Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity

描述（由申请人提供）：我们设计了这个程序项目，以协调围绕神经再生不是功能恢复的同义词的中心主题协同研究工作。我们专注于负责协调肌肉活动和有目的的肢体运动的感觉运动回路中发生的变化。在周围神经切断和再生之后，脊髓回路不能从初级传入神经或运动神经元的中央投射轴突分支恢复关于运动的正常反馈。在前一个资助期，我们发现这些集中投射的轴突及其脊髓连接永久性地丢失或改变，即使外周轴突分支成功地与适当的靶点重新连接。三个项目，每个由一个既定的研究者谁带来了独特的实验专业知识和概念的见解，该计划领导，将推进我们的脊髓回路周围神经损伤和再生的反应的知识。项目1将在体内应用电生理学方法来测试拟议的治疗方法，以改善周围神经损伤后的结果。项目2将使用一种新的病毒逆行标记技术来询问以前无法解决的电路重组问题。项目1和项目2将共同检验由周围神经损伤触发的脊髓回路变化比单突触反射更全面的假设。这些结果将揭示这些变化的本质，解释受伤后运动控制和行为的改变。项目3将定义通过神经肌肉接头处的自发囊泡释放发生的体内信号传导的基础通路，并将确定该通路是否也在外周神经损伤后从运动神经元发出突触剥离的信号。这三个项目都将得到细胞成像、手术和组织处理核心设施（核心B）的协助。该核心提供必要的支持和专业知识，以确保所有三个PPG研究项目程序的一致性和质量。2010年，一个外部咨询委员会对我们的项目进行了审查，得出结论：“这是一个互动性很强的团队，在许多项目中都有重要的智力互动。“我们希望项目之间继续密切合作，将带来显着的附加值，因为我们朝着治疗的发展，以促进神经损伤后的恢复。 公共卫生相关性：我们的首要目标是改善神经系统损伤后的恢复。我们特别关注周围神经损伤后脊髓运动功能的恢复。因为类似的细胞和突触变化也可能作为中枢神经损伤的结果起作用，这项工作也将为促进中风和脊髓损伤等损伤后神经系统损伤的恢复提供信息。 免责声明：来自个别评审员的评论和标准分数以基本上未经编辑的形式提供如下。这些文件是在审查会议之前编写的，在会议讨论之后可能没有更新或修订。因此，在小组讨论或小组最终多数意见结束时，它们可能无法完全反映单个审评员的最终意见。以上讨论的摘要和总结总结了小组讨论的最终结果。 总体评价

DESCRIPTION (provided by applicant): We designed this program project to coordinate synergistic research efforts around the central theme that nerve regeneration is not synonymous with functional recovery. We are uniquely focused on changes occurring in the sensorimotor motor circuits that are responsible for coordinating muscle activity and purposeful limb movement. In the aftermath of peripheral nerve transection and regeneration, spinal circuits do not regain normal feedback about movement from the centrally-projecting axon branches of either primary afferents or motoneurons. In the previous funding period, we discovered that these centrally- projecting axons and their spinal connections are permanently lost or altered, even when peripheral axon branches successfully reconnect with appropriate targets. Three projects, each led by an established investigator who brings unique experimental expertise and conceptual insight to the program, will advance our knowledge of the response of spinal circuits to peripheral nerve injury and regeneration. Project 1 will apply electrophysiological methods in vivo to test a proposed treatment to improve outcome following peripheral nerve injury. Project 2 will use a novel viral retrograde labeling technique to ask questions about circuit reorganization that have previously been impossible to address. Together, Projects 1 and 2 will test the hypothesis that circuit changes in the spinal cord triggered by peripheral nerve injury are more global than the monosynaptic reflex. The results will shed light on the nature of the changes that explain the modification in motor control and behavior after injury. Project 3 will define the pathway that underlies in vivo signaling that occurs via spontaneous vesicle release at the neuromuscular junction and will determine whether this pathway also signals synaptic stripping from motoneurons following peripheral nerve injury. All three projects will be assisted by the Cellular Imaging, Surgery and Tissue Processing Core Facility (Core B). This core provides the support and expertise necessary to ensure consistency and quality of procedures for all three PPG research projects. An external advisory committee reviewing our program project in 2010 concluded, "this is an unusually interactive group with significant intellectual interactions evidet in many of the projects." It is our hope that continued close collaboration between projects, will bring significant added value as we move towards development of therapy to promote recovery following nerve injury. Public Health Relevance: Our overarching goal is to improve recovery following injury to the nervous system. Our specific focus is recovery of spinal cord motor function following peripheral nerve injury. Because similar cellular and synaptic changes might also operate as consequence of central nervous injuries, this work will also inform efforts to promote recovery from nervous system injuries after insults such as stroke and spinal cord injury. Disclaimer: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. These were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion o the final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION