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. ? ?
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