Mapping neurochemical activity of the basal ganglia in pathological behaviors

绘制病理行为中基底神经节的神经化学活性

• 批准号: 9751994
• 负责人: Helen N Schwerdt
• 金额: $ 9.35万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751994
• 关键词: Acute; Affect; Anatomy; Animal Model; Area; Basal Ganglia; Behavior; Behavioral; Biological Markers; Brain; Chemicals; Cholinergic Agonists; Chronic; Classification; Clinical; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Dopamine; Exhibits; Functional disorder; Generations; Geography; Globus Pallidus; Goals; Heterogeneity; Immunohistochemistry; Infusion procedures; Intervention; Investigative Techniques; Knowledge; Label; Levodopa; Maps; Measurement; Measures; Mediating; Mentors; Modeling; Mood Disorders; Moods; Motivation; Motor; Movement; Movement Disorders; Operative Surgical Procedures; Outcome; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacology; Plant Roots; Population; Primates; Process; Rattus; Research; Research Personnel; Rodent; Role; Sampling; Scanning; Signal Transduction; Site; Spatial Distribution; Structure; Structure of subthalamic nucleus; Symptoms; Techniques; Training; Work; base; cell type; disease diagnosis; electrical measurement; improved; in vivo; nervous system disorder; neurochemistry; neurophysiology; neurotransmission; nonhuman primate; operation; potential biomarker; receptor; relating to nervous system; side effect; spatiotemporal; standard of care; striosome; temporal measurement; tool; treatment strategy

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.

需要改进策略来治疗运动障碍，例如帕金森病 (PD)，该病使全世界超过 1000 万人变得虚弱。除了许多其他神经系统疾病外，PD 主要涉及多巴胺神经化学物质失调。目前帕金森病的治疗包括通过全身左旋多巴给药来补充多巴胺。然而，这些治疗的功效有限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不清楚。这种有限的理解阻碍了更好的疗法的开发。研究表明，多巴胺在帕金森病中以空间异质模式失调，并且位点特异性多巴胺作用在病理学的产生中具有特定作用。该提案的目标是动态绘制介导非人类灵长类动物中与 PD 相关的特定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出来，可以在啮齿类动物中进行多巴胺图谱分析。我们最近证实了我们能够使用快速扫描循环伏安法（FSCV）电化学记录在亚秒级时间尺度上测量多巴胺，从而长期测量非人类灵长类动物的多位点多巴胺神经化学物质。该提案的目标 1 是通过受体选择性药理学调节和事后化学标记测量位点的共定位来绘制大鼠纹状体中空间分布的多巴胺信号传导。这一目标的预期结果是根据区域和结构纹状体域对多巴胺动力学进行分类。该提案的目标 2 是在非人类灵长类动物执行任务时测量纹状体部位的多巴胺，将特定部位的多巴胺与 PD 相关的行为指标相关联。这一目标的结果将阐明多巴胺信号如何介导帕金森病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。目标 3 涉及使用啮齿类动物和非人类灵长类动物的急性和慢性帕金森病模型来测量和绘制帕金森病的两个标志（多巴胺和β带局部场电位（LFP））之间的相互作用。同时进行的多巴胺和 LFP 测量将提供更多的病理学定量标记，并改进诊断和治疗 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。这些培训对于 R00 独立调查员阶段的独立过渡至关重要，在此期间将执行目标 3。