Development of an Animal Model of Task Specific Dystonia

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）。我们模拟了 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，为纹状体功能障碍提供了底物。 引人注目的是，训练重复执行灵巧的爪子到达任务的Dlx-CKO小鼠发展为 异常的阶段性肌张力障碍样运动相比之下，这些小鼠不会出现异常运动 在重复执行非灵巧的旋转杆任务之后。该提案将侧重于建立 这个长期寻求的肌张力障碍模型的有效性和实用性。我们推测，ChIs的异常功能， 重复的灵巧肢体运动的设置引起异常的纹状体活动，这导致任务- Dlx-CKO小鼠的特异性肌张力障碍样运动。我们将用三个具体目标来检验这一假设。在 目的1，我们将定义这些小鼠发生异常行为的必要和充分的行为条件， 运动，并试图将我们的发现扩展到DYT 1基因敲入小鼠。在目标2中，我们将检查纹状体 这些运动的发展。在目标3中，我们将使用化学遗传学技术 选择性地操纵Dlx-CKO小鼠的ChI活性，以确定这种特异性细胞类型的调节 可以抑制张力障碍样运动，并确定这些作用的纹状体机制。成功 这些目标的完成将建立具有高结构的任务特异性肌张力障碍的独特模型， 面孔和预测效度。这种模式将发挥强大的影响，肌张力障碍社区允许 详细研究肌张力障碍的网络机制，并提出新的治疗方法。更 总的来说，这个模型将提高对锥体外系和锥体系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.