The two reasons most often given for the generally poor functional outcomes observed after peripheral nervous system (PNS) injury are that regenerating axons in peripheral nerves grow slowly and that muscles are often reinnervated by functionally inappropriate motoneurons. Electrical stimulation (ES) of the cut nerve at the time of its surgical repair promotes a significant enhancement of the growth of regenerating axons that is mediated by neuronal neurotrophins. However, there are many circumstances in which ES could be used and ES also results in an increase in muscle reinnervation by functionally inappropriate motoneurons. Exercise promotes BDNF expression in the brain and spinal cord and this could result in a stimulation of the growth of regenerating axons. The goal of this project is to compare the effects of one form of exercise, treadmill training, to those of ES on axon regeneration in peripheral nerves. A combination of transgenic and knockout mice will be used as a novel model system to investigate whether an exercise- induced enhancement of the growth of regenerating axons is mediated by neuronal neurotrophins. By comparing the effects of treadmill training on axon regeneration directly to those produced by ES, we will evaluate whether the enhancement of axon regeneration produced is similar. Synapse re-formation is a critical part of functional recovery after injury to the PNS, and without intervention, it takes longer than it takes regenerating axons to grow sufficiently to reach the muscles. We will compare the effect of ES and treadmill training on the time course of neuromuscular synapse re-formation in transgenic mice. Because it activates motoneurons naturally via their intrinsic neural circuits, exercise could be a way of enhancing regeneration with less functionally inappropriate reinnervation of muscles than noted with ES. The specificity of reinnervation of four different muscle targets will be compared, using retrograde fluorescent labeling methods, in untreated, electrically stimulated, and treadmill trained mice. Exercise has the potential to ameliorate both of the major issues contributing to poor functional recovery from lesions to the PNS. Its potential for clinical use with low cost and very high benefit is great. This project provides a unique opportunity to provide answers important to questions that will strengthen the basis for such clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057190-05
Application #
7995214
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2007-01-19
Project End
2012-06-30
Budget Start
2011-01-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$295,195
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Jaiswal, Poonam B; English, Arthur W (2017) Chemogenetic enhancement of functional recovery after a sciatic nerve injury. Eur J Neurosci 45:1252-1257
Struebing, Felix L; Wang, Jiaxing; Li, Ying et al. (2017) Differential Expression of Sox11 and Bdnf mRNA Isoforms in the Injured and Regenerating Nervous Systems. Front Mol Neurosci 10:354
Jaiswal, Poonam B; Tung, Jack K; Gross, Robert E et al. (2017) Motoneuron activity is required for enhancements in functional recovery after peripheral nerve injury in exercised female mice. J Neurosci Res :
Gordon, Tessa; English, Arthur W (2016) Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise. Eur J Neurosci 43:336-50
Krakowiak, Joey; Liu, Caiyue; Papudesu, Chandana et al. (2015) Neuronal BDNF signaling is necessary for the effects of treadmill exercise on synaptic stripping of axotomized motoneurons. Neural Plast 2015:392591
Sabatier, Manning J; English, Arthur W (2015) Pathways Mediating Activity-Induced Enhancement of Recovery From Peripheral Nerve Injury. Exerc Sport Sci Rev 43:163-71
English, Arthur W; Wilhelm, Jennifer C; Ward, Patricia J (2014) Exercise, neurotrophins, and axon regeneration in the PNS. Physiology (Bethesda) 29:437-45
Liu, Caiyue; Ward, Patricia J; English, Arthur W (2014) The effects of exercise on synaptic stripping require androgen receptor signaling. PLoS One 9:e98633
Thompson, Nicholas J; Sengelaub, Dale R; English, Arthur W (2014) Enhancement of peripheral nerve regeneration due to treadmill training and electrical stimulation is dependent on androgen receptor signaling. Dev Neurobiol 74:531-40
Wood, Kylene; Wilhelm, Jennifer C; Sabatier, Manning J et al. (2012) Sex differences in the effectiveness of treadmill training in enhancing axon regeneration in injured peripheral nerves. Dev Neurobiol 72:688-98

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