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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要