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.

帕金森病 (PD) 和帕金森谱系障碍会产生运动和认知障碍 损伤。我们建议检查每种类型的行为障碍、程序性学习的损害和左旋多巴引起的运动障碍的发展，以及PD啮齿动物模型中可能存在的纹状体神经可塑性。我们将结合我们和我们中心成员拥有丰富经验的多学科方法：使用系统评分量表进行行为观察、T 型迷宫中的程序任务培训、使用四极管进行慢性神经元集成神经元记录、立即早期基因表达分析、微阵列基因测定和激光捕获显微镜（与项目 4 合作），以及引入 α-突触核蛋白突变（与项目 1 合作和中心外合作）。我们进行了广泛的初步研究，并根据非常有希望的发现形成了三个功能目标，在目标 1 中，我们建议测试在 T 迷宫的程序学习过程中背外侧纹状体中与任务相关的神经元活动的可塑性是否会异常在单侧 6-羟基多巴胺 (6-OHDA) 病变仅限于记录位点周围区域的大鼠中，在目标 2 中，我们建议研究 α-突触核蛋白过度表达对学习相关的影响标准中的神经元可塑性。我们将使用注射的老鼠 携带突变或正常形式的α-突触核蛋白的病毒载体和表达α-突触核蛋白突变的工程小鼠。为了这两个目标，动物将在获得学习任务期间或之后接受慢性间歇性左旋多巴治疗，以测试多巴胺替代疗法对学习和神经元活动的影响。在目标 3 中，我们建议检查 6-OHDA 损伤大鼠中左旋多巴诱导的运动障碍。我们将测量纹状体和基质中立即早期基因的激活，并将表达模式与行为运动障碍相关联。我们还将进行基因检测 使用激光解剖纹状体和基质组织来测量与运动障碍相关的下游基因的差异区室分布。这些实验的结果将产生关于与帕金森综合征有关的两种形式的纹状体可塑性的神经机制的重要知识：与程序性学习相关的以及导致帕金森病和相关运动障碍中左旋多巴诱发的运动障碍的发展。