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。这包括确定运动回路和行为相关回路协调过程中固有的灵活性，以及确定这些事件背后的细胞机制。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。一个定义良好的模型系统，螃蟹口胃神经系统，将被使用。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已识别的调节投射神经元用于改变两个明确定义的运动回路（胃磨（咀嚼）和幽门（咀嚼食物的过滤）回路）输出的机制来扩展先前的工作。本文将验证三个假设：(1)不同的调节输入可以通过不同的细胞机制引发相同的神经元活动模式；(2)负责节律产生的神经元和突触可以通过投射神经元引发的调节而改变；(3)投射神经元活动的电路调节可以决定电路输出。这些研究将使用电生理学和药理学方法来监测和操纵回路和投射神经元的活动。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可以对神经元网络活动进行详细细胞内分析的生物系统之一，其中有一群已识别的投射神经元。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运动功能障碍。

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. This includes determining the flexibility inherent in motor circuits and during coordination of behaviorally-related circuits, plus determining the cellular mechanisms underlying such events. This work focuses on rhythmically active motor circuits, such as those underlying walking, breathing, and chewing. A well-defined 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 mechanisms used by identified modulatory projection neurons to alter the output of two well-defined motor circuits, the gastric mill (chewing) and pyloric (filtering of chewed food) circuits. Three hypotheses will be tested: (1) Different modulatory inputs can elicit the same neuronal activity pattern via distinct cellular mechanisms; (2) The neurons and synapses responsible for rhythm generation can be altered by projection neuron-elicited modulation; (3) Circuit regulation of projection neuron activity can determine circuit output. These studies will be done using electrophysiological and pharmacological approaches to monitor and manipulate the activity of circuit and projection neurons. 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 of neuronal network activity is possible and in which there is a population of identified projection neurons. 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 motor dysfunctions that occur as a result of events such as spinal cord injury and stroke.