Mechanisms of Distorted Inputs in Chronic Spinal Injury

描述（由申请人提供）：在脊髓损伤中，下降输入的丧失不仅损害运动指令，而且损害脊髓兴奋性的下降控制。这项提议的目标是了解脊髓回路行为扭曲的细胞和突触机制，这种扭曲会产生异常的肌肉激活模式和意想不到的运动，如痉挛。为了实现这一目标，我们使用慢性脊髓猫准备来开发一种新的翻译方法，其中我们将细胞机制与系统行为联系起来。我们的结果可能为实验提供明确的预测，以评估这些相同的机制是否发生在人类脊髓损伤受试者中。在完整状态下，大量数据表明，感觉输入对运动输出的影响是集中的，互惠的和一致的。这些效应集中在一个关节的感觉输入主要诱导同一关节的运动输出的意义上，在感觉输入产生的相互作用

DESCRIPTION (provided by applicant): In spinal injury, the loss of descending input not only impairs motor commands but also damages descending control of spinal excitability. The goal of this proposal is to understand the cellular and synaptic mechanisms of the resulting distortions in the behavior of spinal circuits, which can generate aberrant muscle activation patterns and unintended movements like spasms. To achieve this goal, we use our chronic spinal cat preparation to develop a novel translational approach, in which we link cellular mechanisms to system behaviors. Our results potentially provide clear predictions for experiments to evaluate whether these same mechanisms occur in human spinal injured subjects. In the intact state, considerable data show that the effects of sensory inputs on motor outputs are focused, reciprocal and consistent. These effects are focused in the sense that sensory input from one joint primarily induces motor output at that same joint, reciprocal in that sensory inputs generate opposite actions on antagonists and consistent in that sensory inputs generate stable responses to repeated activations. The basic concept underlying this proposal is that the loss of descending control of spinal excitability induces precisely the opposite sensory processing state, one that is diffuse, co- active and inconsistent. Although likely overly simple this concept provides clearly testable hypotheses and moreover is supported by significant data, including our recent preliminary studies. The translational nature of our experimental design arises from two novel techniques that link intracellular measurements to the "real world": 1) synaptic currents are measured during voltage clamp in response to precise movements of the entire hindlimb via a 6 degree of freedom robotic arm and 2) firing patterns from intracellular recordings are compared to firing patterns of populations of motor units recorded by a newly developed electrode array placed on muscle. Both the robotic and the array techniques are already in use in human subjects, thus providing the basis for our proposed predictions for human experiments. Aim 1 seeks to identify the mechanisms of expanded receptive fields by identifying the types of sensory afferents involved. Aim 2 examines the balance of excitation versus inhibition, primarily relying on intracellular recordings. Aim 3 investigates wind-up, both n terms of quantifying its strength and in terms of determining its source in motoneurons versus interneurons. The proposed experiments will provide a new depth of understanding of the distortions in spinal processing of sensory input that emerge in spinal injury. Each aim will provide information critical for developing specific therapeutic interventions, focusing on restoration of normal functional connections and minimization of wind- up.