Striatal Mechanisms of Levodopa-Induced Dyskinesia

项目摘要 左旋多巴诱发的运动障碍(LID)通常发生在帕金森病的长期治疗过程中， 大多数患者在治疗5-10年后会受到影响。异常的不自主运动最终会限制 左旋多巴剂量，通常患者需要脑深部刺激(DBS)。LID的神经机制不是 完全理解，但主要的假设是，左旋多巴触发输入核内的异常活动。 基底节，纹状体。然而，即使在疾病的晚期，左旋多巴仍然有 治疗和病理效果，促进正常运动和不正常的不自主运动。 这种临床观察使我们假设，在纹状体内，不同的神经元群体相互关联 与左旋多巴的运动障碍和促进运动(治疗)作用相比。我们的初步研究表明，大量的 部分纹状体神经元的活动与正常运动的增加或 运动障碍，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 选择性靶向运动神经元，缓解帕金森氏病的运动症状，而不影响 神经元运动障碍和避免运动障碍。使用唤醒行为单单元记录的组合， 光遗传学和LID小鼠模型的体外切片记录，这项建议旨在(1)表征 纹状体直接通路神经元对左旋多巴的反应，包括识别其放电与 运动障碍，(2)确定这些神经元是否导致运动障碍，以及(3)确定潜在的细胞 区分它们的机制(内在兴奋性和/或兴奋性输入的改变)。要测试 运动障碍相关纹状体单位在运动障碍中的因果作用，我们将使用新的转基因工具，靶向 活跃种群中的重组(TRAP)，允许捕获和随后操纵以前的 激活神经元。这些研究将提供第一个关于左旋多巴是否触发治疗的详细观察。 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。 好了！

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. !