Mapping neurochemical activity of the basal ganglia in pathological behaviors

需要改进策略来治疗运动障碍，如帕金森氏病(PD)，这种疾病使全球1000多万人虚弱。帕金森病，除了许多其他神经系统疾病外，还与多巴胺神经化学失调有关。目前对帕金森病的治疗包括通过全身给予L-多巴补充多巴胺。然而，这些治疗方法显示的疗效有限，并可能产生有害的副作用。在这些疾病中，神经化学病理生理学还不是很清楚。这种有限的理解阻碍了更好的治疗方法的开发。已有研究表明，多巴胺在帕金森病发病过程中存在空间异质性，部位特异性的多巴胺操作在帕金森病的发生中起着特殊的作用。这项建议的目标是动态地映射多巴胺信号，这些信号介导了非人类灵长类动物中与帕金森病有关的特定运动和情绪行为。新的阵列神经化学探针已经被开发出来，以允许在啮齿动物中进行多巴胺映射。我们最近证实了我们有能力在非人类灵长类动物中长期测量多部位的多巴胺神经化学物质，使用快速扫描循环伏安法(FSCV)电化学记录在亚秒时间尺度上测量多巴胺。这项建议的目的1是绘制具有受体选择性药理调节和后化学标记的测量部位共定位的大鼠纹状体中的多巴胺信号的空间分布。这一目标的预期结果是根据区域和结构纹状体区域对多巴胺动力学进行分类。这项建议的目标2是在执行非人类灵长类动物的任务中测量纹状体部位的多巴胺，以将部位特异性多巴胺与帕金森病相关的行为指标联系起来。这一目标的结果将阐明多巴胺信号如何调节帕金森病患者关键的运动和情绪行为过程，以及这些信号如何分布在纹状体中。根据目前的症状诊断标准，多巴胺的功能图可以帮助制定更好的治疗策略。目的3使用啮齿动物和非人类灵长类动物的急性和慢性帕金森病模型，测量和定位帕金森病的两个特征--多巴胺和β-频段局部场电位(LFP)之间的相互作用。同时检测多巴胺和LFP将提供更多的病理定量标记物，并使诊断和治疗帕金森病的策略得到改进。AIMS 1和AIMS 2的拟议工作将在K99指导阶段进行，在此期间我将继续进行灵长类神经生理学、外科手术和免疫组织化学方面的培训。这些培训将是在R00独立调查员阶段向独立过渡的关键，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.