Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy

脊髓损伤(SCI)是人类面临的一种严重的医学问题，死亡率高，病程长。 发病率。不幸的是，目前还没有针对脊髓损伤患者的有效治疗方法。腰椎 运动神经元(MN)是运动输出到后肢的最终共同通路。这些的任何减损 MNS会导致后肢瘫痪和肌肉萎缩。当脊髓损伤发生在腰椎水平以上时，即 在平面以上的损伤中，腰椎MNS不直接受到创伤的损害，但它们经历了深刻的 树突萎缩和突触剥离。虽然到目前为止大多数SCI研究都集中在再生或 损伤脊髓在损伤部位的保护作用，很少有研究探讨腰椎MN如何调制 电路会影响脊髓损伤后的病理和功能后果。我们的目标是 开发一种针对脊髓损伤后腰椎MNS的有益的恢复性治疗方法，并在功能上 剖析单个传入通路如何影响腰椎MN重塑和功能恢复。在这 应用，我们提出了一个中心假设，即增加腰椎MN池中局部NT-3的水平将刺激 从不同的传入通路招募备用轴突并增强它们的突触形成 腰椎MNS。因此，腰椎水平神经回路的重建构成了 脊髓损伤后后肢功能恢复。因此，提出了三个具体目标，以 探讨影响腰椎MNS功能的三条主要传入通路，以确定它们在NT中的作用。 3-介导胸段脊髓损伤后腰椎运动回路重构和后肢恢复。这些路径 包括降网状脊髓束(RetST)、降固有脊髓束(DPST)和 背根(DR)传入。一旦定义了每个特定途径的功能角色，我们将使用 以多种途径为靶点的联合治疗方法，以最大化治疗效果。这将通过以下方式完成 唱歌 成年小鼠胸9(T9)挫伤脊髓损伤模型及AAV2-NT-3基因转导方法的实验研究 MNS患者血清NT-3水平的变化。

Spinal cord injury (SCI) is a severe medical problem experienced by humans with high mortality and long term morbidity. Unfortunately, there has been no effective treatment available for SCI patients. 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. When SCI occurs above the lumbar level, namely above-level injury, the lumbar MNs are not directly damaged by the trauma, but they undergo profound dendritic atrophy and synaptic stripping. While most SCI studies to date have focused on the regeneration or protection of the injured spinal cord at the injury site, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. Our goal is to develop a beneficial restorative treatment targeting lumbar MNs after an above-level SCI and to functionally dissect out how individual afferent pathways affect lumbar MN remodeling and functional recovery. In this application, we propose a central hypothesis that increasing local NT-3 levels at lumbar MN pools will stimulate the recruitment of spared axons from distinct afferent pathways and enhance their synaptic formation onto lumbar MNs. Thus, reestablishment of neural circuitry at the lumbar level forms the anatomical basis for hindlimb functional recovery after an above-level SCI. Accordingly, three specific aims are proposed to investigate the three major afferent pathways to influencing lumbar MNs function to determine their roles in NT- 3-mediated remodeling of lumbar motor circuitry and hindlimb recovery after a thoracic SCI. These pathways include the descending reticulospinal tracts (RetST), the descending propriospinal tracts (dPST), and the dorsal roots (DR) afferents. Once the functional role of each specific pathway is defined, we will used combinational approaches to target multiple pathways to maximize the treatment effect. This will be done u sing an adult mouse thoracic 9 (T9) contusive SCI model and an AAV2-NT-3 gene transfer approach to increase the level of NT-3 in MNs.