Propriopsinal neuron function in normal and post-SCI locomotion

摘要：尽管自认识脊髓固有运动回路以来已有100多年的历史，但许多 这些回路的功能细节及其对脊髓损伤(SCI)后恢复的贡献 仍有待确定。功能强大的分子工具的最新发展使功能解剖成为可能 通过可逆性沉默、神经传递和跨突触标记的神经回路。我们将把这些结合起来 具有复杂步态和运动学分析的工具，包括速度相关步态的完整曲目， 为建立和完善先进的神经细胞提供必要的功能和解剖学信息- 大鼠脊髓、身体和四肢的生物力学计算机模型。我们将重点介绍两类脊椎 脊髓中间神经元，即长升(LAPN)和长降(LDPN)固有脊髓神经元， 在两个放大部分中互连前肢和后肢电路以及中央图案生成器，以及 使用半横断和挫伤模型研究它们在完整脊髓和脊髓损伤后的作用。我们的 初步数据显示，这些LAPN/LDPN是参与速度相关步态的重要组成部分 表情。让这些神经元安静下来，会使左右两条腿在每条腰带上部分分离。令人惊讶的是， 在不完全性挫伤后，使这些神经元沉默会导致更好的地面运动 根据目前的知识和对未受伤动物的观察，这一点很难调和。使用基于病毒的 跨突触标记我们将确定感觉、下行和本体脊髓对两个LAPN的输入 和低密度脂蛋白。我们将利用现有和新的生理和生物力学数据(目标1)以及新的 解剖数据(目标2)建立和改进我们的计算模型(目标3)。然后，活体实验和 将并行执行计算机模拟(目标4)，以确定同侧和连合的角色 LAPN和LDPN在运动行为中发挥作用，包括全面的运动步态，以及在恢复过程中 半切伤和不完全性挫伤后的功能。我们建议对Long的更深入的理解 固有脊髓神经元是朝着开发新的治疗工具迈出的重要一步 脊髓损伤后的康复。

Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits, many of the functional details of those circuits and their contributions to recovery following spinal cord injury (SCI) remain to be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine these tools with sophisticated gait and kinematic analyses, that includes the full repertoire of speed dependent gaits, to provide the functional and anatomical information necessary for building and refining an advanced neuro- biomechanical computer model of the rat spinal cord, body and limbs. We will focus on two classes of spinal cord interneurons, the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons, that interconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements, and investigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Our preliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gait expression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisingly, silencing these neurons after an incomplete contusion injury results in better overground locomotion, a result that is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-based trans-synaptic labeling we will determine the sensory, descending and propriospinal inputs onto both LAPNs and LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as new anatomical data (Aim 2) to build and refine our computational model (Aim 3). Then, in vivo experiments and computer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissural LAPNs and LDPNs play in locomotor behavior, including the full range of locomotor gaits, and in recovered function after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of long propriospinal neurons represents an important step towards the development of new therapeutic tools for recovery after SCI.