Control of Motor Systems by Cotransmitters

描述（由申请人提供）：本研究的广泛，长期目标是了解神经递质系统如何控制运动活动。本研究将解决的机制和功能的后果，信号由神经元含有多种神经递质。它将利用一个实验有利的模型，其中有可能确定特定的神经元，表现出特定的递质表型，并确定这些神经元的复杂运动模式的产生的贡献。迄今为止进行的实验已经1）在失智症中定位了含有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仅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央模式发生器（CPG）回路，和3）将GABA-DA共存定位于能够指定该多功能CPG的功能构型的经鉴定的中间神经元。整合神经生理学，神经解剖学和药理学的方法将测试本研究的中心假设：GABA-DA中间神经元是一个多功能的CPG电路固有的可以指定功能的运动模式，通过调制信号。拟议的实验针对三个具体目标来检验这一假设：1）确定DA和GABA对它们共定位的神经元的快速和缓慢突触信号传导的贡献，2）探索共定位的DA和GABA在这些中间神经元显示的多种形式的突触可塑性的调节中的作用，和3）确定共定位的DA和GABA对突触后运动神经元的内在膜特性的调制的各自贡献。这些研究有望带来适用于更复杂大脑（包括人类中枢神经系统）运动控制的见解和原则。鉴于多巴胺能和γ-氨基丁酸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，这些原则也应该为开发治疗和治疗策略提供信息。这个项目的发展目标将使PI继续努力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，例如帕金森病和亨廷顿病，目前被归因于特定脑通路的功能障碍或不平衡。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主要运动障碍的理解。

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.