Motor Circuit Modulation and its Regulation

描述(由申请人提供)：本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潜在运动的神经活动模式。具体地说，这个项目的重点是确定运动回路中固有的灵活性，这种灵活性是对它们从感觉神经元、激素和调制投射神经元接收的输入做出反应而表达的。这包括确定上述电路灵活性背后的细胞机制。这项研究的重点是有节奏的运动神经回路，如行走、呼吸和咀嚼。将使用一个定义良好的小型模型系统--蟹的口胃神经系统。先前的研究已经表明，在所有动物中产生有节奏的运动程序的基本原理都是相同的。这项建议旨在通过确定代谢调节(调制行为的调制)、感觉反馈和共传递在运动模式生成中的作用，利用螃蟹口胃神经系统中明确定义的胃磨(咀嚼)运动回路，来扩展先前的工作。将检验四个假设：(1)不同CPG回路产生的可比运动模式对激素输入和感觉输入做出不同的反应；(2)肽荷尔蒙以不同方式将相同的感觉(本体感受器)输入与由不同CPG电路产生的两个可比运动模式门控；(3)相同的神经调节剂作用于运动系统的多个水平；以及(4)肽能调制可由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、环路神经元、运动神经元、感觉神经元和肌肉纤维的活动。一种名为动态钳位的计算机程序将被用来向单个神经元注入真实版本的突触电流和离子电流。口胃系统是少数几个生物系统之一，可以在已识别的神经元和肌肉水平上对神经元网络活动进行详细的细胞内分析和操作。因此，拟议的研究将为理解数量更大、更难接近的哺乳动物中枢神经系统中的可比事件提供一个有价值的模板。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。项目简介拟议的研究将提供一个细胞水平的生物模型系统，用于了解在数量更大和更难到达的哺乳动物中枢神经系统中发生的可比事件。这包括洞察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的功能后果，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.