Diversity Supplement: Lesion and Activity Dependent Corticospinal Tract Plasticity

皮质脊髓束(CST)损伤剥夺了脊髓回路的运动控制信号。这会导致损失 功能-肌肉无力和瘫痪-以及功能障碍的增加-包括反射亢进和痉挛。至 损伤后修复CST并恢复运动控制，有必要消除由于 损伤后功能丧失和功能障碍的获得。我们在前一个资助期的研究表明， CST损伤后，活动依赖的过程既是功能丧失的基础，也是功能障碍获得的基础。这 这一发现为开发针对靶向活动的新的治疗神经调节方法提供了基础 依赖使用运动皮质(MCx)刺激和经脊髓直流电刺激(TsDC)。 损伤后刺激MCx对CST修复和运动恢复有明显作用。在目标1中，我们将确定 最有效的MCx神经调节治疗，以产生持续性的结构和功能可塑性 皮质脊髓系统。使用不同的刺激模式，我们会问，有效性是否取决于招募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 刺激模式决定解剖和生理结果。知道复苏不仅仅是 当CST萌发时，我们会问疗效是否依赖于在脊髓回路中产生长期的生理变化。 我们最近发现，选择性CST损伤或MCX失活会导致脊髓的跨神经元丢失 胆碱能中间神经元，这种丧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环路重塑促进脊髓 电路维修。我们将询问CST损伤如何影响主要类型的兴奋性运动前中间神经元。 Cst.我们将测试MCx刺激是否改善跨神经元回路变化，然后检查相互作用 针对基于小胶质细胞的脊髓环路重塑和CST萌发的不同修复策略 在目标3中，我们将利用tsDCs对脊髓回路的不同作用来加强修复和 颈椎脊髓损伤后的康复疗效。脊髓回路将运动控制信号与传入信息相结合。 脊髓损伤后，随着运动通路的丧失，节段性传入反馈主导节段回路功能。我们 最近的研究表明，传入竞争会削弱CST连接强度，从而加强传入 综合治理。我们将利用tsDCS的差异化动作来提升备用的CST功能，并削弱 可能“失控”的传入输入，以重新平衡节段性控制。我们将开发一种新的战略， 将神经调节修复与神经调节辅助康复相结合，以促进康复。 成功完成我们的研究将促进我们对损伤机制的理解和 脊髓损伤后新的神经调节修复策略的机制。结果将告诉您如何最好地 将运动行为康复和基于活动的干预相结合，以提供潜在的临床 改善人类颈椎脊髓损伤后运动控制的相关方法。

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.