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）损伤剥夺了运动控制信号的脊柱。 功能 - 肌肉无力和瘫痪ー功能障碍和增益 - 无效的超反射性和痉挛性 修复CST Anjury IND恢复电动机控制，有必要消除由于既有的损害 受伤后功能丧失和功能障碍的增益。 CST损伤后，活动依赖性过程Swandlie既丧失了功能的丧失和功能障碍的增益。 发现Proides为开发新的治疗性神经调节方法的基础来靶向活动 使用运动皮层（MCX）刺激和跨型直流电流刺激（TSDC）的依赖性。 MCX刺激ANJURY在CST修复中有效，AIM 1中的运动恢复。 最有效的MCX神经调节裤，以产生持续的结构和功能性塑料 皮质脊髓系统使用不同的刺激模式，我们将询问功效是否取决于招募CST 轴突生长促进信号传导。 刺激模式决定了解剖学和生理结果。 CST发芽，我们将询问疗效是否取决于产生脊柱回路的长期生理变化。 我们最近表明，选择性的CST损伤或MCX INACX失活会导致脊柱的反式神经元丧失 胆碱能中间神经元和这种sthiss可以通过AIM 2中的脊柱激活来确定。 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。 CST。 维修策略的基于小胶质的脊柱电路重塑和CST发芽不同 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 宫颈科学后的康复功效。 在SCI之后，随着电动路径的损失，RADERD反馈主导了分段电路的功能 最近表明，强化竞争会降低CST连接强度，以加强磨练 集成控制 潜在的“失控”投入，以重新平衡分段。 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。 成功的综合我们的研究将提高我们对损害机制和 SCI之后的新型神经调节CAIR策略的基础机制。 整合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。