Development of an Animal Model of Task Specific Dystonia

任务特异性肌张力障碍动物模型的开发

• 批准号: 10073691
• 负责人: WILLIAM T. DAUER
• 金额: $ 46.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2020-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10073691
• 关键词: Development; Animal; Model; Task; Specific

ABSTRACT The circuit mechanisms that cause dystonia are poorly understood. A prominent hypothesis is that dystonia is caused by aberrant plasticity within motor structures, especially cortical-basal ganglia circuits. The lack of a suitable animal model is a critical barrier to progress. Our preliminary data indicate that we have developed a strategy to generate the first rodent model of human task specific dystonia by uniquely combining genetic and behavioral manipulations. This strategy is based on observations suggesting that dystonia requires “two hits”: a genetic predisposition to abnormal plasticity and a plasticity-inducing environmental trigger (e.g., repetition of specific dexterous movements as with musician's dystonia). We modeled the genetic predisposition with our established model of DYT1 dystonia, caused by inherited mutation in the gene encoding torsinA. TorsinA mutant “Dlx-CKO” mice do not show abnormal movements at baseline, but exhibit selective abnormalities of striatal cholinergic interneurons (ChIs), providing a substrate for striatal and perhaps downstream cortical dysfunction. Strikingly, Dlx-CKO mice trained to repetitively perform a dexterous paw reaching task develop abnormal, phasic, dystonic-like movements. In contrast, these mice do not develop abnormal movements after repetitively performing a non-dexterous rotarod task. This proposal will focus on establishing the validity and utility of this long-sought model of dystonia. We hypothesize that abnormal function of ChIs in the setting of repetitive dexterous limb movements causes 1) abnormal basal ganglia output reminiscent of deep brain recordings of human subjects with dystonia, and 2) task-specific dystonic-like movements in Dlx-CKO mice. We will test this hypothesis with three Specific Aims. In Aim 1, we will define the necessary and sufficient behavioral conditions for these mice to develop abnormal movements. In Aim 2, we will examine the electrophysiology of basal ganglia output nuclei as these movements develop, and compare them to recordings from human dystonia patients. In Aim 3, we will manipulate striatal cholinergic interneurons in Dlx-CKO and wild type mice to define the specific role(s) of these neurons in generating abnormal movements. Successful completion of these Aims will establish a unique model of task specific dystonia with high construct, face and predictive validity. This model will exert a powerful impact on the dystonia community by allowing detailed study of network mechanisms in dystonia and suggesting novel therapeutic approaches. More generally, this model will improve understanding of normal interactions between extrapyramidal and pyramidal motor systems, with broad relevance for a range of movement disorders.

摘要 引起肌张力障碍的电路机制知之甚少。一个突出的假设是，肌张力障碍是 由运动结构，特别是皮质-基底神经节回路的异常可塑性引起。缺乏一个 合适的动物模型是进展的关键障碍。我们的初步数据显示， 开发了一种策略，通过独特的组合， 基因和行为操控这种策略是基于观察表明，肌张力障碍需要 “两次命中”：异常可塑性的遗传倾向和可塑性诱导环境触发（例如， 重复特定的灵巧动作，如音乐家的肌张力障碍）。我们对遗传进行了建模 与我们建立的DYT 1肌张力障碍模型（由基因遗传突变引起） 编码扭转A. TorsinA突变“Dlx-CKO”小鼠在基线时不显示异常运动，但表现出 纹状体胆碱能中间神经元（ChIs）的选择性异常，为纹状体， 下游皮质功能障碍令人惊讶的是，Dlx-CKO小鼠训练重复执行灵巧的 爪子到达任务发展异常，阶段性，肌张力障碍样运动。相比之下，这些小鼠没有 在重复执行非灵巧旋转杆任务后出现异常运动。这项建议会 重点是建立这种长期寻求的肌张力障碍模型的有效性和实用性。我们假设 在重复性灵巧肢体运动的情况下，ChIs的异常功能导致1）异常的基础 神经节输出使人想起患有肌张力障碍的人类受试者的深部脑记录，以及2）任务特异性 Dlx-CKO小鼠的张力障碍样运动。我们将用三个具体目标来检验这一假设。目标1： 将定义这些小鼠发展异常运动的必要和足够的行为条件。 在目标2中，我们将检查这些运动发展时基底神经节输出核的电生理学， 并将其与人类肌张力障碍患者的记录进行比较。在目标3中，我们将操纵纹状体胆碱能 Dlx-CKO和野生型小鼠中的中间神经元，以确定这些神经元在产生 异常的动作成功完成这些目标将建立一个独特的任务具体化模型， 肌张力障碍与高结构，面子和预测效度。这一模式将对世界经济产生重大影响。 通过允许详细研究肌张力障碍中的网络机制并提出新的肌张力障碍社区， 治疗方法。更一般地说，这个模型将提高对正常的相互作用的理解， 锥体外系和锥体运动系统，与一系列运动障碍具有广泛的相关性。