Influence of Environmental Stimulation and Learning on Recovery After Injury

描述(由申请人提供)：先前的研究表明，脊髓内的神经元对反应-结果(工具)关系敏感。通过胸部横断切断与大脑的联系，研究了孤立脊髓中的学习。当一条后腿伸展时，给予一条后腿电击的横断大鼠学会将腿保持在弯曲的位置，从而将净电击暴露降至最低。给予与腿部位置无关的电击(不可控电击)的大鼠不学习，当稍后用可控电击测试时，表现出学习缺陷。有证据表明，无法控制的刺激损害了学习，因为它诱导了一种形式的中枢敏化，饱和了NMDA受体介导的可塑性。无法控制的刺激也会损害挫伤后的恢复。伤后24小时仅刺激6分钟，感觉/运动恢复较差，6周后效果明显。无法控制的刺激也会增加肾功能衰竭的发生率和神经病理性疼痛的迹象。我们的工作假设是，不受调控的伤害性传递(疼痛信号)参与了损害脊髓损伤后恢复的细胞机制。我们的长期目标是确定：导致这种影响的环境，涉及的神经生物学机制，以及可以用来阻止无法控制的伤害性刺激的不利影响的程序。提出了三个目标，将详细说明影响恢复的刺激条件，大脑系统的相对作用，以及与中枢敏化的关系。这些实验建立在长达十年的研究基础上，详细描述了影响分离脊髓功能的条件和神经生物学机制。目标1考察了影响复苏的刺激条件。人们认识到，中度挫伤保留了一些感觉纤维，允许疼痛传递到脊柱上结构。目前尚不清楚大脑系统是否以及如何对刺激对康复的长期影响做出贡献。如果大脑系统受到影响，强度较小，间隔较广，刺激应该会影响恢复。目标2将通过影响备用纤维的生理和药物操作来阐明大脑系统的作用。我们还研究了在损伤部位或损伤部位以下没有输入的情况下，刺激是否影响康复。目的3将评估中枢敏化的诱导(通过外周炎症)是否损害康复，以及防止中枢敏化的药物操作是否具有保护作用。神经损伤后的组织丢失反映了急性损伤和损伤后从几个小时到几天的继发过程的净影响。通过确定影响这些次级过程的因素，可以开发出减少其有害影响的治疗方法。现在用于控制其他情况下的疼痛的治疗方法(例如硬膜外注射)可能有利于康复。目前的赠款将评估这一可能性。

DESCRIPTION (provided by applicant): Prior research has shown that neurons within the spinal cord are sensitive to response-outcome (instrumental) relations. Learning in the isolated spinal cord has been studied by cutting communication with the brain using a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended learn to maintain the leg in a flexed position, thereby minimizing net shock exposure. Rats given shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. Evidence suggests that uncontrollable stimulation impairs learning because it induces a form of central sensitization that saturates NMDA receptor mediated plasticity. Uncontrollable stimulation also impairs recovery after a contusion injury. Just 6 min of stimulation 24 hrs after injury leads to poor sensory/motor recovery and this effect is evident 6 weeks later. Uncontrollable stimulation also increases the incidence of renal failure and signs of neuropathic pain. Our working hypothesis is that unregulated nociceptive transmission (pain signals) engages cellular mechanisms that impair recovery after spinal injury. Our long-term objectives are to identify: the circumstances that cause this effect, the neurobiological mechanisms involved, and procedures that can be used to block the adverse effect of uncontrollable nociceptive stimulation. Three aims are proposed that will detail the stimulus conditions that impact recovery, the relative role of brain systems, and the relation to central sensitization. The experiments build on a decade of research detailing the conditions, and neurobiological mechanisms, that impact function in the isolated spinal cord. Aim 1 examines the stimulus conditions that affect recovery. It is recognized that a moderate contusion spares some sensory fibers that allow pain transmission to supraspinal structures. It is not known whether, and how, brain systems contribute to the long-term effects of stimulation on recovery. If brain systems are involved, less intense, and more widely spaced, stimulation should impact recovery. Aim 2 will clarify the role of brain systems using physiological and pharmacological manipulations that impact spared fibers. We also examine whether stimulation affects recovery in the absence of input at, or below, the site of injury. Aim 3 will evaluate whether the induction of central sensitization (through peripheral inflammation) impairs recovery and whether pharmacological manipulations that prevent central sensitization have a protective effect. The loss of tissue after neural injury reflects the net effect of both the acute injury and secondary processes that extend from hours to days after injury. By identifying factors that influence these secondary processes, treatments can be developed to reduce their harmful effects. Treatments now used to control pain in other situations (e.g., an epidural) could benefit recovery. The present grant will evaluate this possibility.