ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE

多巴胺对运动模式切换的分析

• 批准号: 8291979
• 负责人: JONATHAN THOMAS PIERCE
• 金额: $ 25.56万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291979
• 关键词: Ablation; Address; Animal Model; Animals; Behavior; Behavioral; Biogenic Amines; Caenorhabditis elegans; Calcium; Cells; Deglutition; Dopamine; Electrophysiology (science); Employee Strikes; Environment; Functional disorder; Generations; Genetic; Genetic Models; Goals; Human; Image; Impairment; Invertebrates; Ion Channel; Life; Light; Locomotion; Maps; Membrane; Microfluidics; Modeling; Molecular; Morbidity - disease rate; Motor; Movement; Nematoda; Nervous system structure; Neurons; Parkinson Disease; Pathway interactions; Patients; Pattern; Physiological; Quality of life; Research; Role; Sensory; Serotonin; Signal Transduction; Substantia nigra structure; Suspension substance; Suspensions; Swimming; Synapses; System; Testing; United States; Vertebrates; Walking; Water; Work; base; central pattern generator; cost; dopaminergic neuron; improved; in vivo; insight; motor disorder; neural circuit; neuromechanism; novel; optogenetics; patch clamp; programs; relating to nervous system; tool

DESCRIPTION (provided by applicant): The most debilitating problems in Parkinson's disease block the ability to switch between distinct motor patterns including those required for locomotion. This is caused by loss of dopaminergic signaling due to the degeneration of dopamine neurons in the substantia nigra. The long-term objective of the proposed research is to investigate how changes in dopaminergic function contribute to motor pattern switching. We have recently demonstrated that the powerful genetic model Caenorhabditis elegans resembles humans in that dopamine signaling is an absolute requirement for switching between distinct forms of locomotory behavior. Specifically, C. elegans crawls in a dry environment but swims when suspended in water. By combining behavioral analysis, optogenetics, and neuronal ablation, we have found that dopamine release is both necessary and sufficient to transition from swimming to crawling. We have also found that loss of dopamine neurons results in immobility precisely at the moment of switching between motor patterns in C. elegans - a striking parallel with Parkinson's disease patients. The correspondence between the effects of disruption of dopamine signaling in humans and C. elegans establishes this model organism as an attractive system in which to identify the neuromolecular basis for these switching difficulties. Moreover, the existence of an essentially complete wiring diagram of the C. elegans nervous system together with the fact that it contains exactly eight dopaminergic neurons means that we can study dopamine signaling in unprecedented detail. The proposed research addresses two central questions: First, how does dopamine signaling facilitate a switch to an appropriate motor program, and second, how does switching of motor programs become dysfunctional when dopamine signaling is disrupted? These two questions are addressed in three specific aims that capitalize on our unique expertise in quantitative behavioral analysis and optogenetics as well as electrophysiology and calcium imaging from identified C. elegans neurons in vivo: (1) We will determine which neurons have essential roles in the switch between crawling and swimming with cell ablation and through activation and inhibition of neurons with light-activated ion channels. (2) We will identify the roles of these neurons in intact animals as they switch between crawling and swimming in a microfluidic chamber with functional calcium imaging. (3) We will investigate how dopamine influences the membrane currents and activity of these neurons by performing patch-clamp electrophysiology. The principles uncovered from these studies have the potential to improve understanding of how dopamine is used to switch between motor patterns in humans and how motor pattern initiation and switching becomes dysfunctional in Parkinson's disease.

描述（由申请人提供）：帕金森病中最令人衰弱的问题阻碍了在不同运动模式（包括运动所需的模式）之间切换的能力。这是由于黑质中多巴胺神经元退化导致多巴胺能信号丧失所致。拟议研究的长期目标是研究多巴胺能功能的变化如何促进运动模式切换。我们最近证明，强大的遗传模型秀丽隐杆线虫与人类相似，因为多巴胺信号传导是在不同形式的运动行为之间切换的绝对必要条件。具体来说，线虫在干燥的环境中爬行，但在悬浮在水中时会游泳。通过结合行为分析、光遗传学和神经元消融，我们发现多巴胺的释放对于从游泳到爬行的过渡是必要且充分的。我们还发现，多巴胺神经元的缺失会导致线虫在运动模式切换时精确地保持不动——这与帕金森病患者惊人的相似。人类和线虫中多巴胺信号传导破坏的影响之间的对应关系使该模型生物体成为一个有吸引力的系统，可以在其中识别这些转换困难的神经分子基础。此外，秀丽隐杆线虫神经系统基本完整的接线图的存在，以及它恰好包含八个多巴胺能神经元的事实，意味着我们可以以前所未有的细节研究多巴胺信号传导。拟议的研究解决了两个核心问题：第一，多巴胺信号传导如何促进向适当的运动程序的切换；第二，当多巴胺信号传导被破坏时，运动程序的切换如何变得功能障碍？这两个问题通过三个具体目标得到解决，这些目标利用我们在定量行为分析和光遗传学以及电生理学和体内已识别的秀丽隐杆线虫神经元的钙成像方面的独特专业知识：（1）我们将确定哪些神经元在通过细胞消融以及通过光激活离子通道激活和抑制神经元来在爬行和游泳之间切换。 (2) 我们将通过功能性钙成像来确定这些神经元在完整动物中在微流体室中爬行和游泳之间切换时的作用。 (3)我们将通过膜片钳电生理学研究多巴胺如何影响这些神经元的膜电流和活动。这些研究揭示的原理有可能提高人们对多巴胺如何用于在人类运动模式之间切换以及运动模式启动和切换如何在帕金森病中变得功能障碍的理解。