REGENERATION FAILS TO RESTORE SPINAL CIRCUIT FUNCTION

项目总结（见说明）：中枢突触损伤持续存在于感觉和运动神经元中，这些神经元在神经损伤后再生外周轴突投射。在本研究期间获得的新发现表明，这些损伤改变了关于肌肉长度和运动活动的反馈，并导致负责协调肌肉活动的脊髓回路的显著功能障碍。该建议在研究限制神经修复后运动恢复的中枢机制方面有两个目标：（1）定位所选脊髓回路内的缺陷和不平衡，以及（2）操纵传入神经的活动，试图恢复感觉反馈的有用性。为满足下述具体目的而设计的实验都涉及成年大鼠在选定的几条肌神经切断并手术修复后5个月的体内电生理研究。这里提出的生理学研究将与项目2中的形态学研究相协调，以实现功能-结构解释。具体目标1的动机是在此期间获得的研究结果，这表明违反直觉的概念，即再生的初级传入神经的不活动，促进其恢复与运动神经元的突触传递。实验将操纵传入活动，试图挽救那些通过外周再生恢复拉伸敏感性的传入神经的肌肉长度反馈的中枢传输。具体目标2的重点是从运动神经元，这是由项目1和2所示的是不完整的，尽管外周运动轴突的成功再生的经常性反馈的恢复。接受经常性反馈的脊髓回路的结果修改将详细探讨功能障碍的测试部位。具体目标3将检查与拮抗肌活动失调相关的兴奋性和抑制性脊髓回路的明显失衡。满足这些目标将大大推进该项目的长期目标，即解释神经损伤后在外周成功再生的神经元未能恢复正常的中枢传递。这些中枢损伤与外周的不完全和错误的再生一起合谋阻止神经修复恢复正常运动。通过解决有目的运动缺陷的原因，该项目推进了NINDS的使命，以改善神经系统疾病的治疗。

PROJECT SUMMARY (See Instructions): Central synaptic impairment persists in sensory and motor neurons that regenerate their peripheral axonal projections after nerve injury. New findings obtained in this grant period suggest that these impairments modify feedback about muscle length and motor activity and cause significant dysfunction of spinal circuits responsible for coordinating muscle activity. This proposal has two objectives in studying the central mechanisms that limit recovery of movement following nerve repair: (1) locate deficits within and imbalances between selected spinal circuits and (2) manipulate activity of afferents in attempt to restore the usefulness of sensory feedback. Experiments designed to meet the specific aims described below all involve electrophysiological study in vivo of adult rat¿s months after a selected few muscle nerves are severed and surgically repaired. The physiological studies proposed here will be coordinated with morphological studies in Project 2 in order to enable function-structure interpretations. Specific Aim 1 is motivated by findings obtained in this grant period which suggest the counterintuitive notion that inactivity of regenerated primary afferents promotes their recovery of synaptic transmission with motoneurons. Experiments will manipulate afferent activity in attempt to rescue central transmission of muscle-length feedback for those afferents which recover stretch sensitivity through peripheral regeneration. Specific Aim 2 focuses on the recovery of recurrent feedback from motoneurons which is shown by Projects 1 and 2 to be incomplete despite successful regeneration of peripheral motor axons. Resultant modification of the spinal circuit receiving recurrent feedback will be probed in detail to test sites of dysfunction. Specific Aim 3 will examine apparent imbalances in excitatory and inhibitory spinal circuits associated with dyscoordination of antagonist muscle activity. Meeting these aims will substantially advance this project's long-term goal of explaining the failure to regain normal central transmission from neurons that regenerate successfully in the periphery after nerve injury. These central impairments together with incomplete and misdirected regeneration in the periphery conspire to prevent nerve repair from restoring normal movement. By addressing the causes of deficits in purposeful movement, this project advances the mission of the NINDS to improve treatment of neurological disorders.