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: 10371640
• 负责人: WILLIAM T. DAUER
• 金额: $ 40.84万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371640
• 关键词: Animal Model; Basal Ganglia; Behavior Control; Behavioral; Brain; Brain Diseases; Central Nervous System Diseases; Clinical; Communities; Corpus striatum structure; Data; Development; Disease; Dorsal; Dyskinetic syndrome; Dystonia; Electrophysiology (science); Elements; Exhibits; Face; Functional disorder; Generations; Genes; Genetic Models; Genetic Predisposition to Disease; Goals; Human; Hyperactivity; Impairment; Inherited; Interneurons; Knock-in Mouse; Link; Modeling; Molecular Profiling; Motor; Motor output; Movement; Movement Disorders; Mus; Mutation; Neuronal Plasticity; Neurons; Outcome; Output; Performance; Pharmaceutical Preparations; Phase; Physiological; Prosencephalon; Research Personnel; Rodent; Rodent Model; Role; Seizures; Signal Transduction; Stroke; Structure; Symptoms; Synapses; System; Technology; Testing; Therapeutic; TorsinA; Training; animal model development; awake; base; brain circuitry; cell type; cholinergic; cholinergic neuron; designer receptors exclusively activated by designer drugs; genetic manipulation; human model; human subject; improved; limb movement; model development; motor control; motor disorder; motor symptom; mouse model; musician; mutant; network dysfunction; novel; novel strategies; novel therapeutic intervention; prevent; sensory input; skills

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.

抽象的 引起肌张力障碍的电路机制知之甚少。一个明显的假设是肌张力障碍是 由运动结构中的异常可塑性，尤其是皮质 - 基质神经节电路引起的。缺乏 合适的动物模型是进步的关键障碍。我们的初步数据表明我们有 制定了一种策略来通过独特的结合来生成人类任务特定障碍的第一个啮齿动物模型 遗传和行为操纵。该策略基于观察结果，表明肌张力障碍需要 “两个命中”：对异常可塑性和可塑性引起的环境触发的遗传易感性（例如， 与音乐家的肌张力障碍一样重复特定的灵活运动。我们建模了遗传 与我们既定的dyt1 dystonia模型的易感性，该模型是由基因中的遗传突变引起的 编码Torsina。 Torsina突变体“ DLX-CKO”小鼠在基线时不显示异常运动，而是显示 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。 令人惊讶的是，经过重复执行灵巧的爪的DLX-CKO小鼠达到任务开发 异常，阶段性，类似偶音的运动。相反，这些小鼠不会发展异常运动 重复执行非外界旋转rot任务后。该提议将着重于建立 这种长期肌张力障碍模型的有效性和效用。我们假设Chis在 重复灵敏的肢体运动的设置会导致异常纹状体活动，从而导致任务 - DLX-CKO小鼠中的特定类似肌张力型运动。我们将以三个特定的目的检验这一假设。在 目的1，我们将定义这些小鼠发展异常的必要且有足够的行为条件 运动，并试图将我们的发现扩展到Dyt1敲击小鼠。在AIM 2中，我们将检查纹状体 随着这些运动的发展，电生理学。在翻译目标3中，我们将使用化学发育技术 有选择地操纵DLX-CKO小鼠中的CHI活性，以确定是否调制此特定细胞类型 可以抑制肌张力障碍的运动并定义这些作用的纹状体机制。成功的 这些目的的完成将建立一个独特的任务特定肌张力障碍模型，具有高结构， 面部和预测有效性。该模型将通过允许对Dystonia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了新的治疗方法。更多的 通常，该模型将提高对腹膜外和金字塔之间正常相互作用的理解 电机系统，与一系列运动障碍具有广泛的相关性。