Mapping neurochemical activity of the basal ganglia in pathological behaviors

项目摘要 需要改进的策略来治疗运动障碍，例如帕金森病（PD）， 使全球超过1000万人身体虚弱。PD，除了许多其他神经系统疾病， 中枢涉及多巴胺神经化学失调。目前的治疗方法包括补充 多巴胺通过全身左旋多巴管理。然而，这些治疗显示出有限的功效， 可能会产生有害的副作用。神经化学病理生理学在这些中还没有得到很好的理解。 紊乱这种有限的理解阻碍了更好的治疗方法的发展。已经显示 多巴胺在PD中以空间异质模式失调，并且位点特异性多巴胺 手术在病理学的产生中具有特定的作用。本提案的目标是动态映射 在非人类灵长类动物中，多巴胺信号介导特定的PD相关运动和情绪行为。 新的阵列神经化学探针已被开发，允许在啮齿动物多巴胺映射。我们有 最近证实了我们有能力长期测量非人类的多位点多巴胺神经化学物质， 灵长类动物，使用快速扫描循环伏安法（FSCV）电化学记录来测量多巴胺， 亚秒级的时间尺度本提案的目的1是绘制多巴胺信号在脑内的空间分布图。 大鼠纹状体受体选择性药理学调节和事后化学标记的co- 测量点的定位。这一目标的一个预期结果是多巴胺动力学的分类， 区域和结构纹状体域的术语。该提案的目的2是测量纹状体中的多巴胺 执行非人类灵长类动物任务的位点将位点特异性多巴胺与行为指标相关联 与警局有牵连这一目标的结果将阐明多巴胺信号如何介导键运动， PD中退化的情绪行为过程，以及这些信号如何在PD中分布。 纹状体多巴胺的功能图可以帮助根据目前的情况制定更好的治疗策略。 症状诊断标准。目标3涉及测量和绘制两个标志之间的相互作用 PD、多巴胺和β带局部场电位（LFP），使用啮齿动物中的急性和慢性PD模型 和非人类灵长类动物。同时进行的多巴胺和LFP测量将提供更多的定量结果。 病理学标志物，并能够改善诊断和治疗PD的策略。拟议的工作 目标1和2将在K99指导阶段执行，在此期间，我将继续我的培训， 灵长类神经生理学、外科学和免疫组织化学。这些培训将是过渡到 R00独立调查员阶段的独立性，在此期间将执行目标3。

Project Summary Abstract Improved strategies are needed to treat movement disorders, such as Parkinson’s disease (PD), which debilitates more than 10 million people worldwide. PD, in addition to many other neurological disorders, centrally involve dopamine neurochemical dysregulation. Current treatment for PD involves replenishing dopamine through systemic L-Dopa administration. These treatments, however, display limited efficacy and can have detrimental side-effects. The neurochemical pathophysiology is not well understood in these disorders. This limited understanding hinders development of better therapies. It has been shown that dopamine is dysregulated in a spatially heterogeneous pattern in PD, and the site-specific dopamine operations have specific roles in the generation of pathology. The goal of this proposal is to dynamically map the dopamine signals that mediate specific PD-implicated motor and mood behaviors in nonhuman primates. New arrayed neurochemical probes have been developed to permit dopamine mapping in rodents. We have recently confirmed our ability to measure multi-site dopamine neurochemicals, chronically, in the nonhuman primate, using fast scan cyclic voltammetry (FSCV) electrochemical recording to measure dopamine at subsecond timescales. Aim 1 of this proposal is to chart the spatially-distributed dopamine signaling in the striatum of rats with receptor-selective pharmacological modulation and post-hoc chemically labeled co- localization of measured sites. An expected outcome of this aim is a classification of dopamine dynamics in terms of regional and structural striatal domains. Aim 2 of this proposal is to measure dopamine across striatal sites in the task performing nonhuman primate to correlate site-specific dopamine with metrics of behaviors implicated in PD. The results from this aim will elucidate how dopamine signals mediate key movement and mood behavioral processes that are degraded in PD, and how these signals are distributed across the striatum. A functional map of dopamine could help inform better treatment strategies based on current symptomatic diagnostic criteria. Aim 3 involves measuring and mapping the interaction between two hallmarks of PD, dopamine and beta-band local field potential (LFP), using acute and chronic models of PD in rodents and nonhuman primates. The concurrent dopamine and LFP measurements will provide more quantitative markers of pathology and enable improved strategies for diagnosing and treating PD. The proposed work for Aims 1 and 2 will be performed during the K99 mentored stage, during which I will continue my training in primate neurophysiology, surgery, and immunohistochemistry. These trainings will be pivotal in transitioning to independence in the R00 independent investigator stage, during which Aim 3 will be executed.