Landis Award

兰迪斯奖

基本信息

批准号：
10532481
负责人：
Alexandra Nelson
金额：
$ 16.15万
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：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532481
关键词：
Acute Affect Agonist Antiparkinson Agents Award Basal Ganglia Behavior Behavioral Brain Cells Clinical Complication Corpus striatum structure Data Deep Brain Stimulation Development Disease Dopamine Dose Dyskinetic syndrome Electrophysiology (science)Genetic Genetic Recombination Individual Involuntary Movements L-DOPA induced dyskinesia Levodopa Mediating Motor Movement Mus Neurons Opsin Optics Parkinson Disease Parkinsonian Disorders Pathologic Pathway interactions Patients Pattern Pilot Projects Population Property Reporter Reporting Role Rotation Severities Slice Synapses Testing Therapeutic Therapeutic Effect Transgenic Mice Transgenic Organisms abnormal involuntary movement awake behavioral response brain cell drug development improved in vivo motor symptom mouse model neuromechanism novel optogenetics parkinsonian animal response therapeutic target therapeutically effective tool

项目摘要

Project Summary Levodopa-induced dyskinesia (LID) commonly develops during long-term treatment of Parkinson's Disease, affecting most patients after 5-10 years of treatment. The abnormal involuntary movements eventually limit the levodopa dose, and often patients require deep brain stimulation (DBS). The neural mechanisms of LID are not fully understood, but the leading hypothesis is that levodopa triggers aberrant activity in the input nucleus of the basal ganglia, the striatum. Even in the advanced stages of disease, however, levodopa continues to have both therapeutic and pathological effects, promoting normal movement and abnormal involuntary movements. This clinical observation led us to hypothesize that within the striatum, distinct populations of neurons correlate with dyskinetic versus prokinetic (therapeutic) effects of levodopa. Our pilot studies indicate that a substantial fraction of striatal neurons show strong correlations in their activity with either increased normal movement, or dyskinesia, and few neurons correlate with both responses. By understanding the intrinsic and synaptic properties that distinguish these two groups of striatal neurons, subsequent drug development might be able to selectively target movement neurons, relieving motor symptoms of Parkinson's Disease, without affecting dyskinetic neurons and avoiding dyskinesia. Using a combination of awake-behaving single-unit recordings, optogenetics, and ex vivo slice recordings in a mouse model of LID, this proposal aims to (1) characterize striatal direct pathway neuronal responses to levodopa, including identifying units whose firing correlates with dyskinesia, (2) determine whether these neurons cause dyskinesia, and (3) identify the underlying cellular mechanisms (alterations in intrinsic excitability and/or excitatory inputs) that distinguish them. To test the causal role of dyskinesia-correlated striatal units in dyskinesia, we will use the novel transgenic tool, Targeted Recombination in Active Populations (TRAP), which allows capture and subsequent manipulation of previously activated neurons. These studies will provide the first detailed look at whether levodopa triggers therapeutic and dyskinetic effects through two different striatal effector populations, and begin to dissect the underlying cellular and synaptic mechanisms.

项目概要左旋多巴引起的运动障碍（LID）通常在帕金森病的长期治疗过程中发生，影响大多数患者5-10年的治疗。异常的不自主运动最终限制了左旋多巴剂量，并且通常患者需要深部脑刺激（DBS）。 LID 的神经机制不完全理解，但主要的假设是左旋多巴会引发输入核的异常活动基底神经节，纹状体。然而，即使在疾病晚期，左旋多巴仍然具有兼有治疗和病理作用，促进正常运动和异常不随意运动。这一临床观察使我们推测，在纹状体内，不同的神经元群体相关左旋多巴的运动障碍与促运动（治疗）作用。我们的试点研究表明，大量部分纹状体神经元的活动与正常运动的增加或运动障碍，并且很少有神经元与这两种反应相关。通过了解内在和突触区分这两组纹状体神经元的特性，后续的药物开发可能能够选择性地针对运动神经元，缓解帕金森病的运动症状，而不影响运动障碍神经元并避免运动障碍。使用清醒行为的单个单元记录的组合，光遗传学和 LID 小鼠模型中的离体切片记录，该提案旨在 (1) 表征纹状体直接通路神经元对左旋多巴的反应，包括识别与放电相关的单位运动障碍，(2) 确定这些神经元是否引起运动障碍，以及 (3) 识别潜在的细胞区分它们的机制（内在兴奋性和/或兴奋性输入的改变）。测试运动障碍相关纹状体单位在运动障碍中的因果作用，我们将使用新型转基因工具，靶向活跃群体中的重组（TRAP），允许捕获并随后操纵先前的激活的神经元。这些研究将首次详细研究左旋多巴是否会触发治疗和运动障碍效应通过两个不同的纹状体效应器群体，并开始剖析潜在的细胞和突触机制。