A novel combinatorial approach to restore motor function after spinal cord injury

摘要(综述)：脊髓损伤(SCI)常因以下原因而导致永久性瘫痪 损伤的轴突不能再生。尽管受伤的CS轴突不会再生长到 脊髓损伤后的损伤，它们与上面的固有脊髓神经元形成新的联系 (吻侧)在这些损伤中造成有限恢复的损伤 模特们。在本研究中，我们提出了双管齐下的策略，以同时诱导重新 损伤的皮质脊髓(CS)轴突在病变部位以外的生长和增强 损伤的CS轴突和固有脊髓神经元之间的连接重建 SCI。降低磷酸酶和张力蛋白同源物可促进CS轴突生长 (PTEN)在感觉运动皮质的活动。我们的初步数据显示CS增加 缺乏编码信号素6D受体的PlexA1的小鼠SC后的连通性。自.以来 PlexA1突变体中受损的CS轴突不会越过病变部位，我们的初步研究 数据有力地表明，受损的CS轴突和本体脊髓之间有新的联系 脊髓损伤后，神经元通过未损伤的腹侧区域增强以补偿 CS输入的丢失。根据这些初步数据，这一中心假设 建议将Sema6D-PlexA1和Pten信令的组合调制 促进CS与固有脊髓神经元连接的重新布线以及 颈椎水平脊髓损伤后CS轴突损伤。因此，这些干预措施将改善 功能CS连接和运动恢复。在目标1中，我们将确定是否 感觉运动皮质中PlexA1和Pten的缺失将增强连接性 损伤的CS轴突和固有脊髓神经元之间的关系 单独使用PlexA1或Pten。在目标2中，我们将确定PlexA1、Pten或 PlexA1/Pten缺失增加了受损的CS神经元和肌肉之间的回路。 最后，在目标3中，我们将检查缺乏运动的小鼠的运动恢复是否得到增强 感觉运动皮质中的PlexA1和Pten。

Abstract (Summary): Spinal cord injury (SCI) often causes permanent paralysis due to failure of injured axons to regenerate. Although injured CS axons do not re-grow beyond the lesion after SCI, they form new connections with propriospinal neurons above (rostral to) the lesion which contributes to the limited recovery seen in these injury models. In this study, we propose two-pronged strategies to simultaneously induce re- growth of injured corticospinal (CS) axons beyond the lesion site and enhance remodeling of connectivity between injured CS axons and propriospinal neurons after SCI. CS axonal growth can be promoted by reducing phosphatase and tensin homolog (Pten) activity in the sensorimotor cortex. Our preliminary data reveal increased CS connectivity after SC in mice lacking PlexA1 encoding a semaphorin6D receptor. Since injured CS axons in PlexA1 mutants do not pass beyond the lesion site, our preliminary data strongly suggest that new connections between injured CS axons and propriospinal neurons are enhanced through the uninjured ventral regions after SCI to compensate for the loss of CS inputs. Based on these preliminary data, the central hypothesis of this proposal is that a combined modulation of Sema6D-PlexA1 and Pten signaling will facilitate rewiring of CS connectivity with propriospinal neurons as well as re-growth of injured CS axons after SCI at cervical levels. Therefore, these interventions will improve functional CS connectivity and motor recovery. In Aim 1, we will determine whether deletion of both PlexA1 and Pten in the sensorimotor cortex will enhance connectivity between injured CS axons and propriospinal neurons to a greater degree than the loss of PlexA1 or Pten alone. In Aim 2, we will determine whether PlexA1, Pten, or PlexA1/Pten deletion increases circuits between injured CS neurons and muscles. Finally, in Aim 3, we will examine whether motor recovery is enhanced in mice lacking PlexA1 and Pten in the sensorimotor cortex.