Axon Regeneration after Spinal Cord Injury in Mice

描述（由申请人提供）：我们最近发现了小鼠脊髓损伤后皮质脊髓束（CST）轴突再生发芽的一种形式。这种再生发芽，也许还有其他形式的轴突再生，在编码轴突生长抑制分子（Nogo）的基因被删除的某些小鼠品系中得到增强。正常小鼠的局部再生性生长和转基因小鼠的增强生长是那种可以恢复神经元池的下行输入，介导损伤部位附近的运动功能。这种形式的增长可能是特别重要的病变后，在颈部水平，其中增长，甚至一个单一的节段可以恢复功能的运动神经元供应的关键肌肉群的前肢。这些小鼠提供了一个机会，问一个关键的问题，以前是不可能解决的有限的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发生的CST轴突的局部轴突生长反应的性质，并测试这种生长介导节段性运动回路功能恢复的假设。我们将量化在胸部和颈部水平以及在相同动物中损伤后再生CST发芽的时间过程和程度，评估在再生生长期间是否分别发生后肢和前肢运动功能的恢复。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相关联。为了检验恢复是由于神经再支配的假设，我们将在携带延迟突触沃勒变性（WldS）的突变的小鼠中进行平行实验，其中神经再支配也被延迟，并使用转基因小鼠，表现出增强的再生发芽和真正的长道再生，（缺乏Nogo的小鼠品系）以精确地定义CST再生与低于损伤水平的运动功能恢复之间的关系。总之，这些研究将提供关于小鼠皮质脊髓束轴突生长能力的关键数据库，这对于涉及转基因小鼠的未来研究至关重要。

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.