Optogenetic dissection of striatal circuits in a mouse model of human dystonia

人类肌张力障碍小鼠模型纹状体回路的光遗传学解剖

基本信息

批准号：
9114179
负责人：
Alexandra Nelson
金额：
$ 17.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114179
关键词：
Address Animal Model Animals Applications Grants Area Basal Ganglia Behavioral Biochemical Brain Brain Injuries Cells Clinical Corpus striatum structure Development Disease Dissection Doctor of Philosophy Dyskinetic syndrome Dystonia Electromyography Electrophysiology (science)Functional disorder Future Genes Genotype Health Human Hyperactive behavior In Vitro Inherited Laboratories Lead Learning Light Long-Term Depression Long-Term Potentiation Mentors Modeling Monitor Movement Movement Disorders Mus Nature Neurologic Neurology Neurons Paroxysmal Dystonia Pathway interactions Patients Pattern Phenotype Physicians Physiological Population Primary Dystonias Research Research Personnel Research Proposals Resources Role Scientist Secondary Dystonia Site Slice Structure Symptoms Synapses Synaptic plasticity Techniques Testing Time Training Transgenic Mice Whole-Cell Recordings Wild Type Mouse awake base behavioral neurology career career development comparative efficacy fluorophore human disease in vivo mouse model nervous system disorder neural patterning neuropathology neurophysiology neurotransmission new therapeutic target novel optogenetics post-doctoral training reduce symptoms relating to nervous system skills symptomatic improvement theories therapeutic development therapy development tool

项目摘要

DESCRIPTION (provided by applicant): Primary dystonias are disabling neurological conditions which begin in the prime of patients' lives. Scientists have identified genes involved i some inherited forms of the disease, but little is known about the pathophysiology, and at present treatments is limited and symptomatic in nature. As the brains of such patients show no neuropath logical abnormalities, it is hypothesized that dystonia is a disease of abnormal circuit activity. This proposal is aimed at dissecting the circuitry of one of the key movement control centers, the striatum, in a mouse model of dystonia. In examining the striatal circuitry, we hope to identify new targets for therapeutic development in dystonia as well as other hyperkinetic movement disorders. We propose to use several novel tools to better understand circuit dysfunction in dystonia. First, we plan to use a new mouse model of a human dystonia, paroxysmal nonkinesigenic dyskinesia (PNKD), which is one of very few animal models that recapitulate the clinical features of human dystonia. Second, we plan to employ a new experimental tool, ontogenetic, which allows researchers to control the activity of specific cell populations in the brain. In Aim 1, we will use ontogenetic and in vivo electrophysiology to identify the pathological firing patterns of striatal neurons in awake-behaving PNKD mice, and for the first time distinguish how differences in the activity of direct-pathway and indirect- pathway neurons contribute to dystonia. In Aim 2, we will use in vitro electrophysiology to determine the cellular and synaptic substrate for the pathological firing patterns identified in PNKD mice in vivo. Finally, in Aim 3, we will take what we have learned from both in vivo and in vitro studies of dystonic mice to determine what aspects of aberrant striatal activity are necessary and sufficient to cause dystonia, by using ontogenetic in behaving animals. We will also ontogenetically modify striatal firing patterns to reduce or eliminate the symptoms of dystonia in PNKD mice. Overall, we are hopeful this line of research will not only shed light on long-held theories about basal ganglia circuit dysfunction in dystonia, but will yield new areas fo therapeutic development. I am a physician-scientist with a strong commitment to a career in academic neurology, focused on identifying the circuit basis of neurological disease. I combine PhD and postdoctoral training in neurophysiology with subspecialty training in behavioral neurology and movement disorders. The career development entailed in this research proposal will bring my skills into mouse models of neurological disease and cultivate cutting-edge neurophysiological and optogenetic techniques as a means of understanding and disrupting abnormal patterns of neural activity. The mentoring entailed in this proposal will provide me the scientific and professional resources to continue my own development as an investigator, enabling me to submit competitive grant applications and lead my own laboratory in the future.

描述（由申请人提供）：原发性肌张力障碍是在患者生命的黄金时期开始的致残性神经系统疾病。科学家们已经确定了与这种疾病的某些遗传形式有关的基因，但对其病理生理学知之甚少，目前的治疗方法有限，而且本质上是针对症状的。由于此类患者的大脑没有表现出神经病理学异常，因此推测肌张力障碍是一种异常回路活动的疾病。该提案旨在剖析肌张力障碍小鼠模型中关键运动控制中心之一纹状体的电路。在检查纹状体回路时，我们希望找到肌张力障碍和其他多动性运动障碍治疗开发的新靶点。我们建议使用几种新颖的工具来更好地了解肌张力障碍的回路功能障碍。首先，我们计划使用一种新的人类肌张力障碍小鼠模型，即阵发性非运动性运动障碍（PNKD），这是极少数能够概括人类肌张力障碍临床特征的动物模型之一。其次，我们计划采用一种新的实验工具，即个体发生学，它允许研究人员控制大脑中特定细胞群的活动。在目标 1 中，我们将利用个体发生学和体内电生理学来识别清醒行为 PNKD 小鼠纹状体神经元的病理放电模式，并首次区分直接通路和间接通路神经元活动的差异如何影响肌张力障碍。在目标 2 中，我们将利用体外电生理学来确定 PNKD 小鼠体内病理放电模式的细胞和突触底物。最后，在目标 3 中，我们将利用从肌张力障碍小鼠的体内和体外研究中学到的知识，通过使用行为动物的个体发育来确定异常纹状体活动的哪些方面对于引起肌张力障碍是必要和充分的。我们还将在个体发育上修改纹状体放电模式，以减少或消除 PNKD 小鼠的肌张力障碍症状。总的来说，我们希望这一系列研究不仅能够阐明关于肌张力障碍基底神经节回路功能障碍的长期理论，而且能够为治疗开发带来新的领域。我是一名医师科学家，坚定地致力于学术神经病学的职业生涯，专注于确定神经系统疾病的回路基础。我将神经生理学的博士和博士后培训与行为神经学和运动障碍的亚专业培训结合起来。这项研究计划所涉及的职业发展将把我的技能带入神经疾病的小鼠模型中，并培养尖端的神经生理学和光遗传学技术，作为理解和破坏神经活动异常模式的手段。该提案所涉及的指导将为我提供科学和专业资源，以继续我作为一名研究人员的发展，使我能够提交竞争性资助申请并在未来领导我自己的实验室。