Optical dissection of intracortical circuits supporting motor recovery after spinal cord injury

项目概述：皮质运动网络是一个关键的，如果经常被忽视，运动恢复后， 脊髓损伤（SCI）。皮层网络需要通过离皮层神经元来指导输出 投射到脑干和脊髓，这些网络的可塑性将是不可或缺的， 学习如何使用因SCI或治疗干预而改变的脊髓回路。康复是必要的， 皮质脊髓依赖性前肢功能的恢复和 破坏了皮质运动地图目前还不清楚是什么潜在的电路机制支持 SCI后的皮质重组，或者这种广泛的重组是否是支持功能的必要条件， 复苏长期目标是开发利用皮层可塑性的治疗干预措施， 促进SCI康复。本提案的总体目标是确定皮质内回路 负责恢复熟练的前肢功能核心假设是潜在的皮质内联系 从去传出后肢到前肢区域的投射是康复介导的恢复所必需的。 熟练掌握颈脊髓损伤后的前肢功能。拟议研究的理由是， 运动皮层如何整合SCI后的电路变化将有助于我们针对运动神经元的新疗法。 复苏提出了以下三个具体目标：1）记录皮质内的内源性活动 神经元在康复介导的恢复从SCI; 2）确定水平的结构变化， 脊髓损伤康复过程中的水平连接; 3）确定水平连接对运动的贡献 SCI后的康复对于第一个目标，该方法将记录相互连接的后肢的活动， 在熟练的前肢行为期间前肢运动区域，以确定它们对康复的反应 SCI的。在第二个目标中，该方法将对皮质内轴突的结构变化进行成像， 树突棘在体内纵向从SCI康复过程中。在第三个目标中，方法将是1） 在清醒、行为正常的小鼠中沉默相互连接的神经元，以确定它们对恢复的贡献，以及2） 刺激相互连接的神经元并测量前肢运动诱发电位。拟议的研究是 创新之处在于他们将脊髓损伤研究的重点从轴突再生转移到皮质内 解释脊髓回路变化所需的网络。拟议的研究具有重要意义 因为他们将提供一个详细的了解电路重塑的机制， 复苏预计完成拟议的研究将决定在多大程度上 皮质内神经元可塑性是皮质运动映射重组的基础，并支持术后功能恢复。 SCI.这些发现将为建立治疗进展奠定基础，并规定 对于急性和慢性SCI，最适合采取的策略是。

PROJECT SUMMARY: Cortical motor networks are a critical, if often overlooked, mediator of motor recovery after spinal cord injury (SCI). Cortical networks are required for instructing output through the corticofugal projections to the brainstem and spinal cord, and the plasticity of these networks will be indispensable for re- learning how to use the spinal circuits altered by SCI or therapeutic intervention. Rehabilitation is necessary for both the recovery of corticospinal-dependent forelimb function and the commensurate reorganization of disrupted cortical motor maps. It remains unknown what the underlying circuit mechanisms are that support cortical reorganization after SCI, or whether such broad reorganization is necessary to support functional recovery. The long-term goal is to develop therapeutic interventions that take advantage of cortical plasticity to promote recovery from SCI. The overall objective for this proposal is to identify the intracortical circuitry responsible for restoring skilled forelimb function. The central hypothesis is that latent intracortical connections projecting from de-efferented hindlimb to forelimb areas are required for rehabilitation-mediated recovery of skilled forelimb function after cervical SCI. The rationale for the proposed research is that the knowledge of how the motor cortex incorporates circuit changes after SCI will help us to target new therapies for motor recovery. The following three specific aims are proposed: 1) Record the endogenous activity from intracortical neurons during rehabilitation-mediated recovery from SCI; 2) Determine the structural changes in horizontal connections during rehabilitation from SCI; and 3) Identify the contribution of horizontal connections to motor recovery after SCI. For the first aim, the approach will be to record activity from interconnected hindlimb and forelimb motor regions during skilled forelimb behavior in order to determine their response to rehabilitation from SCI. In the second aim, the approach will be to image structural changes of intracortical axons and dendritic spines in vivo longitudinally during rehabilitation from SCI. In the third aim, the approach will be to 1) silence interconnected neurons in awake, behaving mice to determine their contribution to recovery, and 2) stimulate interconnected neurons and measure forelimb motor evoked potentials. The proposed studies are innovative in that they shift the focus of spinal cord injury research from axon regeneration to the intracortical networks required for interpreting the changes in spinal cord circuitry. The proposed studies are significant because they will provide a detailed understanding of the mechanisms of circuit remodeling that influence recovery. The expectation is that completion of the proposed research will determine the extent to which intracortical neuron plasticity underlies cortical motor map reorganization and supports functional recovery after SCI. These findings will establish a foundation upon which to build therapeutic advances and dictate which strategies are most appropriate to pursue for both acute and chronic SCI.