Mechanisms of Distorted Inputs in Chronic Spinal Injury

描述（由申请人提供）：在脊髓损伤中，下行输入的丧失不仅损害运动指令，而且损害脊髓兴奋性的下行控制。该提案的目标是了解脊髓回路行为中导致扭曲的细胞和突触机制，这可能会产生异常的肌肉激活模式和痉挛等意外运动。为了实现这一目标，我们使用我们的慢性脊髓猫制剂开发了一种新的翻译方法，其中我们将细胞机制与系统行为联系起来。我们的研究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的受试者。在完整状态下，大量的数据表明，感觉输入对运动输出的影响是集中的，相互的和一致的。这些效应集中在这样一个意义上，即来自一个关节的感觉输入主要诱导同一关节的运动输出，这是相互的，因为感觉输入产生运动输出。 对拮抗剂的相反作用，并且在感觉输入对重复激活产生稳定反应方面是一致的。这一提议的基本概念是，脊髓兴奋性下降控制的丧失恰恰诱导了相反的感觉处理状态，即弥散、共同活动和不一致的感觉处理状态。虽然这个概念可能过于简单 提供了明确的可验证的假设，而且得到了重要数据的支持，包括我们最近的初步研究。我们实验设计的转化性质源于两种将细胞内测量与“真实的世界”联系起来的新技术：1）通过6自由度机械臂，在电压钳期间响应于整个后肢的精确运动测量突触电流，以及2）将来自细胞内记录的放电模式与由新开发的电极记录的运动单位群体的放电模式进行比较放置在肌肉上的阵列。机器人和阵列技术都已经在人类受试者中使用，从而为我们提出的人类实验预测提供了基础。目的1试图通过识别感觉传入的类型来确定感受野扩大的机制。目的2检查兴奋与抑制的平衡，主要依赖于细胞内记录。目的3调查风了，无论是在量化其强度和确定其来源的运动神经元与中间神经元。拟议的实验将提供一个新的深度理解的扭曲，在脊髓损伤中出现的感觉输入脊髓处理。每个目标都将为制定具体的治疗干预措施提供关键信息，重点是恢复正常的功能连接和最大限度地减少风。

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.