Axon Regeneration after Spinal Cord Injury in Mice

描述（由申请人提供）：我们最近在小鼠脊髓损伤后发现了皮质-脊髓束（CST）轴突再生发芽的一种形式。这种再生发芽，或许还有其他形式的轴突再生，在某些编码轴突生长抑制分子（Nogo）的基因被删除的小鼠品系中得到增强。正常小鼠的局部再生生长和转基因小鼠的增强生长可以恢复损伤部位附近介导运动功能的神经元池的下降输入。这种形式的生长在颈椎水平病变后尤其重要，其中即使是单个节段的生长也可以恢复前肢关键肌群的运动神经元的功能。这些小鼠提供了一个机会来提出一个以前无法解决的关键问题——有限的CST再生是否足以恢复自愿（CST介导的）运动功能。在本项目中，我们将定义正常小鼠脊髓损伤后CST轴突局部轴突生长反应的性质，并验证这种生长介导节段性运动回路功能恢复的假设。我们将量化在同一动物的胸椎和颈椎损伤后再生CST发芽的时间过程和程度，评估在再生生长期间后肢和前肢运动功能是否分别恢复。这些分析将使我们能够将再生生长的性质和程度与功能结果联系起来。为了验证恢复是由于神经再生的假设，我们将在携带延迟突触沃勒氏变性（wld）突变的小鼠中进行平行实验，其中再神经再生也被延迟，并使用表现出增强再生发芽和真正的长束再生的转基因小鼠（缺乏Nogo的小鼠系）来精确定义CST再生与运动功能恢复之间的关系损伤水平以下。总之，这些研究将为小鼠皮质-脊髓束轴突的生长能力提供一个重要的数据基础，这将对未来涉及转基因小鼠的研究至关重要。

DESCRIPTION (provided by applicant): We have recently discovered a form of regenerative sprouting of cortico-spinal tract (CST) axons following spinal cord injury in mice. This regenerative sprouting, and perhaps other forms of axon regeneration, are enhanced in certain lines of mice in which genes encoding axon growth inhibitory molecules (Nogo) have been deleted. The local regenerative growth in normal mice and the enhanced growth in genetically modified mice is of the sort that could restore descending input to neuron pools mediating motor function near the site of injury. This form of growth could be especially important following lesions at the cervical level, where growth over a even single segment could restore function to motoneurons supplying critical muscle groups of the forelimb. These mice provide the opportunity to ask a key question that was previously impossible to address-whether limited CST regeneration is sufficient to restore voluntary (CST-mediated) motor function. In the present project, we will define the nature of the local axonal growth responses of CST axons that occur after spinal cord injury in normal mice, and test the hypothesis that this growth mediates recovery of function in segmental motor circuitry. We will quantify the time course and extent of regenerative CST sprouting following injuries at both the thoracic and cervical levels and in the same animals, assess whether recovery of hindlimb and forelimb motor function respectively occurs during the period of regenerative growth. These analyses will allow us to correlate the nature and extent of regenerative growth with functional outcome. To test the hypothesis that recovery is due to reinnervation, we will carry out parallel experiments in mice carrying a mutation that delays Wallerian degeneration of synapses (WldS), in which reinnervation is also delayed, and use genetically modified mice that exhibit enhanced regenerative sprouting and bona fide long-tract regeneration (lines of mice that lack Nogo) to precisely define the relationship between CST regeneration recovery of motor function below the level of the injury. Together, these studies will provide a critical data base regarding the growth capacity of cortico-spinal tract axons in mice, which will be essential for future studies involving genetically modified mice.