Experimental spinal cord injury (SCI) models have helped define levels of structural and functional plasticity within the spinal cord and affected muscles. Peripheral nerve grafts (PNGs) support the regeneration of acute and chronically injured neurons although growth beyond the graft, back into the spinal cord, is limited in terms of the number and length of axonal extension. Digestion of inhibitory proteoglycans with Chondroitinase is partially effective in increasing axonal outgrowth and there is evidence of functional synaptic connection between regenerated axons and spinal cord neurons. Exercise-induced increase of neurotrophic factors in thoracic and lumbar spinal cord is correlated with the restoration of motoneuron excitability (spinal reflexes) to near normal activity. Despite these successes there remain thousands of injured neurons that are not involved in reorganization and repair of the injured spinal cord. Our objectives are to address mechanistic questions related to the potential for exercise to provide trophic factor cues to potentially promote the regenerative response of injured neurons and/or to activate spinal networks to facilitate receptivity of regenerating axons.
Aim 1 will address the hypothesis that exercise will promote regeneration of acute and/or chronically injured axons into a PNG, using an adult rat lower thoracic level transection injury, separate PNGs to support growth of descending vs. ascending axons and treadmill step training. Tract tracing methods will define the regenerative effort of motor and sensory neurons.
Aim 2 will test whether exercise increases axonal outgrowth from a PNG and determine possible functional improve- ment related to regenerated axons by performing sensorimotor behavior, kinematic and electrophysiological analyses. In separate groups we will test whether activity-dependent plasticity is achieved with either/or an acute or delayed treatment approach. To advance the preclinical translation of our treatment strategy, results from SCI rats will be applied to a spinalized cat preparation to test whether exercise and transplantation promote regeneration-based functional recovery in a large animal model. Overall, these experiments will provide fundamental information about cellular and functional aspects of spinal cord reorganization in acute and chronic stages of SCI that will be instrumental in designing strategies for repair.

Public Health Relevance

Here we will combine transplantation and exercise treatment strategies to determine if the regenerative effort of injured neurons can be enhanced in acute and chronically injured animals. This observation directiy impacts the overwhelming number of spinal cord injured patients because of the perception that most surgical interventions should be delayed until the individual is stable and opportunities for spontaneous recovery have subsided.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS055976-07
Application #
8652510
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$252,569
Indirect Cost
$89,094
Name
Drexel University
Department
Type
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Hayakawa, Kazuo; Haas, Christopher; Jin, Ying et al. (2015) Glial restricted precursors maintain their permissive properties after long-term expansion but not following exposure to pro-inflammatory factors. Brain Res 1629:113-25

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