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理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。具体来说，该项目侧重于确定运动回路中固有的灵活性，这种灵活性是对来自感觉神经元、激素和调节投射神经元的输入的响应。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的活跃运动回路，比如那些潜在的行走、呼吸和咀嚼。将使用一个定义良好的小型模型系统——螃蟹口胃神经系统。先前的研究表明，在所有动物中，韵律运动程序的产生都是基于相同的一般原理。本研究旨在通过确定蟹口胃神经系统中定义明确的胃磨（咀嚼）运动回路在运动模式产生中的超调节（调节作用的调节）、感觉反馈和共传递的作用来扩展先前的工作。将测试四个假设：(1)由不同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)一种肽激素将相同的感觉（本体感受器）输入不同地连接到由不同CPG回路产生的两种可比较的运动模式；(3)同一神经调节剂作用于运动系统的多个水平；(4)肽能调节可以通过gaba能共传递来调节。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、感觉神经元和肌肉纤维的活动。一个名为“动态钳”（Dynamic Clamp）的计算机程序将被用于向单个神经元注入真实版本的突触和离子电流。口胃系统是为数不多的生物系统之一，在已识别的神经元和肌肉的水平上，可以对神经元网络活动进行详细的细胞内分析和操作。因此，拟议的研究将提供一个有价值的模板，以理解在数字上更大，更不易接近的哺乳动物中枢神经系统中的可比事件。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。拟议的研究将提供一个细胞水平的模型生物系统，以了解在数字上更大且不易接近的哺乳动物中枢神经系统中的可比事件。这包括深入了解感觉和运动功能障碍的功能后果，这些功能障碍是由于脊髓损伤和中风等事件造成的，当下行调节投射和/或感觉反馈受损或其行为改变时。

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.