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.

皮质脊髓区（CST）损伤剥夺了运动控制信号的脊柱回路。这导致失去 功能 - 肌肉的无力和瘫痪 - 功能障碍 - 包括超反射和痉挛。到 受伤后修复CST并恢复运动控制 受伤后功能丧失和功能障碍的增益。我们在以前的资助期间的研究表明 CST损伤后的功能丧失和功能障碍的增益均依赖于活动依赖性过程。这 发现为开发新的治疗神经调节方法为靶向活动提供了基础 使用运动皮层（MCX）刺激和跨脊柱直流电流刺激（TSDC）的依赖性。 受伤后MCX刺激可有效CST修复和运动恢复。在AIM 1中，我们将确定 最有效的MCX神经调节处理可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，我们将询问有效是否取决于招募CST 轴突生长促进信号。使用光遗传学识别激活的CST轴突，我们将测试 刺激模式决定了解剖学和身体结果。知道恢复不仅仅是 CST发芽，我们将询问有效性是否取决于产生脊柱回路的长期生理变化。 我们最近表明，选择性CST损伤或MCX失活会导致脊柱的跨神经元丧失 胆碱能中间神经元，并且可以通过脊柱激活来挽救这种损失。在AIM 2中，我们将确定如何 MCX神经调节调节损伤后的跨神经元节段重塑以促进脊柱 电路维修。我们将询问CST伤害如何影响主要的兴奋性前神经元的主要类别 CST。我们将测试MCX模拟是否可以改善反式神经元电路的变化，然后检查相互作用 维修策略的针对基于小胶质细胞的脊柱电路重塑和CST发芽的不同。 在AIM 3中，我们将利用TSDC对脊柱电路的差异作用，以增强维修和 宫颈科学后的康复效率。脊柱电路与传入信息集成了电机控制信号。 SCI之后，随着电动路径的损失，免于传入的反馈主导了节段电路函数。我们 最近表明，传入竞争会降低CST连接强度，以增强传入 集成控制。我们将使用TSDC的差异作用来促进不幸的CST功能和弱 可能“失控”传入输入，以重新平衡分段控制。我们将制定一种新颖的策略 将基于神经调节的修复与神经调节辅助康复相结合，以促进恢复。 成功完成我们的研究将提高我们对损害机制和 SCI后新型神经调节修复策略的基础机制。结果将告知如何最好 集成运动行为康复和基于活动的干预措施，以提供潜在的临床 宫颈SCI后改善人类运动控制的相关方法。