Preferential motor reinnervation is modulated by both repair site and distal nerve environments

To restore function after nerve injury, axons must regenerate from the injury site to the periphery, then reinnervate appropriate end organs when they arrive. Only 10 % of adults who suffer nerve injury will regain normal function, often because axons regenerate to functionally inappropriate targets (Brushart, 2011). The peripheral destination of these axons is largely determined by the pathways they enter at the site of nerve repair. To improve clinical outcomes, it is thus critical to improve the accuracy of axon pathfinding. In rodents, motor axons regenerating in mixed nerve preferentially reinnervate pathways leading to muscle, a process termed preferential motor reinnervation (PMR). Previous experiments have shown that PMR can be enhanced by predegenerating nerve grafts to enhance growth factor production and remove inhibitory factors (Abdullah et al., 2013). The current experiments explore the relative contributions of motor pathways, sensory pathways, and the repair environment to this enhancement. Sensory and/or motor pathways within rat femoral nerve grafts were predegenerated for 3 weeks to optimize growth factor production (Brushart et al., 2013) or for 12 weeks to deplete it. Optimizing the environment within previously motor Schwann cell tubes promoted PMR, regardless of whether adjacent sensory pathways were optimized or chronically denervated. However, this positive effect was abolished when sensory pathways were undergoing acute Wallerian degeneration immediately after nerve repair. The repair environment thus precluded motor axon pathfinding in spite of an optimized distal motor pathway. When sensory pathways were optimized and motor pathways were chronically denervated, not only was PMR abolished, but motoneurons failed to respond to the greater volume of growth factors in the sensory nerve. Small sensory neurons, however, selectively reinnervated cutaneous nerve under these conditions. These experiments thus strengthen the concept that, in adult rats, sensory and motor pathways have unique identities capable of influencing both sensory and motor axon regeneration. Furthermore, they demonstrate that, in the rat, delaying nerve repair for 3 weeks to enhance growth factor production and clear the products of acute Wallerian degeneration can enhance regeneration specificity without the need for exogenous treatments.