Insufficient regeneration of central nervous system (CNS) axons contributes to persisting neurological dysfunction after spinal cord injury (SCI). Peripheral nerve grafts (PNGs) support regeneration by thousands of injured intraspinal axons and help them bypass some of the extracellular barriers that form after SCI. However this number represents but a small portion of the total number of axons that are injured. Here we tested if rhythmic sensory stimulation during cycling exercise would boost the intrinsic regenerative state of neurons to enhance axon regeneration into PNGs after a lower thoracic (T12) spinal transection of adult rats. Using True Blue retrograde tracing, we show that 4 weeks of cycling improves regeneration into a PNG from lumbar interneurons but not by primary sensory neurons. The majority of neurons that regenerate their axon are within 5mm of the lesion and their number increased 70% with exercise. Importantly propriospinal neurons in more distant regions (5–20 mm from the lesion) that routinely exhibit very limited regeneration responded to exercise by increasing the number of regenerating neurons by 900%. There was no exercise-associated increase in regeneration from sensory neurons. Analyses using fluorescent in situ hybridization showed that this increase in regenerative response is associated with changes in levels of mRNAs encoding the regeneration associated genes (RAGs) GAP43, β-actin and Neuritin. While propriospinal neurons showed increased mRNA levels in response to SCI alone and then to grafting and exercise, sensory neurons did not respond to SCI, but there was a response to the presence of a PNG. Thus, exercise is a non-invasive approach to modulate gene expression in injured neurons leading to an increase in regeneration. This sets the stage for future studies to test whether exercise will promote axon outgrowth beyond the PNG and reconnection with spinal cord neurons, thereby demonstrating a potential clinical application of this combined therapeutic intervention.

Therapeutic interventions after spinal cord injury (SCI) routinely are designed to address multiple aspects of the primary and/or secondary damage that occurs. Exercise has a demonstrated efficacy for post-SCI complications such as cardiovascular dysfunction, neuropathic pain, and chronic inflammation, yet there is little understanding of the mechanisms by which improvements might result from this non-invasive approach. Here we review several of our observations of molecular and cellular changes within the injured spinal cord following acute or delayed exercise regimens that illustrate the potential for positive effects on neuroprotection and rehabilitation. Further, we provide new information about the role of exercise in promoting the regeneration of spinal axons into peripheral nerve grafts (PNGs) placed immediately or 6 weeks after injury. Acute and chronically injured propriospinal neurons within the lumbar spinal cord displayed the greatest propensity for enhanced regeneration after exercise, which correlates with the direct sensory input to this region from exercised hindlimb muscles. Future studies will extend these observations by testing whether exercise will boost the regenerative effort of axons to extend beyond the graft, interact with intraspinal targets, and establish functional connections across a lesion.

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