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。尽管受损的神经可以再生并重新支配周围目标，但正常运动功能的完全恢复是不寻常的。绝大多数人留下了永久性的运动缺陷。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（如运动）的脊髓反射回路紊乱。例如，在周围神经和再生后，来自肌梭的IA组初级传入输入不再强烈地兴奋同侧肌和同侧肌的脊髓运动神经元。 一种新的治疗方法，可以指导恢复适当的感觉运动连接的脊髓可以改善周围神经损伤和再生后的功能恢复。在过去的30年里，我们已经开发并应用了一种独特的操作性条件反射方案，用于诱导活动依赖性CNS可塑性，探索其机制，并将其用于治疗。该方案诱导来自大脑的下行通路中的活动，其可以改变特定的脊髓反射通路，例如H反射的完全脊髓和大部分单突触通路，脊髓牵张反射的电模拟物（即，膝跳反射（knee-jerk reflex）。在运动受损的不完全脊髓损伤的动物或人中，适当的反射条件反射协议可以恢复更正常的运动。此外，最近的初步数据表明，反射条件反射也可以改善运动大鼠坐骨神经切断和再生。 基于这项工作，我们假设，一个适当的反射操作性条件反射协议可以改善运动后周围神经损伤和再生。为了验证这一假设，我们将横切大鼠的右侧坐骨神经，修复（即，再对抗）神经以使再生发生，并评估上调节（即，增加）或下调（即，降低）右比目鱼肌H反射。在目标1中，我们将确定在坐骨神经再生期间向上或向下调节比目鱼肌H反射对运动的影响。在目标2中，我们将确定在坐骨神经再生已经发生后，上调或下调比目鱼肌H反射对运动的影响。每个目标将研究三个大鼠组：向上调节;向下调节;和对照（即，简单地测量H反射）。我们将从生理学上评估这些群体（即，自发EMG活动，H反射），功能上（即，在跑步机运动期间的EMG和运动学），和化学上的（即，推定的初级传入末梢（即，比目鱼肌运动神经元上含有囊泡谷氨酸转运蛋白1（VGLUT 1）的终末）。 在每个目标的数据收集结束时，我们预计比目鱼肌H反射将更大，运动将更好（例如，更长的步数，更好的右/左行走时间和髋高度）。此外，我们预计VGLUT 1（即，假定的初级传入终末）在上调节大鼠的比目鱼肌运动神经元上将更多和/或更大。 因此，本建议旨在评估一种新的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。如果这项工作是成功的，它将验证反射操作性条件反射作为一种新的方法，可以补充标准的康复治疗方案，并促进周围神经损伤和再生后有用功能的恢复;它将为这种新的治疗方法的临床转化铺平道路。