Sympathetic Function in Neural Injuries

周围神经损伤很常见，美国每年报告的新病例超过20万例 只有一个州。这些人中只有10%左右恢复了大部分功能。美国有17730个新的脊柱 每年的脐带损伤，一生的成本可达每人500万美元(不包括工资损失)。神经 损伤，特别是脊髓损伤显著影响长期生活质量，大多数受伤的人 寻求相关残疾和疼痛的持续治疗。对贫穷最常见的解释是 功能结果是轴突再生缓慢而低效的过程。脊髓内的轴突和 神经由运动轴突、感觉轴突和交感轴突组成，损伤后发生可塑性。一位批评者 神经科学中的知识鸿沟是理解交感轴突终末在 神经肌肉突触，与神经肌肉接头相关的交感轴突如何对神经作出反应 损伤，以及它们对功能恢复或功能障碍的贡献。初步证据表明 神经肌肉接头的交感神经支配可以调节线粒体的呼吸和 生物发生、突触稳定性和肌肉力量，以及控制肌肉对运动和 活动。这个K01方案的首要假设是，交感神经元是 神经肌肉单位在正常和病理条件下的功能和代谢稳定性。我们将首先 用一种新的方法测试交感神经活动在代谢和运动控制中的必要性和充分性 技术，生物发光光遗传学(BL-OG)在正常、未受伤的动物中的研究。我的研究表明 运动和神经元活动显著促进外周轴突再生并显著改善 临床前模型中完全性神经和脊髓损伤后的功能恢复。然而，虽然 临床科学家认识到锻炼对促进轴突再生和新陈代谢健康的重要性， 运动的翻译潜力有很多局限性。许多患者不适合进行应有的锻炼 无法康复的并发症，外科神经修复后肢体的必要固定， 运动剂量要求不明，患者依从性低。进一步的限制是，近70%的 患有脊髓损伤的人的骨骼肌是瘫痪的，而且没有电击治疗指南。 麻木肌肉的诱导运动。实验证据还表明，交感神经轴突再生 甚至可能被某些类型的治疗所抑制，例如电刺激。因此，这个项目的其他目标 研究工作是研究交感神经活性增加是促进还是抑制交感神经轴突 周围神经损伤后的再生，以及2)可以挽救肌肉的生物能量和运动控制缺陷 在脊髓损伤后。

Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. There are 17,730 new U.S. spinal cord injuries annually, and the lifetime costs can reach $5 million per person (not including lost wages). Nerve injury and especially spinal cord injury significantly impact long-term quality of life, and most injured individuals seek continued treatments for associated disabilities and pain. The most common explanation for poor functional outcomes is the slow and inefficient process of axon regeneration. Axons within the spinal cord and nerve consist of motor, sensory, and sympathetic axons, which undergo plasticity after injury. A critical knowledge gap in neuroscience is understanding the purpose of sympathetic axon terminals within the neuromuscular synapse, how sympathetic axons associated with neuromuscular junctions respond to neural injuries, and what their contribution is to functional recovery or dysfunction. Preliminary evidence suggests that the sympathetic innervation of neuromuscular junctions can modulate mitochondrial respiration and biogenesis, synaptic stability, and muscle strength as well as control the muscle response to exercise and activity. The overarching hypothesis of this K01 proposal is that sympathetic neurons are required for the functional and metabolic stability of the neuromuscular unit in normal and pathological conditions. We will first test the necessity and sufficiency of sympathetic nerve activity on metabolic and motor control using a novel technology, BioLuminescent OptoGenetics (BL-OG) in normal, uninjured animals. My research has shown that exercise and neuronal activity strikingly enhance peripheral axon regeneration and significantly improves functional recovery following complete nerve and spinal cord injuries in preclinical models. However, while clinician scientists recognize the importance of exercise to promote axon regeneration and metabolic health, the translational potential of exercise has many limitations. Many patients are not candidates for exercise due to co-morbidities that preclude rehabilitation, necessary immobilization of a limb following surgical nerve repair, unknown dose requirement of exercise, and low patient compliance. Further limitations are that nearly 70% of the skeletal muscle of people with a spinal cord injury is paralyzed, and there are no guidelines for electrically induced exercise of paralyzed muscle. Experimental evidence also shows that sympathetic axon regrowth may even be inhibited by certain types of treatments, such as electrical stimulation. Thus, other goals of this work are to investigate whether increasing sympathetic activity 1) promotes or inhibits sympathetic axon regeneration after peripheral nerve injury, and 2) can rescue the muscle bioenergetic and motor control deficits after spinal cord injury.