Motor Circuit Modulation and its Regulation

描述（由申请人提供）：该项目的长期目标是在细胞水平上了解中枢神经系统如何选择和产生运动背后的神经元活动模式。具体而言，该项目的重点是确定运动回路中固有的灵活性，这些灵活性是在响应从感觉神经元，激素和调节投射神经元接收的输入时表达的。这包括确定上述电路灵活性背后的细胞机制。这项工作的重点是有节奏地活跃的运动回路，如那些潜在的步行，呼吸和咀嚼。一个定义明确的小模型系统，蟹口胃神经系统，将被使用。先前的研究表明，所有动物产生节律性运动程序的基本原理都是相同的。这项建议的目的是扩展以前的工作，确定metamodulation（调制的调制作用），感觉反馈和cotransmission对运动模式的生成使用定义明确的胃磨（咀嚼）运动电路在螃蟹的口胃神经系统的作用。四个假设将被测试：（1）由不同的CPG回路产生的可比较的运动模式对激素输入和感觉输入的反应不同;（2）肽激素差异地门控相同的感觉输入。（本体感受器）输入到由不同的CPG回路产生的两个可比较的运动模式;（3）同一神经调质作用于运动系统的多个水平;（4）肽能调节可通过GABA能共传递调节。这些研究将使用电生理学和药理学方法来监测和操纵投射神经元、回路神经元、运动神经元、感觉神经元和肌纤维的活动。一个名为动态钳的计算机程序将被用来将突触和离子电流的真实版本注入单个神经元。口胃系统是为数不多的生物系统之一，其中详细的细胞内分析和神经元网络活动的操纵，在确定的神经元和肌肉的水平，是可能的。因此，拟议的研究将提供一个有价值的模板，了解可比的事件，在数字上更大，更难接近的哺乳动物中枢神经系统。它还将有助于理解由于脊髓损伤和中风等事件而发生的感觉和运动功能障碍。项目叙述拟议的研究将提供一个细胞水平的模型生物系统，以了解可比的事件在数字上更大，更难接近的哺乳动物中枢神经系统。这包括提供洞察的感觉和运动功能障碍的功能后果发生的事件，如脊髓损伤和中风，当下行调节投射和/或感觉反馈受到损害或其行动被改变。

DESCRIPTION (provided by applicant): The long-term goals of this project are to understand, at the cellular level, how the central nervous system selects and generates the neuronal activity patterns underlying movement. Specifically, this project focuses on determining the flexibility inherent in motor circuits that is expressed in response to input they receive from sensory neurons, hormones and modulatory projection neurons. This includes determining the cellular mechanisms underlying the aforementioned circuit flexibility. This work focuses on rhythmically active motor circuits, such as those underlying walking, breathing, and chewing. A well-defined small model system, the crab stomatogastric nervous system, will be used. Previous work has shown that the same general principles underlie the generation of rhythmic motor programs in all animals. This proposal aims to extend previous work by determining the roles of metamodulation (modulation of a modulatory action), sensory feedback and cotransmission on motor pattern generation using the well-defined gastric mill (chewing) motor circuit in the crab stomatogastric nervous system. Four hypotheses will be tested: (1) Comparable motor patterns generated by distinct CPG circuits respond differently to a hormonal input and a sensory input; (2) a peptide hormone differentially gates the same sensory (proprioceptor) input to two comparable motor patterns generated by distinct CPG circuits; (3) the same neuromodulator acts at multiple levels of a motor system, and (4) peptidergic modulation can be regulated by GABAergic cotransmission. These studies will be done using electrophysiological and pharmacological approaches to monitor and manipulate the activity of projection neurons, circuit neurons, motor neurons, sensory neurons and muscle fibers. A computer program called the Dynamic Clamp will be used to inject realistic versions of synaptic and ionic currents into single neurons. The stomatogastric system is one of the few biological systems in which a detailed intracellular analysis and manipulation of neuronal network activity, at the level of identified neurons and muscles, is possible. Thus, the proposed studies will provide a valuable template for understanding comparable events in the numerically larger and less accessible mammalian central nervous system. It will also facilitate understanding the sensory and motor dysfunctions that occur as a result of events such as spinal cord injury and stroke. PROJECT NARRATIVE The proposed studies will provide a cellular-level model biological system for understanding comparable events in the numerically larger and less accessible mammalian central nervous system. This includes providing insight into the functional consequences of sensory and motor dysfunctions that occur as a result of events such as spinal cord injury and stroke, when descending modulatory projections and or sensory feedback is compromised or their actions are altered.