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: 10176602
• 负责人: John H Martin
• 金额: $ 34.34万
• 依托单位: CITY COLLEGE OF NEW YORK
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176602
• 关键词: Advanced Development; Anatomy; Animals; Automobile Driving; Axon; Behavioral; Biological Markers; Cathodes; Cervical; Cervical spinal cord injury; Characteristics; Chronic; Corticospinal Tracts; Dependence; Elements; Feedback; Fiber; Foundations; Functional disorder; Funding; Goals; Growth; Hand functions; Human; Hyperreflexia; Impairment; Injury; Interneurons; Interruption; Intervention; Knowledge; Lead; Lesion; Mediating; Methods; Modeling; Molecular; Motor; Motor Cortex; Motor Pathways; Movement; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Neurons; Outcome; Paralysed; Pattern; Pharmacology; Physiological; Process; Publishing; Pyramidal Tracts; Recovery; Rehabilitation therapy; Research; Runaway; Sensory; Signal Transduction; Spinal; Spinal Cord; Spinal Injuries; Spinal cord injury; Structure; Synapses; Synaptic plasticity; System; Testing; Translating; Up-Regulation; Upper Extremity; axon growth; base; cholinergic; clinically relevant; functional outcomes; functional plasticity; gain of function; improved; loss of function; motor control; motor function improvement; motor recovery; motor rehabilitation; neuroregulation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optogenetics; postsynaptic; recruit; relating to nervous system; repair strategy; repaired; spasticity; spinal cord repair; synaptogenesis

Corticospinal tract (CST) injury deprives spinal circuits of movement control signals. This leads to loss of function—muscle weakness and paralysis—and gain of dysfunction—including hyperreflexia and spasticity. To repair the CST after injury and restore motor control, it is necessary to abrogate the impairments due to both the loss of function and gain of dysfunction following injury. Our research during the prior funding period shows that activity-dependent processes underlie both the loss of function and gain of dysfunction after CST injury. This finding provides the foundation for developing new therapeutic neuromodulatory approaches to target activity dependence using motor cortex (MCX) stimulation and transspinal direct current stimulation (tsDCS). MCX stimulation after injury is effective in CST repair and motor recovery. In Aim 1 we will determine the most effective MCX neuromodulation treatment to produce persistent structural and functional plasticity of the corticospinal system. Using different stimulation patterns, we will ask if efficacy depends on recruiting CST axon growth-promoting signaling. Using optogenetics to identify activated CST axons, we will test how stimulation patterns determine anatomical and physiological outcomes. Knowing that recovery is more than CST sprouting, we will ask if efficacy depends on producing long-term physiological changes in spinal circuits. We recently showed that selective CST injury or MCX inactivation produces trans-neuronal loss of spinal cholinergic interneurons and that this loss can be rescued by spinal activation. In Aim 2 we will determine how MCX neuromodulation regulates transneuronal segmental circuit remodeling after injury to promote spinal circuit repair. We will ask how CST injury impacts the major class of excitatory premotor interneurons of the CST. We will test if MCX stimulation ameliorates trans-neuronal circuit changes and then examine the interplay of repair strategies differentially targeting microglial-based spinal circuit remodeling and CST sprouting In Aim 3 we will harness the differential actions of tsDCS on spinal circuits to enhance repair and rehabilitation efficacy after cervical SCI. Spinal circuits integrate motor control signals with afferent information. After SCI, with the loss of motor pathways, spared afferent feedback dominates segmental circuit function. We recently showed that afferent competition diminishes CST connection strength, to reinforce afferent over integrated control. We will use the differential actions of tsDCS to promote spared CST function and weaken potentially “runaway” afferent input, to rebalance segmental control. We will develop a novel strategy that combines neuromodulation-based repair with neuromodulation-assisted rehabilitation to promote recovery. Successful completion of our studies will advance our understanding of the mechanisms of impairment and the mechanisms underlying novel neuromodulatory repair strategies after SCI. Results will inform how best to integrate motor behavioral rehabilitation and activity-based interventions to provide potentially clinically relevant approaches to improve motor control in humans after cervical SCI.

皮质脊髓束（CST）损伤剥夺了脊髓回路的运动控制信号。这导致了损失 功能-肌肉无力和麻痹-以及功能障碍的增加-包括反射亢进和痉挛。到 修复受伤后的CST和恢复运动控制，有必要废除由于这两个损伤， 功能丧失和损伤后功能障碍的获得。我们在上一个资助期的研究表明， 活动依赖性过程是CST损伤后功能丧失和功能障碍获得的基础。这 这一发现为开发新的治疗性神经调节方法提供了基础 使用运动皮层（MCX）刺激和经脊髓直流电刺激（tsDCS）的依赖性。 损伤后刺激MCX对CST修复和运动恢复有效。在目标1中，我们将确定 最有效的MCX神经调节治疗，以产生持续的结构和功能可塑性， 皮质脊髓系统使用不同的刺激模式，我们将询问疗效是否取决于招募CST 轴突生长促进信号。使用光遗传学来识别激活的CST轴突，我们将测试如何 刺激模式决定解剖学和生理学结果。知道康复不仅仅是 CST萌芽，我们会问，疗效是否取决于脊髓回路的长期生理变化。 我们最近发现，选择性CST损伤或MCX失活可导致脊髓背角跨神经元丢失。 胆碱能中间神经元，这种损失可以通过脊髓激活来挽救。在目标2中，我们将确定如何 MCX神经调节调节损伤后跨神经元节段性回路重塑以促进脊髓损伤 电路维修我们将探讨CST损伤如何影响大脑皮层主要的兴奋性前运动中间神经元。 正新轮胎我们将测试MCX刺激是否改善跨神经元回路的变化，然后检查相互作用 修复策略差异靶向基于小胶质细胞的脊髓回路重塑和CST发芽 在目标3中，我们将利用tsDCS对脊髓回路的差异作用来增强修复和 颈脊髓损伤后康复疗效观察脊髓回路整合了运动控制信号和传入信息。 脊髓损伤后，随着运动通路的丧失，备用传入反馈支配节段回路功能。我们 最近表明，传入竞争减弱了CST连接强度，以加强传入， 综合控制我们将利用tsDCS的微分作用来促进备用CST功能， 潜在的“失控”传入输入，以重新平衡节段控制。我们将制定一项新的战略， 结合基于神经调节的修复和神经调节辅助康复以促进恢复。 成功完成我们的研究将促进我们对损伤机制的理解， 脊髓损伤后神经调节修复新策略的机制。结果将告知如何最好地 综合运动行为康复和基于活动干预， 相关的方法，以改善运动控制在人类颈椎脊髓损伤后。