DEVELOPING NEW TOOLS TO UNDERSTAND THE ROLE OF INTERNEURONS IN REWIRING AFTER SPINAL CORD INJURY.

 描述(由申请人提供)：脊髓损伤(SCI)是一种使人虚弱的疾病，导致约265,000名美国人严重丧失运动功能和生活质量下降。多年来，研究脊髓损伤的人一直认为，降压束的长期再生是恢复功能的关键。然而，最近的研究表明，功能的恢复是由于这些束与脊髓固有神经元的局部重新连接以及脊髓内备用神经组织的可塑性。为了更好地了解这种再生是如何发生的，我们需要确定哪些神经元群体参与了脊髓损伤后的这些局部重新连接事件。虽然在模型生物体中已经很好地定义了通过中央模式发生器参与运动的局部回路，但有助于节律产生和频率调制的中间神经元(IN)回路的全部细节仍然存在 被定义为哺乳动物的。目前，通过分子和/或转录因子图谱评估的发育同一性与通过电生理学和/或连接模式评估的功能同一性之间存在明确联系的例子很少。需要新的工具来更好地了解不同的脊髓损伤人群在脊髓损伤后功能恢复中的作用，并开发针对这些人群的潜在干预措施。该项目将开发分离和培养脊髓腹侧神经元群体的工具。我们将开发一个体外平台，使我们能够研究模型系统中INS、运动神经元(MNS)和皮质神经元之间的连接，并确定促进这些网络功能连接的线索。最后，我们将检验移植的脊髓MN和IN群体对脊髓损伤大鼠模型功能恢复的贡献。

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a debilitating condition that results in significant loss of motor function and reduction in quality of life for the approximatel 265,000 Americans affected. For many years, a dogma held by those studying SCI was that long-range regeneration of descending tracts was the key to regaining function. However, more recent research has shown that functional recovery is due to local rewiring of these tracts to propriospinal neurons and plasticity of spared neural tissue within the spinal cord. To better understand how this regeneration occurs, we need to identify which neuronal populations are involved in these local rewiring events after SCI. While the local circuitry that contributes to locomotion via central pattern generators is well defined in model organisms, the full details of the interneuron (IN) circuitry contributing to rhythm generation and frequency modulation are still being defined in mammals. Currently, very few examples exist with firm links between developmental identity, as assessed by molecular and/or transcription factor profiles, and functional identity, as assessed by electrophysiology and/or connectivity patterns. New tools are needed to better understand the role of different spinal INs populations in functional recovery after SCI and to develop potential interventions to target these populations. This project will develop tools to isolate and culture ventral spinal neuron populations. We will develop an in vitro platform that will allow us to study connectivity between INs, motoneurons (MNs), and cortical neurons in a model system and to define cues that promote functional connectivity of these networks. Finally, we will examine the contributions of transplanted spinal MN and IN populations to functional recovery in a rat model of spinal cord injury.