Serotonergic facilitation of spinal stepping by epidural stimulation: mechanisms

描述（由申请人提供）：很明显，当应用一种或多种干预措施时，成年大鼠在脊髓完全横断胸中段后可以产生协调的、重量支撑的后肢行走，例如，阶梯训练、药理学调节和/或腰骶脊髓的硬膜外刺激。在进行一系列研究时，我们和其他人已经观察到腰骶脊髓沿着有显著水平的喙尾异质性，这在生理学、生化学和行为学上都得到了证实。具体而言，诱导的步进具有独特的特征，这些特征取决于受刺激的脊髓节段、被激活的多巴胺能受体的类型以及参与脊髓运动产生的那些神经元的解剖位置。本建议的目的是确定起源的这种rostrocaudal异质性的步进特性，可以归因于主要5-HT 2A/C和5-HT 1/7受体在成年，完整的脊髓大鼠。我们将确定这些受体亚型中的每一种都能在多大程度上有助于改善步进，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，我们将确定这种脊髓节段异质性如何在完全脊髓损伤后的几周内发生变化，有和没有机器人控制的步骤训练，以及诱导多突触反射的能力如何与运动能力的恢复成功相关。这些研究还将产生进一步开发新电极阵列所需的数据，用于刺激脊髓上的特定部位，并证明这种新电极阵列技术在改善脊髓损伤后的步行能力方面的潜在作用。实际上，这些研究将提供确定开发临床干预的可行性所需的基础数据，该临床干预包括使用电极阵列的硬膜外刺激结合药理学调节和运动训练，以使严重受伤的个体恢复承重能力。公共卫生相关性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）证明通过阵列刺激脊髓特定区域以改善脊髓损伤后的步行能力的潜力。具体地说，这些研究将证明开发包括脊髓刺激的临床干预的可行性（通过放置在脊髓表面上的电极阵列）结合药理学调节（给予增强脊髓反应性的药物）和运动训练（踩在跑步机上）以使严重脊髓损伤的个体能够恢复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.