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: 8735198
• 负责人: John H Martin
• 金额: $ 33.13万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735198
• 关键词: Acute; Affect; Animals; Axon; Behavioral; Brain; Brain Injuries; Brain Stem; Chronic; Contralateral; Corticospinal Tracts; Dependence; Distal; Dorsal; Electric Stimulation; Forelimb; Frequencies; Funding; Gene Transfer; Goals; Human; Impairment; Injury; Interneurons; Ipsilateral; Lead; Lesion; Locomotion; Locomotor Recovery; Mediating; Modeling; Motor; Motor Cortex; Motor Neurons; Muscle; Neurons; Pathway interactions; Pattern; Proteins; Pyramidal Tracts; Rattus; Recovery; Role; Secure; Side; Signal Transduction; Specificity; Spinal; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Synapses; System; Testing; Therapeutic; Translations; clinically relevant; injured; insight; motor control; novel therapeutics; optogenetics; public health relevance; relating to nervous system; repaired; research study; response; transmission process

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.

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性可塑性，实现脑或脊髓损伤后受损皮质脊髓束（CST）的显着修复。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；它们本身无法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)，该损伤消除了一个运动皮层 (M1) 的所有 CST 轴突。这种病变消除了受影响的对侧脊髓上的大部分 CST，仅保留稀疏的同侧 CST 轴突。 PTX 从幸存的同侧 CST 中产生显着的发芽，我们假设这是适应性的，因为受伤后 M1 电刺激会促进这种发芽，从而导致运动恢复。 PTX 还会产生本体感觉传入萌芽和脊髓神经元变化，我们假设这些变化是适应不良的，因为它们会导致痉挛和虚弱。 目标 1 将确定单侧 CST 损伤后脊柱反应性变化的活动依赖性。我们假设活动丧失，而不仅仅是身体联系的丧失，是受伤后反应性变化的重要触发因素。我们将单方面灭活 M1 以确定 CST 变化（目标 1A）以及脊髓中间神经元和运动神经元功能损伤（目标 1B）的活动依赖性。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（目标 1C）。 在目标 2 中，我们将确定脊髓激活在消除损伤后适应不良的节段变化和促进幸存 CST 的运动功能中的作用。我们假设损伤后刺激脊髓回路会增加它们对来自幸存的 CST 轴突信号的反应。目标 2A 使用光遗传学方法直接测试这一假设，以时间精度激活脊髓中间神经元，并使用经脊髓直流电刺激 (tsDC)（一种具有翻译潜力的激活方法）。脊髓刺激可在 CST 丧失后提供节段激活。在目标 2B 中，我们将确定 tsDC 是否会促进备用 CST 连接的萌发、消除适应不良的脊柱变化，并共同加强 M1 到肌肉的通路。在目标 2C 中，我们将确定 tsDC 是否促进 PTX 后的行为恢复。 目标 3 将利用短期功能性 M1 可塑性和脊柱激活相结合，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“自上而下”的 M1 激活与“自下而上”的脊柱激活相结合，以实现新颖的治疗见解。我们假设高频模式 M1 电刺激产生的有效短期可塑性会增强并产生幸存的 CST 轴突的萌芽。增强的 CST 信号现在将通过脊髓激活来放大。在目标 3A 中，我们研究了模式化 M1 刺激（单独或与 tsDC 结合）对 CST 传输和 M1 皮质内回路的急性影响。目标 3B 将确定慢性模式 M1 刺激是否促进 CST 萌芽、连接强度和运动恢复，以及 tsDC 是否影响反应。 Aim 3C 结合了皮质和脊髓刺激，以恢复临床相关皮质损伤模型中的远端前肢运动功能。