Development of an Animal Model of Task Specific Dystonia

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)选择性异常，为纹状体功能障碍提供底物。 令人惊讶的是，DLX-CKO小鼠被训练成重复执行灵活的爪子伸展任务 异常的、阶段性的、强直性的运动。相比之下，这些小鼠不会出现异常运动 在重复执行非灵巧的旋转机器人任务之后。这项提案将侧重于建立 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CHIS的异常功能在 重复灵巧的肢体运动会导致纹状体活动异常，从而导致任务-- DLX-Cko小鼠特殊的fic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……里面 目的1.确定这些小鼠发生异常的必要条件和充分的行为条件 运动，并试图将我们的fi扩增到DYT1基因敲除小鼠。在目标2中，我们将检查纹状体 随着这些运动的发展而产生的电生理学。在翻译目标3中，我们将使用化学遗传技术 有选择地操纵DLX-cko小鼠的CHI活性，以确定这一特定的fic细胞类型的调节 可以抑制肌张力障碍样运动，并去fiNe纹状体机制的这些影响。成功 这些目标的完成将建立一种独特的高结构fic肌张力障碍任务模型， 面子和预测效度。这一模式将对肌张力障碍社区产生强大的影响， 详细研究肌张力障碍的网络机制，并提出新的治疗方法。更多 一般而言，该模型将提高对锥体外系和锥体之间正常相互作用的理解 运动系统，与一系列运动障碍具有广泛的相关性。

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 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 abnormal striatal activity which leads to 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, and attempt to extend our findings to DYT1 knock-in mice. In Aim 2, we will examine striatal electrophysiology as these movements develop. In translational Aim 3, we will use chemogenetic technology to selectively manipulate ChI activity in Dlx-CKO mice to determine whether modulation of this specific cell type can suppress dystonic-like movements and to define the striatal mechanism of these effects. 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.