Functional Development of Motor Networks

 描述(申请人提供)：运动是脊椎动物所有行为形式的基础，由脊髓内的兴奋和抑制回路驱动。在运动过程中，这些网络向支配四肢和躯干肌肉的运动神经元发出有节奏的命令。在所有脊椎动物中，运动神经元及其目标肌肉系统(运动单位)被组织为功能增效剂和拮抗剂。兴奋回路确保功能协同运动单位的协调激活，而抑制回路维持功能拮抗运动单位的交替。随着运动产生的强度更大，可以施加更大力量的较大运动单位被有序地招募到活动池中，与它们的大小、兴奋性和目标肌肉结构相关的特征相匹配。然而，无论运动强度如何，对抗的运动单位通常是交替激活的。尽管数十年来一直在研究负责左右或屈伸交替的脊髓抑制回路，但对抑制如何组织以确保在运动速度或力量变化时不同大小的运动单位的适当激活知之甚少。我们的目标是以斑马鱼为模型系统，确定系统相互抑制模式的存在，这些模式有助于协调运动过程中脊髓运动神经元的招募模式。我们将测试这一假设，即抑制性突触连接的强度在发育过程中以一种有序的方式出现，并根据运动神经元内的速度进行映射，这样，较快速度的抑制作用发生得更早、更近，而较慢速度的抑制作用发生得更晚、更远。我们在这里揭示的模式将为抑制和运动神经元兴奋性的正常功能整合提供关键的机械洞察力，它们的中断是许多运动疾病和障碍的基础。

 DESCRIPTION (provided by applicant): Movements underlie all forms of vertebrate behavior and are driven by excitatory and inhibitory circuitry within the spinal cord. During locomotion, these networks generate rhythmic commands to motor neurons innervating muscles in the limbs and trunk. In all vertebrates, the motor neurons and their target musculature (motor units) are organized as functional synergists and antagonists. While excitatory circuits ensure the coordinated activation of functionally synergistic motor units, inhibitory circuits maintain the alternation of functionally antagonistic ones. As movements are generated with greater intensity, larger motor units that can exert greater force are recruited into the active pool in an orderly fashion that matches features related to their size, excitability and target musculature. However, regardless of intensity of locomotion, antagonistic motor units are typically activated in alternation. Despite decades of work studying the spinal inhibitory circuitry responsible for left-right or flexor-extensor alternation, relatively little is known about how inhibition is organized o ensure the appropriate activation of motor units of differing sizes during variations in movement speed or strength. Our goal is to determine the existence of systematic patterns of reciprocal inhibition that help coordinate the recruitment patterns of spinal motor neurons during locomotion using zebrafish as a model system. We will test the hypothesis that the strength of inhibitory synaptic connections arises in an orderly fashion during development and is mapped according to speed within motor neurons, such that inhibition at faster speeds arrives early and more proximally, while inhibition at slower speeds arrives later and more distally. The patterns we reveal here will provide critical mechanistic insight into the normal functional integration of inhibition and motor neuron excitability, disruptions of which underlie numerous motor diseases and disorders.