Lesion and activity dependent corticospinal tract plasticity

描述（由申请人提供）：我们实验的总体目标是利用活动来促进皮质脊髓束（CST）部分损伤后的皮质脊髓系统功能，例如大多数脊髓损伤或中风后。损伤后CST连接通过反应性发芽和功能恢复自发修复，但两者都是有限的。然而，我们的研究表明，增加空闲CST的活性可以用来促进修复和运动恢复。这是基于我们的研究结果，即成熟大鼠的CST选择性电刺激，如在发育中，增加CST轴突的生长并促进脊髓连接的形成。重要的是，我们新发表的初步研究结果表明，刺激损伤后保留的CST轴突增加了反应性发芽。加强CST连接，并能改善运动技能。我们在成年大鼠中使用可重复的部分损伤模型，单侧锥体束（PT）病变，从一个皮层破坏CST。与人类一样，大鼠的CST在很大程度上是交叉的，但也有相当一部分轴突是同侧终止的。单侧PT损伤后，病变对侧脊髓失去对侧CST密集投影；只剩下稀疏的同侧轴突。我们的研究集中在这些同侧CST轴突作为部分脊髓损伤和中风后的备用轴突模型。在拟议的实验中，我们将通过电刺激PT中剩余的CST轴突来选择性地激活未受损的CS系统，以增强PT损伤后的自发恢复。在目的1中，我们将确定脊髓受损侧的同侧CST末端与机械感觉传入之间的特定相互作用是否会限制CST的生长，以及CST活动的增强是否会减轻这种情况。在Aim 2中，我们将确定PT损伤后增加的发芽是否会导致同侧CST轴突与受损侧已识别的脊髓神经元类别之间更“对侧”的连接模式，这种模式可能确保更强的运动神经元激活。我们还将确定活动是否会增加脑干运动中心的生长，这些运动中心包括间接皮质通路到脊髓的继电器。在目标3中，我们将确定在PT病变后增强CST活动是否促进熟练肢体运动的恢复，以及这种恢复在多大程度上是由受损或未受损的一侧介导的。阐明自发性神经中枢系统修复的系统水平机制，以及选择性神经中枢刺激增强修复的能力，将有助于设计促进损伤后运动技能恢复的新策略。我们的研究具有很强的潜力，可以转化为脑或脊髓损伤患者。使用经颅磁刺激（TMS）可以在人类中实现非侵入性的Mi流出选择性刺激。我们的刺激方法可能适用于不同程度的严重程度和受伤后的不同时间。公共卫生相关性：我们实验的总体目标是促进脊髓损伤或中风后的运动功能。我们集中在皮质脊髓束，主要的运动控制途径在人类。利用大鼠模型，我们通过电刺激增加损伤后皮质脊髓束的神经活动，以恢复与脊髓运动控制中心失去的连接。我们将确定大脑皮层、脑干和脊髓可塑性在恢复熟练运动功能中的重要性。

DESCRIPTION (provided by applicant): The overall goal of our experiments is to use activity to promote corticospinal system function after partial injury to the corticospinal tract (CST), such as occurs after most spinal cord injuries or stroke. Repair of CST connections through reactive sprouting and recovery of function occurs spontaneously after injury, but both are limited. However, our studies show that augmenting the activity of the spared CST can be used to promote repair and motor recovery. This is based on our findings that selective electrical stimulation of the CST in the mature rat, as in development, increases CST axon outgrowth and promotes formation of spinal connections. Importantly, our newly published and preliminary findings show that stimulation of CST axons spared after injury augments reactive sprouting. strengthens CST connections, and can improve motor skills. We use a reproducible partial injury model in the adult rat, a unilateral pyramidal tract (PT) lesion, which destroys the CST from one cortex. The rat CST, like in humans, is largely crossed, but there is a significant contingent of axons that terminate ipsilaterally. After unilateral PT damage, the spinal cord contralateral to the lesion losses its dense contralateral CST projection; only the sparse ipsilateral axons remain. Our studies focus on these ipsilateral CST axons as a model of spared axons after partial spinal cord injury and stroke. In the proposed experiments we will selectively activate the undamaged CS system by electrical stimulation of spared CST axons in the PT, to augment spontaneous recovery after PT lesion. In Aim 1 we will determine whether specific interactions between spared ipsilateral CST terminations on the impaired side of the spinal cord and mechanosensory afferents limit CST outgrowth, and if augmenting CST activity mitigates this. In Aim 2 we will determine if augmenting sprouting after PT lesion leads to a more "contralateral" pattern of connections between spared ipsilateral CST axons and identified spinal neuron classes on the impaired side, a pattern that may ensure stronger motoneuron activation. We will also determine if activity augments outgrowth into brain stem motor centers that comprise relays for indirect cortical paths to the spinal cord. In Aim 3 we will determine if augmenting CST activity after PT lesion promotes recovery of skilled limb movements and the extent to which this recovery is mediated by the damaged or undamaged side. Elucidating systems-level mechanisms of spontaneous CS system repair, and the capacity for selective CS stimulation to augment repair, will help to devise new strategies for promoting recovery of motor skills after injury. Our research has the strong potential to be translated to patients with brain or spinal cord injury. Selective stimulation of the Mi outflow can be achieved non-invasively in humans using transcranial magnetic stimulation (TMS). Our stimulation approach would likely apply to various levels of severity and different times after injury. PUBLIC HEALTH RELEVANCE: The overall goal of our experiments is to promote motor function after spinal cord injury or stroke. We focus on the corticospinal tract, the principal motor control pathway in humans. Using a rat model, we increase neural activity of the corticospinal tract after injury, by electrical stimulation, to restore lost connections to spinal cord motor control centers. We will determine the importance of plasticity in the cerebral cortex, brain stem, and spinal cord in recovery of skilled motor function.