Lesion and Activity Dependent Corticospinal Tract Plasticity

我们的总体目标是利用成熟运动系统的非凡活动依赖可塑性， 实现脑或脊髓损伤后受损皮质脊髓束（CST）的显著修复。我们的目标是促进 不完全损伤后保留的CST的运动功能。这些备用连接稀疏且薄弱; 他们自己也不能进行有效的运动控制。我们的大鼠研究使用单侧锥体束病变（PTX）， 从一个运动皮层（M1）消除所有CST轴突。这种病变消除了受影响的大部分CST 对侧脊髓，仅剩下稀疏的同侧CST轴突。PTX产生显著的发芽， 备用同侧CST，我们假设这是适应性的，因为损伤后的M1电刺激促进了这一点 发芽导致运动功能恢复PTX还产生本体感受传入发芽和脊髓神经元变化， 我们假设是适应不良，因为它们会导致痉挛和虚弱。 目的1探讨单侧CST损伤后脊髓反应性改变的活动依赖性。我们假设 活动的丧失，不仅仅是身体连接的丧失，是受伤后反应性变化的重要触发因素。我们 将单方面检测M1，以确定CST变化（Aim 1A）和脊髓损伤的活动依赖性。 中间神经元和运动神经元功能（Aim 1B）。我们将确定光遗传学激活脊髓神经元的作用。 中间神经元对M1失活产生的反应性脊髓变化的影响（Aim 1C）。 在目标2中，我们将确定脊髓激活在消除适应不良的节段性变化中的作用， 损伤和促进备用CST的运动功能。我们假设在受伤后刺激脊髓回路 会增加它们对来自备用CST轴突的信号的反应。目的2A使用光遗传学方法直接测试这一假设。 一种以时间精确性激活脊髓中间神经元的方法，以及跨脊髓直流电刺激（tsDC）， 激活方法与翻译潜力。脊髓刺激在CST丧失后提供节段性激活。在Aim中 2B我们将确定tsDC是否促进备用CST连接的萌芽，消除适应不良的脊柱变化， 共同加强了M1到肌肉的通路。在目标2C中，我们将确定tsDC是否促进术后行为恢复。 PTX。 目标3将利用短期功能性M1可塑性和脊髓激活相结合，以加强CST 连接，增强CST生长，并促进损伤后的运动功能。我们将联合收割机“自上而下”的M1激活 用“自下而上”的脊髓激活来实现新的治疗见解。我们假设，强大的短期可塑性， 产生的高频模式M1电刺激，加强和产生发芽备用CST轴突。 增强的CST信号现在将被脊髓激活放大。在目标3A中，我们研究了模式化M1的急性效应， 刺激，单独和与tsDC组合，对CST传输和M1皮质内回路。目标3B将确定是否 慢性模式化M1刺激促进CST发芽、连接强度和运动恢复，如果 tsDC影响响应。目的3C结合皮层和脊髓刺激，恢复远端前肢运动功能， 临床相关皮质病变模型。 !

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. !