Lesion and Activity Dependent Corticospinal Tract Plasticity

描述（由申请人提供）：我们的总体目标是利用成熟运动系统非凡的活动依赖可塑性，在脑或脊髓损伤后实现受损皮质脊髓束（CST）的显著修复。我们的目的是促进不完全性损伤后CST的运动功能。这些多余的连接是稀疏而脆弱的；它们本身不能发挥重要的运动控制作用。我们的大鼠研究使用单侧锥体束损伤（PTX），消除了一个运动皮层（M1）的所有CST轴突。这种病变消除了对侧受影响脊髓上的大部分CST，仅留下稀疏的同侧CST轴突。PTX会使未受伤的同侧CST产生显著的新芽，我们假设这是适应性的，因为损伤后的M1电刺激促进了这种新芽，导致运动恢复。PTX还会产生本体感觉传入芽和脊髓神经元的变化，我们假设这些变化是不适应的，因为它们会导致痉挛和虚弱。目的1将确定单侧CST病变后脊柱反应性变化的活动依赖性。我们假设，活动丧失，而不仅仅是连接的物理丧失，是损伤后反应性变化的重要触发因素。我们将单侧灭活M1，以确定CST变化（Aim 1A）和脊髓中间神经元和运动神经元功能损伤（Aim 1B）的活性依赖性。我们将确定脊髓中间神经元的光遗传学激活对M1失活产生的反应性脊柱变化的影响（Aim 1C）。在目标2中，我们将确定脊髓激活在消除损伤后不适应的节段性变化和促进备用CST运动功能中的作用。我们假设在损伤后刺激脊髓回路会增加它们对来自未受损伤的CST轴突的信号的反应。Aim 2A直接验证了这一假设，使用光遗传学方法以时间精度激活脊髓中间神经元，以及跨脊髓直流电刺激（tsDC），一种具有翻译电位的激活方法。脊髓刺激在CST丧失后提供节段性激活。在Aim 2B中，我们将确定tsDC是否促进了CST连接的生长，消除了不适应的脊柱变化，并共同加强了m1到肌肉的通路。在Aim 2C中，我们将确定tsDC是否促进PTX后的行为恢复。Aim 3将利用短期功能性M1可塑性和脊髓激活相结合，加强CST连接，促进CST生长，促进损伤后的运动功能。我们将“自上而下”的M1激活与“自下而上”的脊髓激活结合起来，以获得新的治疗见解。我们假设，高频模式m1电刺激产生的强大的短期可塑性，加强并产生了空闲CST轴突的发芽。增强CST信号现在将通过脊髓激活来放大。在Aim 3A中，我们研究了模式M1刺激单独或联合tsDC对CST传递和M1皮质内回路的急性影响。Aim 3B将确定慢性模式M1刺激是否促进CST发芽、连接强度和运动恢复，以及tsDC是否影响反应。目的：在具有临床意义的皮质损伤模型中，3C联合皮质和脊髓刺激恢复前肢远端运动功能。

DESCRIPTION (provided by applicant): Our overall goal is to take advantage of the extraordinary activity-dependent plasticity of the mature motor systems, to achieve significant repair of the damaged corticospinal tract (CST) after brain or spinal cord injury. We aim to promote the motor functions of the CST spared after an incomplete injury. These spared connections are sparse and weak; by themselves, they cannot exert significant motor control. Our rat studies use a unilateral pyramidal tract lesion (PTX) that eliminates all CST axons from one motor cortex (M1). This lesion eliminates most of the CST on the affected contralateral spinal cord, with only sparse ipsilateral CST axons remaining. PTX produces significant sprouting from the spared ipsilateral CST, which we hypothesize is adaptive because M1 electrical stimulation after injury promotes this sprouting, leading to motor recovery. PTX also produces proprioceptive afferent sprouting and spinal neuron changes that we hypothesize are maladaptive, because they can lead to spasticity and weakness. Aim 1 will determine the activity dependence of spinal reactive changes after unilateral CST lesion. We hypothesize that activity loss, not just the physical loss of connections, is an important trigger for reactive changes after injury. We will unilaterally inactivate M1 to determine the activity dependence of CST changes (Aim 1A) and impairments in spinal interneuron and motoneuron function (Aim 1B). We will determine the effects of optogenetic activation of spinal interneurons on reactive spinal changes produced by M1 inactivation (Aim 1C). In Aim 2 we will determine the role of spinal cord activation in abrogating maladaptive segmental changes after injury and in promoting the motor functions of the spared CST. We hypothesize that stimulating spinal circuits after injury will increase their response to signals from spared CST axons. Aim 2A directly tests this hypothesis using the optogenetic approach to activate spinal interneurons with temporal precision, and trans-spinal direct current stimulation (tsDC), an activation approach with translational potential. Spinal stimulation provides segmental activation after CST loss. In Aim 2B we will determine if tsDC promotes sprouting of spared CST connections, abrogates maladaptive spinal changes and, together, strengthens the M1-to-muscle pathway. In Aim 2C we will determine if tsDC promotes behavioral recovery after PTX. Aim 3 will harness short-term functional M1 plasticity and spinal activation in combination, to strengthen CST connections, enhance CST outgrowth, and promote motor function after injury. We combine "top down" M1 activation with "bottom up" spinal activation to achieve novel therapeutic insights. We hypothesize that potent short-term plasticity, produced by high-frequency patterned M1electrical stimulation, strengthens and produces sprouting of spared CST axons. Augmented CST signals will now be amplified by spinal activation. In Aim 3A we study the acute effects of patterned M1 stimulation, alone and combined with tsDC, on CST transmission and M1 intracortical circuits. Aim 3B will determine if CST sprouting, connection strength, and locomotor recovery are promoted by chronic patterned M1 stimulation, and if tsDC affects the response. Aim 3C combines cortical and spinal stimulation to restore distal forelimb motor function in a clinically relevant cortical lesion model.