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 导致肌张力障碍的回路机制还知之甚少。一个突出的假设是肌张力障碍是 由运动结构内异常的可塑性引起，尤其是皮质-基底节环路。缺乏一种 合适的动物模型是取得进展的关键障碍。我们的初步数据显示，我们有 开发了一种策略来生成人类任务种类的fi第一啮齿动物模型fic肌张力障碍通过唯一地结合 基因和行为操控。这一策略是基于观察表明肌张力障碍需要 两个命中：对异常可塑性的遗传易感性和诱发可塑性的环境触发(例如， 重复特殊的fic灵活动作，如音乐家的肌张力障碍)。我们模拟了基因 我们已建立的DYT1肌张力障碍模型的易感性，由基因的遗传突变引起 编码TorsinA。TorsinA突变“DLX-CKO”小鼠在基线时没有表现出异常运动，但表现出 纹状体胆碱能中间神经元(CHI)的选择性异常，为纹状体和可能 下游皮质功能障碍。令人惊讶的是，DLX-CKO小鼠被训练成重复地执行灵巧的 伸爪任务会出现异常的、阶段性的、强直性运动。相比之下，这些小鼠则不会 在重复执行非灵巧的旋转机器人任务后，出现异常动作。这项提议将 重点是建立这一长期寻求的肌张力障碍模型的有效性和实用性。我们假设 重复灵巧肢体运动环境中CHIS功能异常导致1)基础异常 神经节输出让人想起患有肌张力障碍的受试者的脑深部记录，以及2)特定于任务的 DLX-CKO小鼠的肌张力障碍样运动。我们将用三个特定的fic目标来检验这一假设。在目标1中，我们 是否会为这些小鼠产生异常运动提供必要和充分的行为条件？(fidefiNe) 在目标2中，我们将研究随着这些运动的发展，基底节输出核团的电生理学。 并将它们与人类肌张力障碍患者的录音进行比较。在目标3中，我们将操纵纹状体胆碱能 DLX-CKO和野生型小鼠的中间神经元对fiNe的特异性fic在生成中的作用(S) 不正常的动作。这些目标的成功完成将建立一种独特的任务规格fic模式。 肌张力障碍具有较高的结构、面子和预测效度。这一模式将对 通过允许详细研究肌张力障碍的网络机制并提出新的 治疗方法。更广泛地说，该模型将改进对正常交互的理解 锥体外系和锥体运动系统，与一系列运动障碍有广泛的相关性。