ENSEMBLE RECORDINGS IN MODELS OF NEURODEGENERATIVE DISEASE

神经退行性疾病模型中的集合记录

• 批准号: 6347675
• 负责人: Ann M Graybiel
• 金额: $ 12.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347675
• 关键词: 6 hydroxydopamine; Parkinson's disease; alpha synuclein; animal genetic material tag; basal ganglia; behavioral /social science research tag; cerebrum; corpus striatum; disease /disorder model; dopamine; ethology; gene induction /repression; genetically modified animals; laboratory mouse; learning; neural information processing; neurogenetics; neurotoxicology; psychomotor function; regulatory gene

The experiments proposed have as their goal combining gene-based and neurobiology-based methods to advance understanding of the fundamental neurobiology of the nigrostriatal system and its particular disruption in Parkinson's disease. Our proposed approach is to develop and implement studies of striatal ensemble activity in the mouse, with the immediate aim of studying transgenic mice generated by our colleagues in the Center, and with the long-term goal of taking advantage of the extraordinary opportunities to examine the fundamental molecular and neurologic bases of parkinsonian disorders by studying mice reengineered to over or under express genes implicated in parkinson's disease. We propose to use two methods to record ensemble activity in the mouse striatum, both based on our ongoing work in the rat. First, we propose to use multiple tetrode assemblies to record simultaneously from striatal neurons as mice undergo training on procedural learning tasks. Second, we propose to monitor the striatal induction of immediate-early genes (IEGs) by local cortical microstimulation and by dopamine receptor agonist treatments, and by combinations of these treatments. For each of these two methods of ensemble activity recording, we then propose to study the effects on the activity of localized striatal dopamine depletion. Based on work from our own and other laboratories, we hypothesize that such dopamine deletion will produce disruption of neuronal coding of procedural tasks by striatal neurons, and disruption of corticostriatal transmission. Finally, we propose to use these functional assays to test transgenic mice produced by members of the Center to examine the neurobiologic consequences of expressing human alpha-synuclein in the mouse (Hyman), and of deletion or mutation of the torsin A gene in transgenic mice (Breakefield). These experiments should significantly advance understanding of the neurobiology of nigrostriatal function and specific gene-based changes in this function in murine models designed to discover the pathogenesis of Parkinson's disease.

所提出的实验的目标是将基于基因的 神经生物学为基础的方法，以促进对基本的理解 黑质纹状体系统的神经生物学及其在 帕金森氏症。我们建议的方法是制定和实施 小鼠纹状体整体活动的研究，其直接目的是 研究转基因小鼠，这些小鼠是由我们中心的同事们培育的， 长期目标是利用 有机会研究的基本分子和神经基础， 帕金森氏症通过研究小鼠重新设计， 表达与帕金森病有关的基因。我们建议使用两个 记录小鼠纹状体整体活动的方法，两者都基于 我们正在进行的老鼠实验首先，我们建议使用多个四极管 组件，同时记录从纹状体神经元作为小鼠经历 程序性学习任务培训。第二，我们建议监察 纹状体诱导的即时早期基因（IEGs）的局部皮质 微刺激和多巴胺受体激动剂治疗，以及 这些治疗的组合。对于这两种方法中的每一种， 合奏活动记录，然后，我们建议研究的影响， 局部纹状体多巴胺耗竭的活动。根据我们的工作， 我们和其他实验室，我们假设这种多巴胺缺失 将通过纹状体神经元对程序性任务的编码产生破坏， 神经元和皮质纹状体传递的破坏。最后我们 建议使用这些功能测定来测试由以下方法产生的转基因小鼠 中心的成员检查神经生物学的后果， 在小鼠中表达人α-突触核蛋白（Hyman），以及缺失或 转基因小鼠中torsin A基因的突变（Breakefield）。这些 实验应该显着促进对神经生物学的理解 黑质纹状体功能和这种功能的特定基因变化 在设计用于发现帕金森病发病机制的小鼠模型中， 疾病