Control of Motor Systems by Cotransmitters

描述(由申请人提供)：这项研究的广泛、长期目标是了解神经递质系统如何控制运动活动。这项研究将解决包含多种神经递质的神经元发出信号的机制和功能后果。它将利用一个实验上有利的模型，在该模型中，可以识别表现出特定递质表型的特定神经元，并确定这些神经元在复杂运动模式生成中的作用。到目前为止进行的实验已经定位了海兔中含有GABA和多巴胺(DA)的神经元，2)证明这些主要神经递质系统的重叠或共存只发生在5个神经元中，所有这些神经元都参与了控制摄食的中央模式生成器(CPG)电路，以及3)GABA和DA共存于已识别的中间神经元，这可以确定这个多功能CPG的功能配置。方法将神经生理学、神经解剖学和药理学结合起来，验证本研究的中心假设：多功能CPG环路固有的GABA-DA中间神经元可以通过调制信号指定功能运动模式。实验针对三个具体目的来验证这一假说：1)确定DA和GABA对共同定位的神经元的快慢突触信号的贡献；2)探讨DA和GABA共同定位在这些中间神经元表现出的多种形式的突触可塑性调节中的作用；以及3)确定DA和GABA共同定位对突触后运动神经元固有膜特性的调制各自的贡献。这些研究承诺将带来对包括人类中枢神经系统在内的更复杂大脑的运动控制具有适用性的见解和原则。鉴于多巴胺和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所起的关键作用，这些原则也应该指导我们努力开发治疗和治疗策略。该项目的发展目标将使私人投资能够继续努力，以获得有竞争力的研究支持。鉴于对最近提案的积极评价，预计这一目标将在本赠款期间实现。 公共卫生相关性：几种主要的神经运动障碍，如帕金森氏病和亨廷顿病，目前被归因于特定大脑通路的故障或不平衡。这个项目将研究含有特定信号分子或神经递质的脑细胞对运动控制的贡献。这项研究将增加我们对大脑回路如何控制运动行为以及当这些回路受损时如何导致重大运动障碍的理解。

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.