Exercise and NT-3-mediated lumbar motoneuron plasticity and recovery after SCI

脊髓损伤(SCI)是影响美国军队受伤人员的最严重的致残疾病之一。 不幸的是，目前还没有针对脊髓损伤患者的有效治疗方法。开发新的修复策略以 减轻脊髓损伤的破坏性并将其转化为临床是将得到改善的迫切医疗需求 患有脊髓损伤的退伍军人的生活质量。腰椎运动神经元(MN)是运动的最终共同通路 输出到后肢。这些MN的任何损害都可能导致后肢瘫痪和肌肉萎缩。这个 腰椎MN可因腰髓直接损伤或间接损伤而受损。 位于颈椎或胸部水平的腰髓以上(称为平面以上损伤)。对于后者，腰椎MNS 没有直接受到创伤的伤害，但它们经历了严重的树突萎缩和突触剥离 失神经支配的脊髓上和固有脊髓轴突。这种改变的MN形态和突触变化可能 导致后肢肌肉的运动输出受损，因此运动功能受损。虽然大多数人 脊髓损伤的研究主要集中在损伤部位脊髓的再生或保护上，很少有人研究。 研究探索了腰椎MN回路的调制如何影响病理和功能 上级SCI后的后果。我们研究的目标是了解腰椎MN是如何改变的 以上节段脊髓损伤后的解剖和功能，以及有益的恢复性治疗如何影响他们的 重组和功能后果。神经营养因子是一类调节神经元的蛋白质家族 存活，轴突生长，突触可塑性和神经传递。其中，神经营养因子-3(NT-3)起作用 通过促进多条脊髓通路中轴突的生长和突触的可塑性，在运动恢复中发挥特殊的作用。 外源性给予NT-3已被认为是治疗脊髓损伤的一种潜在的治疗方法。这使得 美国将提出第一个假设，即MNS逆行运输的NT-3病毒的释放将导致 MN池周围局部NT-3水平的升高，促进了腰椎运动神经回路的重塑 促进脊髓损伤后的生理和行为恢复。我们和其他人也展示了 单独的运动训练改善了SCI后的协调运动功能。运动训练也包括 促进神经元存活和可塑性的脊髓内神经营养因子水平的增加， 神经回路的重组，以及突触功能和行为的改善。因此，我们 提出第二个假设，即运动训练将协同增强NT-3的效果，可能是通过 重塑备用下行脊髓环路并促进其功能联系的形成 患有腰椎MNS。应用成年小鼠T9中度挫伤脊髓损伤模型和腺相关病毒 编码NT-3的血清2型载体(AAV2-NT-3)的基因转移方法，我们提出了3个特异性目标 NT-3促进脊髓损伤后恢复的机制及长期疗效 那 (1) D 使用临床上可行的分娩途径进行治疗，(2)确定运动训练是否会增强 NT-3对脊髓损伤后腰椎MN回路重塑和功能恢复的影响 (3)确定腰椎MN的特定下行通路在其调节能力中的功能作用 最佳治疗后腰椎神经回路和功能恢复。完成本提案将不会 仅允许我们揭示NT-3/运动训练介导的MN回路重塑的基本机制 而且还确定了针对后肢运动恢复的新的治疗策略。

Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, no effective treatment has been available for SCI patients. Developing novel repair strategies to mitigate the devastating nature of SCI and translating them clinically are urgent medical needs that will improve quality of life of our veterans with SCI. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. The lumbar MNs could be impaired by a direct injury to the lumbar cord or by an indirect injury occurring at levels above the lumbar cord at cervical or thoracic levels (called above-level injuries). For the latter, the lumbar MNs are not directly injured by the trauma, but they undergo profound dendritic atrophy and synaptic stripping from denervated supraspinal and propriospinal axons. Such altered MN morphological and synaptic changes could result in impaired motor outputs to hindlimb muscles and therefore impaired locomotor functions. While most SCI studies have been focused on the regeneration or protection of injured spinal cord at the site of injury, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. The goal of our research is to understand how lumbar MNs are altered anatomically and functionally after an above-level SCI and how a beneficial restorative treatment affects their reorganization and functional consequences. Neurotrophins are a family of proteins that regulate neuronal survival, neurite outgrowth, synaptic plasticity and neurotransmission. Among them, Neurotrophin-3 (NT-3) plays a particular role in motor restoration by promoting axon growth and synaptic plasticity in multiple spinal pathways. Exogenous administration of NT-3 has been proposed as one potential therapeutic treatment for SCI. This allows us to propose the first hypothesis that the release of retrogradely transported NT-3 from MNs will result in an elevation of local NT-3 levels around the MN pools, promoting remodeling of lumbar motor circuitry, and enhancing physiological and behavioral recoveries following an above-level SCI. We and others also showed exercise training alone improved coordinated motor function following SCIs. Exercise training also contributed to the increased levels of intraspinal neurotrophic factors that promote neuronal survival and plasticity, to the reorganization of neuronal circuitry, and to improvements in synaptic function and behavior. Therefore, we propose the second hypothesis that exercise training will synergistically enhance the effect of NT-3 perhaps by remodeling the spared descending spinal circuits and facilitating the formation of their functional connections with lumbar MNs. Using an adult mouse T9 moderate contusive SCI model and an adeno-associated virus serotype 2 vector encoding NT-3 (AAV2-NT-3) gene transfer approach, we propose 3 Specific Aims to etermine the mechanism by which NT-3 improves recovery after SCI and the long-term efficacy of the NT-3 that (1) d treatment using a clinically feasible delivery route, (2) determine whether exercise training will enhance the effects of NT-3 on the remodeling of lumbar MN circuitry and functional recovery after an above-level SCI, and (3) determine the functional roles of specific descending pathways to lumbar MNs in their ability to modulate lumbar neural circuitry and functional recovery after the optimal treatment. Completion of this proposal will not only allow us to reveal fundamental mechanisms of NT-3/exercise training-mediated remodeling of MN circuitry but also to identify new therapeutic strategies targeting hindlimb locomotor recovery.