Serotonergic facilitation of spinal stepping by epidural stimulation: mechanisms

描述（由申请人提供）：很明显，成年大鼠在完成中胸椎脊髓横断后，在应用一种或多种干预措施（例如，步骤训练、药理调节和/或腰骶脊髓硬膜外刺激）时，可以产生协调的、体重支撑的后肢行走。在进行一系列研究时，我们和其他人已经观察到沿腰骶脊髓存在显著的背足异质性，这在生理学、生物化学和行为学上都得到了证明。具体来说，诱发踏步的独特特征依赖于受刺激的脊髓节段，药理学上激活的血清素能受体的类型，以及参与脊髓运动产生的神经元的解剖位置。本研究旨在确定成年完整脊柱大鼠中主要由5-HT2A/C和5-HT1/7受体引起的步进特征的背侧异质性的起源。我们将确定每种受体亚型对改善步进的贡献程度，它们如何独特地调节特定屈肌和伸肌的激活模式，以及对后肢运动学的相应影响。此外，我们将确定在完全性脊髓损伤后的几周内，有或没有机器人控制的步进训练，脊髓节段异质性是如何变化的，以及诱导多突触反射的能力如何与运动能力的成功恢复相关。这些研究还将产生进一步开发用于刺激脊髓硬膜外特定部位的新电极阵列所需的数据，并证明这种新电极阵列技术在提高脊髓损伤后行走能力方面的潜在作用。实际上，这些研究将提供必要的基础数据，以确定开发临床干预措施的可行性，包括使用电极阵列硬膜外刺激，结合药物调节和运动训练，使严重受伤的个体重新获得负重能力。拟议的研究将产生所需的数据：1)进一步开发用于刺激脊髓的电极阵列；2)证明通过该阵列刺激脊髓特定区域以提高脊髓损伤后行走能力的潜力。具体来说，这些研究将证明开发一种临床干预的可行性，包括脊髓刺激（通过放置在脊髓表面的电极阵列），结合药理学调节（给药以增强脊髓的反应性）和运动训练（踩跑步机），使严重脊髓损伤的个体重新获得负重站立和行走能力。

DESCRIPTION (provided by applicant): It is clear that an adult rat can generate coordinated, weight-supported hindlimb stepping after a complete mid- thoracic transection of the spinal cord when one or more interventions are applied, e.g., step training, pharmacological modulation, and/or epidural stimulation of the lumbosacral spinal cord. While conducting a series of studies, we and others have observed a significant level of rostrocaudal heterogeneity along the lumbosacral spinal cord, as demonstrated physiologically, biochemically, and behaviorally. Specifically, there are unique features of the induced stepping that are dependent on the spinal cord segment stimulated, the type of serotonergic receptors that are activated pharmacologically, and in the anatomical location of those neurons that participate in the generation of spinal locomotion. The present proposal is designed to identify the origin of this rostrocaudal heterogeneity in stepping characteristics that can be attributed to principally 5-HT2A/C and 5-HT1/7 receptors in adult, complete spinal rats. We will determine the degree to which each of these receptor subtypes can contribute to improved stepping, how they uniquely modulate the activation patterns of specific flexor and extensor muscles, and the consequential effects on the kinematics of the hindlimbs. In addition, we will determine how this spinal cord segmental heterogeneity changes in the weeks after a complete spinal injury, with and without robotically controlled step training, and how the capability to induce polysynaptic reflexes relates to the success in the recovery of locomotor ability. These studies also will generate the data needed to further the development of a new electrode array to be used to stimulate specific sites on the spinal cord epidurally and to demonstrate the potential role of this new electrode array technology in improving stepping ability after a spinal cord injury. In effect, these studies will provide the fundamental data needed to determine the feasibility of developing a clinical intervention consisting of epidural stimulation using an electrode array in combination with pharmacological modulation and motor training to enable severely injured individuals to regain weight-bearing capability. PUBLIC HEALTH RELEVANCE The proposed studies will generate the data needed 1) to further the development of an electrode array to be used to stimulate the spinal cord, and 2) to demonstrate the potential of using stimulation of specific regions of the spinal cord through the array for improving stepping ability after a spinal cord injury. Specifically, these studies will demonstrate the feasibility of developing a clinical intervention consisting of stimulation of the spinal cord (via the electrode array placed on the surface of the spinal cord) in combination with pharmacological modulation (administration of drugs that enhance the responsiveness of the spinal cord) and motor training (stepping on a treadmill) to enable severely spinal cord injured individuals to regain weight-bearing standing and stepping capabilities.