Lesion and activity dependent corticospinal tract plasticity

病变和活动依赖性皮质脊髓束可塑性

• 批准号: 7730193
• 负责人: John H Martin
• 金额: $ 2.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-19 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730193
• 关键词: Adult; Affect; Axon; Behavioral; Brain; Brain Stem; Cell Nucleus; Cerebral cortex; Chronic; Contralateral; Corticospinal Tracts; Deafferentation procedure; Development; Electric Stimulation; Ensure; Fiber; Forelimb; Goals; Human; Impairment; Injury; Ipsilateral; Left; Lesion; Limb structure; Mediating; Modeling; Motor; Motor Cortex; Motor Neurons; Motor Skills; Neurons; Pathway interactions; Patients; Pattern; Publishing; Pyramidal Tracts; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Sensory; Severities; Shapes; Side; Spinal; Spinal Cord; Spinal cord damage; Spinal cord injury; Stroke; Synapses; System; Time; Transcranial magnetic stimulation; Translating; base; gray matter; improved; limb movement; motor control; public health relevance; relating to nervous system; repaired; research study; response; visual motor

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.

描述（由申请人提供）：我们实验的总体目标是使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发生。通过反应性发芽和功能恢复来修复CST连接，受伤后自发发生，但两者均受到限制。但是，我们的研究表明，增强保险CST的活性可用于促进修复和运动恢复。这是基于我们的发现，即成熟大鼠中CST的选择性电刺激会增加CST轴突的生长并促进脊柱连接的形成。重要的是，我们新发表的初步发现表明，受伤后幸免的CST轴突增强了反应性发芽。加强CST连接，并可以提高运动技能。我们在成年大鼠（一种单侧锥体区（PT）病变中使用可重现的部分损伤模型，从一个皮层破坏了CST。与人类一样，大鼠CST在很大程度上交叉，但是有大量的轴突以同侧终止。单侧PT损伤后，病变对侧的脊髓损失其密集的对侧CST投射。仅存在稀疏的同侧轴突。我们的研究将这些同侧CST轴突侧重于部分脊髓损伤和中风后作为储物轴突的模型。在拟议的实验中，我们将通过对PT中保留的CST轴突进行电刺激来选择性地激活未损坏的CS系统，以增强PT病变后自发恢复。在AIM 1中，我们将确定在脊髓受损和机械感应传递在受损的一侧的较低的同侧CST终止之间的特定相互作用是否限制了CST的生长，以及是否增加了CST活性会减轻这种情况。在AIM 2中，我们将确定PT病变后增加发芽是否会导致保存的同侧CST轴突之间更“对侧”的连接模式，并在受损方面鉴定出脊柱神经元类别，这种模式可以确保更强的运动神经元激活。我们还将确定活性增加了脑干运动中心的生长，该中心构成了脊髓间接皮质路径的继电器。在AIM 3中，我们将确定PT病变后的CST活动是否会促进熟练的肢体运动的恢复，以及该恢复的程度是由受损或未损坏的一侧介导的。阐明自发CS系统维修的系统级别机制以及选择性CS刺激增强修复的能力，将有助于制定新的策略，以促进受伤后的运动技能恢复。我们的研究具有将大脑或脊髓损伤患者转化为强大的潜力。可以使用经颅磁刺激（TMS）在人类中无创实现MI流出的选择性刺激。我们的刺激方法可能适用于受伤后各种程度的严重程度和不同的时间。公共卫生相关性：我们实验的总体目标是在脊髓损伤或中风后促进运动功能。我们专注于皮质脊髓区，这是人类的主要运动控制途径。使用大鼠模型，我们通过电刺激增加了受伤后皮质脊髓道的神经活动，以恢复与脊髓运动控制中心失去的连接。我们将确定可塑性在大脑皮层，脑干和脊髓恢复熟练运动功能方面的重要性。