Mapping neurochemical activity of the basal ganglia in pathological behaviors

需要改进的策略来治疗运动障碍，例如帕金森病（PD），全球有1000多万人患有这种疾病。除了许多其他神经系统疾病之外，PD还集中涉及多巴胺神经化学失调。目前对PD的治疗包括通过全身性L-多巴给药补充多巴胺。然而，这些治疗显示出有限的功效，并且可能具有有害的副作用。这些疾病的神经化学病理生理学尚未得到很好的理解。这种有限的理解阻碍了更好的治疗方法的发展。研究表明，多巴胺在PD中以空间异质性模式失调，并且位点特异性多巴胺操作在病理的产生中具有特定作用。该提案的目标是动态映射介导非人类灵长类动物中特定PD相关运动和情绪行为的多巴胺信号。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。我们最近证实了我们的能力，以测量多位点多巴胺神经化学物质，长期，在非人类灵长类动物，使用快速扫描循环伏安法（FSCV）电化学记录，以测量多巴胺在亚秒的时间尺度。该提议的目的1是绘制具有受体选择性药理学调节和测量位点的事后化学标记共定位的大鼠纹状体中的空间分布多巴胺信号传导。这一目标的预期结果是多巴胺动力学的区域和结构纹状体域的分类。该建议的目的2是测量执行任务的非人灵长类动物的纹状体部位的多巴胺，以将部位特异性多巴胺与PD中涉及的行为指标相关联。这一目标的结果将阐明多巴胺信号如何介导PD中退化的关键运动和情绪行为过程，以及这些信号如何分布在纹状体中。多巴胺的功能图可以帮助根据当前的症状诊断标准提供更好的治疗策略。目的3涉及测量和映射PD的两个标志，多巴胺和β带局部场电位（LFP）之间的相互作用，使用啮齿动物和非人灵长类动物的急性和慢性PD模型。同时进行的多巴胺和LFP测量将提供更多的病理学定量标志物，并能够改进诊断和治疗PD的策略。目标1和2的拟议工作将在K99指导阶段进行，在此期间，我将继续接受灵长类动物神经生理学、外科手术和免疫组织化学方面的培训。这些培训将是在R 00独立研究者阶段向独立性过渡的关键，在此期间将执行目标3。

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 sub-second 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.