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: 8900740
• 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/8900740
• 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 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; nerve transection; novel; novel therapeutics; peripheral nerve regeneration; 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，其中包括许多退伍军人。尽管受伤的神经可以再生并重新支配周围目标，但完全恢复正常运动功能是不寻常的。绝大多数人都患有永久性运动缺陷。脊髓中不适当的感觉运动连接会导致这些缺陷：支持运动等运动功能的脊髓反射回路发生紊乱。例如，在周围神经和再生之后，来自肌梭的IA组初级传入输入不再强烈兴奋同向肌和增效肌的脊髓运动神经元。 一种可以指导脊髓中适当的感觉运动连接恢复的新治疗方法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中枢神经系统可塑性，探索其机制，并将其用于治疗。该方案诱导大脑下行通路的活动，可以改变特定的脊髓反射通路，例如 H 反射的整个脊髓和大部分单突触通路，脊髓牵张反射的电模拟（即膝跳反射） 。对于运动受损的不完全脊髓损伤的动物或人，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能力。 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，我们将横断大鼠的右侧坐骨神经，修复（即重新对抗）神经以便发生再生，并评估上调（即增加）或下调（即减少）的影响右比目鱼肌 H 反射。在目标 1 中，我们将确定在坐骨再生期间上调或下调比目鱼肌 H 反射对运动的影响。在目标 2 中，我们将确定坐骨再生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：上调大鼠组；上调大鼠组；向下调节；和控制（即，简单地测量 H 反射）。我们将从生理学（即自发 EMG 活动、H 反射）、功能（即跑步机运动过程中的 EMG 和运动学）和免疫组织化学（即假定的初级传入终端（即含有囊泡谷氨酸转运蛋白 1 的终端）上评估这些组。 VGLUT1)) 在比目鱼肌运动神经元上）。 在每个目标的数据收集结束时，我们预计与对照组相比，上调大鼠的比目鱼肌 H 反射会更大，运动会更好（例如，步数更长，时间和臀部高度的右/左对称性更好）大鼠或下调大鼠。此外，我们预计在上调大鼠的比目鱼肌运动神经元上，VGLUT1（即假定的初级传入末梢）将更多和/或更大。 因此，该提案旨在评估一种新颖且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损伤。如果这项工作成功，将验证反射操作条件反射作为一种新方法，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；它将为这种新疗法的临床转化铺平道路。