Consequences of Synucleinopathy and Dopamine Depletion

突触核蛋白病和多巴胺耗竭的后果

• 批准号: 6842098
• 负责人: Ann M Graybiel
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842098
• 关键词: 6 hydroxydopamine; Parkinson' s disease; abnormal involuntary movement; alpha synuclein; behavior test; behavioral /social science research tag; brain disorder chemotherapy; corpus striatum; disease /disorder model; dopamine; gene expression; gene induction /repression; genetically modified animals; laboratory mouse; laboratory rat; learning; levodopa; molecular pathology; neural plasticity; neurobiology; neurogenetics; neuropharmacology; neurophysiology; psychomotor function; regulatory gene; substantia nigra

Parkinson's disease (PD) and Parkinson's-spectrum disorders produce both motor and cognitive impairments. We propose to examine behavioral disturbance of each type, impairmen t of procedural learning and development of L-dopa induced dyskinesias, and the striatal neural plasticity that may under lie them in rodent models of PD. We will combine multi-disciplinary methods that we and members of our Center have extensive experience with: behavioral observation using systematic rating scales, training on procedural tasks in a T-maze, chronic neuronal ensemble neuronal recording with tetrodes, analysis of immediate early gene expression, microarray gene assays and laser capture microscopy (collaboration With Project 4), and introduction of alpha-synuclein mutations (collaboration with Project 1 and extra-Center collaborations). We have carried out extensive preliminary studies and formed three functional Aims based on highly promising findings, in Aim 1, we propose to test whether plasticity in task-related neuronal activity in the dorsolateral striatum during a procedural learning in a T-maze will be abnormal in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions restricted to the area around the recording sites, in Aim 2, we propose to study the effects of alpha-synuclein overexpression on learning-related neuronal plasticity in the stdatum. We will use rats injected with viral vectors carrying mutant or normal forms of alpha-synuclein and engineered mice expressing alpha-synuclein mutations. Both of these Aims, animals will receive chronic intermittent L-dopa treatment either during or after acquisition of the learning task to test the effects of dopamine replacement therapy on learning and neuronal activity. In Aim 3, we propose to examine L-dopa induced dyskinesias in rats with 6-OHDA lesions. We will measure the activation of immediate early genes in the striosomes and in the matrix and will correlate the expression patterns with behavioral dyskinesias. We will also perform gene assays using laser-dissected striosome and matrix tissues to measure differential compartmental distributions of downstream genes in relation to dyskinesias. The results of these experiments will yield important knowledge about neural mechanisms underlying two forms of striatal plasticity implicated in parkinsonian syndromes: that related to procedural learning and that leading to the development of L-dopa induced dyskinesia in PD and related movement disorders.

帕金森氏病（PD）和帕金森氏症状疾病会产生运动和认知 障碍。我们建议检查每种类型的行为扰动，这是L-DOPA诱导的运动障碍的程序学习和开发的障碍，以及在PD啮齿动物模型中可能存在的纹状体神经可塑性。我们将结合我们和中心成员具有丰富经验的多学科方法：使用系统的评分量表进行行为观察，对T迷宫中的程序任务的培训，慢性神经元合成神经元记录，分析与早期基因表达，Microarray Gene Assays和Laser caption Seraln and andry Al anty Al antry andry and andry Al and andry Al a andry and andry andry andry andry Al and andry Al and in natry Project 4），以及4） （与项目1和中心合作的合作）。我们已经进行了广泛的初步研究，并基于高度有希望的发现形成了三个功能目标，在AIM 1中，我们建议测试与任务相关的神经元活动中的可塑性在触发过程中的过程学习过程中是否具有限制性的6-Hydroxydroxypopamine（6-型）lise（6-- a-hyda）（6-- a-hyda）（6-- a）（6-- lIS）（6-- lIS）（6-- lIS）（6-- lIS）（6-- liS）。 AIM 2，我们建议研究α-突触核蛋白过表达对STDATUM中与学习相关的神经元可塑性的影响。我们将使用注射老鼠 载有突变体或正常形式的α-核蛋白的病毒载体和表达α-突触核蛋白突变的工程小鼠。这两个目的都是在获得学习任务期间或之后，动物将接受慢性间歇性L-DOPA治疗，以测试多巴胺替代疗法对学习和神经元活性的影响。在AIM 3中，我们建议检查L-DOPA诱导的患有6-OHDA病变的大鼠的运动障碍。我们将测量静脉体和基质中早期基因的立即激活，并将表达模式与行为运动障碍相关联。我们还将执行基因测定 使用激光驱动的曲局组和基质组织来测量下游基因与运动障碍有关的差异分布。这些实验的结果将产生有关涉及帕金森综合症的两种形式的纹状体可塑性的神经机制的重要知识：与程序学习有关，并导致L-DOPA诱导的PD和相关运动障碍中L-DOPA诱导的发育不良。