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）：原发性肌张力障碍正在禁用从患者生命开始的神经系统疾病。科学家已经确定了涉及的基因，这是该疾病的某些遗传形式，但对病理生理学知之甚少，目前治疗本质上是有限的和有症状的。由于此类患者的大脑没有神经变化的逻辑异常，因此假设肌张力障碍是一种异常回路活性的疾病。该建议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。在检查纹状体电路时，我们希望确定肌张力障碍以及其他超动运动障碍的新目标。我们建议使用几种新型工具来更好地了解肌张力障碍的电路功能障碍。首先，我们计划使用人类肌张力障碍的新小鼠模型，阵发性非杀伤性运动障碍（PNKD），该模型是少数几个概括人肌张力局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，即个体遗传学，该工具使研究人员能够控制大脑特定细胞群体的活性。在AIM 1中，我们将使用个体发育和体内电生理学来识别醒目的PNKD小鼠中纹状体神经元的病理触发模式，并且首次首次区分直接呼吸道和间接神经元活动的差异如何有助于反肿瘤。在AIM 2中，我们将使用体外电生理学来确定体内PNKD小鼠中鉴定的病理发射模式的细胞和突触底物。最后，在AIM 3中，我们将从体内和肌张力障碍小鼠的体外研究中学到的知识，以确定通过在行为动物中使用个体遗传学的异常纹状体活性的哪些方面是必要且足以引起肌张力障碍的。我们还将在地上修改纹状体射击模式，以减少或消除PNKD小鼠中肌张力障碍的症状。总体而言，我们希望这一研究不仅能阐明有关肌张力障碍基底神经节电路功能障碍的长期理论，而且还会产生治疗性开发的新领域。我是一名医生科学家，对学术神经病学职业有坚定的承诺，重点是识别神经疾病的电路基础。我将神经生理学的博士学位和博士后培训与行为神经病学和运动障碍的专科培训相结合。这项研究提案中所需的职业发展将使我的技能成为神经疾病的小鼠模型，并培养尖端的神经生理学和光遗传学技术，以理解和破坏神经活动的异常模式。该提案中需要的指导将为我提供科学和专业的资源，以继续作为调查员继续自己的发展，使我能够提交竞争性的赠款申请，并在将来领导自己的实验室。