Operant Conditioning of Spinal Reflexes to Improve Function after Nerve Injury

脊髓反射的操作性调节以改善神经损伤后的功能

• 批准号: 8729102
• 负责人: Jonathan Rickel Wolpaw
• 金额: --
• 依托单位: STRATTON VETERANS ADMIN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729102
• 关键词: Address; Affect; American; Animals; Axon; Axotomy; Behavior; Clinical; Conditioned Reflex; Data; Data Collection; Disease; Electrodes; Goals; H-Reflex; Height; Hip region structure; Human; Implant; Knee; Label; Left; Length; Locomotion; Locomotor Recovery; Measures; Methods; Motor; Motor Neurons; Motor Skills; Muscle; Muscle Spindles; Musculoskeletal System; Natural regeneration; Nerve; Nerve Regeneration; Neuronal Plasticity; Operant Conditioning; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral nerve injury; Posterior Tibial Nerves; Presynaptic Terminals; Protocols documentation; Rattus; Recovery; Recovery of Function; Reflex action; Regimen; Rehabilitation therapy; Spinal; Spinal Cord; Spinal cord injury; Sprague-Dawley Rats; Sum; Synapses; Testing; Therapeutic; Time; Translations; Veterans; Walking; Work; analog; base; brain pathway; conditioning; functional disability; functional outcomes; improved; improved functioning; injured; kinematics; motor control; motor deficit; motor function improvement; nerve injury; novel; novel therapeutics; public health relevance; reinnervation; repaired; restoration; sciatic nerve; spinal reflex; stretch reflex; tibialis anterior muscle; vesicular glutamate transporter 1

DESCRIPTION (provided by applicant): Peripheral nerve injuries affect hundreds of thousands of Americans every year, including many Veterans. Even though injured nerves can regenerate and reinnervate peripheral targets, complete recovery of normal motor function is unusual. A large majority are left with permanent motor deficits. Inappropriate sensorimotor connections in the spinal cord contribute to these deficits: the spinal reflex circuits that support motor functions such as locomotion are disordered. For example, after peripheral nerve and regeneration, Group IA primary afferent input from muscle spindles no longer strongly excites the spinal motoneurons of homonymous and synergist muscles. A new therapeutic method that can guide the restoration of appropriate sensorimotor connections in the spinal cord could improve functional recovery after peripheral nerve injury and regeneration. Over the past 30 years, we have developed and applied a unique operant conditioning protocol for inducing activity-dependent CNS plasticity, exploring its mechanisms, and using it therapeutically. This protocol induces activity in descending pathways from the brain that can modify specific spinal reflex pathways, such as the wholly spinal and largely monosynaptic pathway of the H-reflex, the electrical analog of the spinal stretch reflex (i.e., the knee-jerk reflex). In animals or people with incomplete spinal cord injuries that have impaired locomotion, an appropriate reflex conditioning protocol can restore more normal locomotion. Furthermore, recent preliminary data suggest that reflex conditioning can also improve locomotion in rats that have undergone sciatic nerve transection and regeneration. Based on this work, we hypothesize that an appropriate reflex operant conditioning protocol can improve locomotion after peripheral nerve injury and regeneration. To test this hypothesis, we will transect the right sciatic nerve in rats, repair (i.e., reoppose) the nerve so that regeneratin occurs, and assess the impact of up-conditioning (i.e., increasing) or down-conditioning (i.e, decreasing) the right soleus H-reflex. In Aim 1, we will determine the locomotor impact of up- or down-conditioning the soleus H-reflex during the period of sciatic regeneration. In Aim 2, we will determine the locomotor impact of up- or down-conditioning the soleus H-reflex after sciatic regeneration has already occurred. Each aim will study three rat groups: up-conditioned; down-conditioning; and control (i.e., the H-reflex is simply measured). We will assess these groups physiologically (i.e., spontaneous EMG activity, H-reflexes), functionally (i.e., EMG and kinematics during treadmill locomotion), and immunohistochemically (i.e., putative primary afferent terminals (i.e., terminals containing vesicular glutamate transporter-1 (VGLUT1)) on soleus motoneurons). At the end of data collection for each aim, we expect that the soleus H-reflex will be larger and locomotion will be better (e.g., longer steps, better right/left symmetryin timing and hip heights) in up- conditioned rats than in control rats or down-conditioned rats. Furthermore, we expect that VGLUT1 (i.e., putative primary afferent terminals) will be more numerous and/or larger on soleus motoneurons of up- conditioned rats. Thus, this proposal seeks to evaluate a novel and clinically practical therapeutic approach to reducing the functional impairments associated with peripheral nerve injury and regeneration. If this work is successful, it will validate reflex operant conditioning as a new method that can compliment standard rehabilitation regimens and enhance the recovery of useful function after peripheral nerve injury and regeneration; and it will prepare the way for clinical translation of this novel therapy.

描述（由申请人提供）： 周围神经损伤每年影响数十万美国人，包括许多退伍军人。即使受伤的神经可以再生并重新弥补外围靶标，但正常运动功能的完全恢复是不寻常的。绝大多数人都有永久性运动不足。脊髓中不适当的感觉运动连接导致了这些缺陷：支持运动功能（例如运动）的脊柱反射电路是无序的。例如，在周围神经和再生之后，肌肉旋转的IA组主要传入输入不再强烈激发同义和协同肌肉的脊柱运动神经元。 一种新的治疗方法，可以指导脊髓中适当的感觉运动连接的恢复可以改善周围神经损伤和再生后的功能恢复。在过去的30年中，我们开发并应用了独特的操作调节方案来诱导活动依赖性的CNS可塑性，探索其机制并在治疗上使用它。该方案在大脑的降途径中诱导活性，这些途径可以改变特定的脊柱反射途径，例如H反射的完全脊柱和很大程度上的单突触途径，脊柱拉伸反射的电类似物（即膝盖 - jerk Reflex）。在动物或不完全脊髓损伤的患者中，适当的反射调节方案可以恢复更正常的运动。此外，最近的初步数据表明，反射调节还可以改善经历坐骨神经横断和再生的大鼠的运动。 基于这项工作，我们假设适当的反射操作调节方案可以改善周围神经损伤和再生后的运动。为了检验这一假设，我们将在大鼠中横断右坐骨神经，修复神经（即重新释放）神经，使再生蛋白发生，并评估上调节（即增加）或下调（即减少）的影响（即减少）右Soleus H-Reflex。在AIM 1中，我们将在坐骨神经再生期间确定上比索的上调或下调的运动影响。在AIM 2中，我们将确定已经发生了坐骨神经再生后的比目鱼h反射的运动影响。每个目标都将研究三个老鼠组：上调；下调；和控制（即，简单地测量H反射）。 We will assess these groups physiologically (i.e., spontaneous EMG activity, H-reflexes), functionally (i.e., EMG and kinematics during treadmill locomotion), and immunohistochemically (i.e., putative primary afferent terminals (i.e., terminals containing vesicular glutamate transporter-1 (VGLUT1)) on soleus motoneurons). 在每个目标的数据收集结束时，我们希望比索鲁斯H反射会更大，并且在适应大鼠或下调的大鼠中，运动的运动会更好（例如，更长的步骤，更长的步骤，更好的右/左对称性定时和臀部高度）。此外，我们预计VGLUT1（即推定的原发性传入终端）将在适应大鼠的比目鱼Motoneron上更加多，并且/或/或更大。 因此，该建议旨在评估一种新型和临床实用的治疗方法，以减少与周围神经损伤和再生相关的功能障碍。如果这项工作成功，它将验证反射操作条件作为一种新方法，可以补充标准康复方案，并增强周围神经损伤和再生后有用功能的恢复；它将为这种新型疗法的临床翻译做准备。