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

描述(由申请人提供)：我们设计了这个项目，以协调围绕中心主题的协同研究努力，即神经再生不是功能恢复的同义词。我们特别关注负责协调肌肉活动和有目的的肢体运动的感觉运动运动回路中发生的变化。在周围神经切断和再生后，脊髓环路不能从初级传入或运动神经元的中央投射轴突分支恢复正常的运动反馈。在之前的资助期间，我们发现这些中央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，每个项目都由一名知名的研究人员领导，他为该项目带来了独特的实验专业知识和概念洞察力，将促进我们对脊髓回路对周围神经损伤和再生的反应的了解。项目1将在体内应用电生理学方法来测试一种拟议的治疗方法，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不可能解决的关于电路重组的问题。总而言之，项目1和项目2将检验这样一个假设，即周围神经损伤引发的脊髓回路变化比单突触反射更具全局性。这一结果将有助于揭示损伤后运动控制和行为改变的本质。项目3将定义体内通过神经肌肉连接处自发释放小泡而发生的信号传递的途径，并将确定该途径是否也传递周围神经损伤后运动神经元突触剥离的信号。所有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。这一核心提供了必要的支持和专业知识，以确保所有三个PPG研究项目的程序的一致性和质量。一个外部顾问委员会在2010年审查了我们的项目，得出的结论是：“这是一个不寻常的互动小组，在许多项目中都有重要的智力互动。”我们希望，随着我们朝着促进神经损伤后康复的治疗方法的发展前进，项目之间的持续密切合作将带来显著的附加值。 公共卫生相关性：我们的首要目标是促进神经系统损伤后的恢复。我们的重点是周围神经损伤后脊髓运动功能的恢复。由于类似的细胞和突触变化也可能是中枢神经损伤的结果，这项工作也将促进从中风和脊髓损伤等侮辱后的神经系统损伤中恢复的努力。 免责声明：来自个人评审员的批评和标准分数以基本上未经编辑的形式在下面提供。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，它们可能不能完全反映个别审评员在小组讨论结束时的最后意见或小组的最终多数意见。以上讨论摘要概述了小组讨论的最终结果。 总体方案评估

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