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.

摘要