CKO mice adapt their reaching strategies. With training, they more consistently contacted the target. Grooming patterns of Dlx-CKO mice are more disorganized than in control mice, as evidenced by a higher proportion of non-chain grooming. However, when Dlx-CKO mice engage in syntactic chains, they execute them similarly to control mice. These abnormalities may provide targets for preclinical intervention trials, as well as facilitate determination of the physiologic path from torsinA dysfunction to motor phenotype.
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