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。通过切断与大脑的交流，使用胸部横断研究了离体脊髓的学习。横断大鼠给予电击一条后腿时，腿是延长学习，以保持腿在一个弯曲的位置，从而最大限度地减少净休克暴露。给予与腿部位置无关的电击（不可控电击）的大鼠不学习，并且在随后用可控电击进行测试时表现出学习缺陷。有证据表明，不可控制的刺激损害学习，因为它诱导了一种形式的中枢敏化，饱和NMDA受体介导的可塑性。不可控制的刺激也会损害挫伤后的恢复。损伤后24小时仅刺激6分钟会导致感觉/运动恢复不良，并且这种效果在6周后明显。不可控的刺激也会增加肾衰竭的发生率和神经性疼痛的体征。我们的工作假设是，不受调节的伤害性传递（疼痛信号）参与损害脊髓损伤后恢复的细胞机制。我们的长期目标是确定：导致这种效应的环境，所涉及的神经生物学机制，以及可用于阻断不可控制的伤害性刺激的不良影响的程序。提出了三个目标，将详细的刺激条件，影响恢复，大脑系统的相对作用，以及中央敏化的关系。这些实验建立在十年的研究基础上，详细说明了影响离体脊髓功能的条件和神经生物学机制。目标1考察影响复苏的刺激条件。一般认为，中度挫伤会保留一些感觉纤维，使疼痛传递到棘上结构。目前尚不清楚大脑系统是否以及如何对刺激对恢复的长期影响做出贡献。如果大脑系统参与，强度较低，间隔较宽，刺激应该会影响恢复。目的2将阐明大脑系统的作用，使用生理和药理学操作，影响备用纤维。我们还研究了刺激是否会影响恢复的情况下，输入，或以下，受伤的网站。目的3将评估中枢致敏（通过外周炎症）的诱导是否损害恢复，以及预防中枢致敏的药理学操作是否具有保护作用。神经损伤后的组织损失反映了急性损伤和损伤后数小时至数天的继发过程的净效应。通过确定影响这些次级过程的因素，可以开发治疗方法以减少其有害影响。现在用于控制其他情况下疼痛的治疗（例如，硬膜外麻醉）可能有利于恢复。目前的赠款将评估这种可能性。

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.