Control of Motor Systems by Cotransmitters

描述（由申请人提供）：本研究的长期目标是了解神经递质系统如何控制运动活动。本研究将探讨含有多种神经递质的神经元信号传导的机制和功能后果。它将利用一个实验上有利的模型，在这个模型中，有可能识别出表现出特定递质表型的特定神经元，并确定这些神经元对复杂运动模式产生的贡献。迄今为止进行的实验1)定位了海马体中含有GABA和多巴胺（DA）的神经元，2)证明了这些主要神经递质系统的重叠或共定位只发生在五个神经元中，所有这些神经元都参与控制进食的中枢模式发生器（CPG）回路，3)定位了GABA-DA共存的中间神经元，这些中间神经元可以指定多功能CPG的功能配置。结合神经生理学、神经解剖学和药理学的方法将检验本研究的中心假设：GABA-DA中间神经元是多功能CPG回路固有的，可以通过调节信号指定功能性运动模式。提出的实验有三个具体目的来验证这一假设：1)确定DA和GABA对其共定位神经元的快速和缓慢突触信号的贡献，2)探索共定位DA和GABA在调节这些中间神经元表现出的多种形式的突触可塑性中的作用，以及3)确定共定位DA和GABA对突触后运动神经元内在膜特性的调节各自的贡献。这些研究有望为包括人类中枢神经系统在内的更复杂的大脑运动控制提供见解和原理。鉴于多巴胺能和gaba能神经递质系统在我们目前对主要神经运动障碍的理解中的关键作用，这些原理也应该为制定治疗和治疗策略提供信息。该项目的发展目标将使私家侦探得以继续努力获得有竞争力的研究支持。鉴于对最近的建议的积极评价，预期这一目标将在这一赠款期间实现。

DESCRIPTION (provided by applicant): The broad, long-term objective of this research is to understand how neurotransmitter systems control motor activity. The present study will address the mechanistic and functional consequences of signaling by neurons that contain multiple neurotransmitters. It will utilize an experimentally favorable model in which it is possible to identify specific neurons that exhibit a particular transmitter phenotype and to determine the contribution of those neurons to the generation of complex motor patterns. Experiments conducted to date have 1) localized the neurons that contain GABA and dopamine (DA) in Aplysia, 2) demonstrated that the overlap, or colocalization, of these major neurotransmitter systems occurs in only five neurons, all of which participate in the central pattern generator (CPG) circuit that controls feeding, and 3) localized GABA-DA coexistence to identified interneurons that can specify the functional configuration of this multifunctional CPG. Methods integrating neurophysiology, neuroanatomy, and pharmacology will test the central hypothesis of this study: GABA-DA interneurons that are intrinsic to a multifunctional CPG circuit can specify functional motor patterns via modulatory signaling. The proposed experiments address three specific aims that test this hypothesis: 1) determine the contributions of DA and GABA to rapid and slow synaptic signaling by the neurons in which they are colocalized, 2) explore the roles of colocalized DA and GABA in the regulation of multiple forms of synaptic plasticity that these interneurons display, and 3) determine the respective contributions of colocalized DA and GABA to the modulation of intrinsic membrane properties of postsynaptic motor neurons. These studies promise to lead to insights and principles that will have applicability to motor control in more complex brains, including the human central nervous system. In view of the pivotal role of dopaminergic and GABAergic neurotransmitter systems in our present understanding of major neurological movement disorders, these principles should also inform efforts to develop therapeutic and treatment strategies. The developmental objectives of this project will enable the PI to continue his efforts to acquire competitive research support. In view of positive evaluations of recent proposals, it is anticipated that this objective will be achieved during this grant period. Public Health Relevance: Several major neurological movement disorders, such as Parkinson's Disease and Huntington's Disease, are currently attributed to the malfunctioning or imbalance of specific brain pathways. This project will examine the contributions of brain cells that contain specific signaling molecules, or neurotransmitters, to the control of movement. This investigation will increase our understanding of how brain circuits control motor behavior and how major movement disorders result when these circuits are compromised.