A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

肌张力障碍病理生理学的二次假设：DYT1 小鼠的小脑-丘脑-纹状体功能障碍和连接

• 批准号: 10508076
• 负责人: Lauren Nicole Miterko
• 金额: $ 7.03万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508076
• 关键词: Adolescent; Affect; Alleles; Anatomy; Animal Model; Anti-Cholinergics; Architecture; Behavior; Behavioral; Brain; Brain imaging; Cerebellar Diseases; Cerebellum; Clinical; Corpus striatum structure; Coupled; DNA Sequence Alteration; Data; Development; Disease; Dorsal; Drug usage; Dyskinetic syndrome; Dystonia; Electrophysiology (science); Engineering; Etiology; Exhibits; Face; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Goals; Imaging Techniques; Impairment; Internal Ribosome Entry Site; Interneurons; Machine Learning; Microscopy; Modeling; Modernization; Morphology; Motor; Movement; Movement Disorders; Mus; Mutation; Neuroanatomy; Neurons; Pathway interactions; Penetrance; Prosencephalon; Proteins; Research Personnel; Role; Structure; Synapses; TOR1A gene; Techniques; Testing; Thalamic structure; Therapeutic; Time; TorsinA; Viral; Work; base; career; cholinergic; design; effective therapy; human model; imaging modality; loss of function; motor disorder; mouse model; multidisciplinary; neuroimaging; neuroregulation; novel; novel strategies; novel therapeutic intervention; pediatric dystonia; protein function; rabies viral tracing; recruit; synaptogenesis; targeted treatment; tool; translational neuroscience

ABSTRACT Dystonia is neurodevelopmental disease characterized by involuntary twisting movements. Effective dystonia treatments remain elusive because the dysfunctional circuit(s) that cause and perpetuate the motor abnormalities is largely uncharacterized. One limitation to advancing our understanding of dystonia pathophysiology and developing novel therapeutic strategies is the lack of etiologically based animal models that exhibit overt dystonia-like behaviors. We overcame this limitation by engineering a mouse model that exhibits robust motor abnormalities starting in juvenile development, following a disruption of the dystonia gene, TOR1A.TorsinA, the protein that is made from the TOR1A, is important during brain development for synaptogenesis and its loss results in abnormal functional connectivity. I will use our novel mouse model to investigate how a loss of torsinA function in brain motor circuits causes dystonia. I will test a new idea: that dystonia results from sequential insults. First, genetic mutations cause a small but critical group of neurons to make aberrant anatomical connections. Then, sustained circuit dysfunction reinforces abnormal movements. These studies are possible because of multiple uniquely designed “tools" my lab has created and the advanced brain imaging methods that have been developed at UT Southwestern, where the study will be performed. This proposal will also advance our understanding of dystonia by identifying the brain circuit changes required to propagate and suppress motor dysfunction. This understanding will inform future work aimed at developing effective therapies for dystonia.

抽象的 肌张力障碍是一种以不自主扭转运动为特征的神经发育疾病。 治疗方法仍然难以捉摸，因为导致运动异常并使其长期存在的功能失调的回路 很大程度上是未知的，这是推进我们对肌张力障碍病理生理学和理解的一个限制。 开发新的治疗策略是缺乏基于病因学的动物模型，这些模型表现出明显的 我们通过设计表现出强大运动能力的小鼠模型克服了这一限制。 肌张力障碍基因 TOR1A.TorsinA 被破坏后，从青少年发育开始出现异常。 由 TOR1A 制成的蛋白质，在大脑发育过程中对于突触发生及其丢失非常重要 我将使用我们的新型小鼠模型来研究 TorsinA 的缺失是如何导致功能连接异常的。 大脑运动回路的功能会导致肌张力障碍，我将测试一个新想法：肌张力障碍是由连续的损伤引起的。 首先，基因突变会导致一小部分但关键的神经元产生异常的解剖学连接。 然后，持续的回路功能障碍会强化异常运动，因为这些研究是可能的。 我的实验室创造了多种独特设计的“工具”，以及先进的脑成像方法 该研究将在德克萨斯大学西南分校开发，该提案也将推进我们的研究。 通过识别传播和抑制运动所需的脑回路变化来理解肌张力障碍 这种理解将为未来旨在开发肌张力障碍有效疗法的工作提供信息。