ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE

多巴胺对运动模式切换的分析

• 批准号: 8478221
• 负责人: JONATHAN THOMAS PIERCE
• 金额: $ 24.73万
• 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/8478221
• 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; 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）：帕金森氏病中最令人衰弱的问题阻止了在不同的运动模式之间切换（包括运动所需的运动）的能力。这是由于多巴胺神经元在黑质中的变性引起的多巴胺能信号传导丧失。拟议研究的长期目标是研究多巴胺能功能的变化如何有助于运动模式转换。我们最近证明，强大的遗传模型秀丽隐杆线虫类似于人类，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要求。具体来说，秀丽隐杆线虫在干燥的环境中爬行，但在悬浮在水中时游泳。通过将行为分析，光遗传学和神经元消融结合在一起，我们发现多巴胺释放既需要且足以从游泳到爬行。我们还发现，在秀丽隐杆线虫中，多巴胺神经元的损失正是在运动模式之间切换的那一刻，这与帕金森氏病患者相似。人类和秀丽隐杆线虫中多巴胺信号传导的破坏作用之间的对应关系建立了这种模型的生物体，是一个有吸引力的系统，在该系统中，可以识别这些切换困难的神经分子基础。此外，秀丽隐杆线虫神经系统的本质完整接线图以及它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来研究多巴胺信号传导。拟议的研究解决了两个主要问题：首先，多巴胺信号如何促进转向适当的电机程序，其次，当多巴胺信号被中断时，运动程序的切换如何功能失调？ 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）我们将确定这些神经元在完整动物中的作用，因为它们在具有功能性钙成像的微流体室中的爬行和游泳之间切换。 （3）我们将研究多巴胺如何通过进行贴片钳电生理学来影响这些神经元的膜电流和活性。这些研究发现的原理有可能提高人们对多巴胺在人类运动模式之间如何切换以及运动模式的启动和开关如何在帕金森氏病中功能失调的理解。