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，成年大鼠在进行完整的胸中横断脊髓后，可以产生协调的、重量支持的后肢踏步，例如，阶梯训练、药物调节和/或腰椎脊髓的硬膜外刺激。在进行一系列研究的同时，我们和其他人观察到了沿腰骶脊髓的吻尾部异质性的显著水平，这在生理、生化和行为上都得到了证实。具体地说，诱导台阶有一些独特的特征，取决于刺激的脊髓节段，药物激活的5-羟色胺能受体的类型，以及参与脊髓运动产生的神经元的解剖位置。本研究的目的是确定成年完整脊髓大鼠在步态特征上的吻尾异质性的来源，这种异质性主要归因于5-HT2A/C和5-HT1/7受体。我们将确定每一种受体亚型对改善步态的贡献程度，它们如何独特地调节特定屈肌和伸肌的激活模式，以及由此对后肢运动学的影响。此外，我们将确定在完全脊髓损伤后的几周内，在有和没有机器人控制的阶梯训练的情况下，这种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有关。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，并展示这种新的电极阵列技术在改善脊髓损伤后步行能力方面的潜在作用。实际上，这些研究将提供必要的基本数据，以确定开发一种临床干预的可行性，该干预包括使用电极阵列进行硬膜外刺激，并结合药物调节和运动训练，使严重受伤的个人能够恢复负重能力。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)展示通过该阵列刺激脊髓特定区域以提高脊髓损伤后步行能力的潜力。具体地说，这些研究将论证开发一种临床干预的可行性，该干预包括刺激脊髓(通过放置在脊髓表面的电极阵列)，结合药物调节(给药以增强脊髓的响应性)和运动训练(踩在跑步机上)，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.