Accelerated axon outgrowth, guidance, and target reinnervation across nerve transection gaps following a brief electrical stimulation paradigm

Laboratory investigation

Bhagat Singh M.Pharm. 1 , Qing-Gui Xu M.D., Ph.D. 1 , Colin K. Franz Ph.D. 1 , Rumi Zhang M.S. 2 , Colin Dalton Ph.D. 2 , Tessa Gordon Ph.D. 3 , Valerie M. K. Verge Ph.D. 4 , Rajiv Midha M.D., F.R.C.S.C. 1 and Douglas W. Zochodne M.D., F.R.C.P.C. 1
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  • 1 Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary;
  • 2 Advanced Micro/nanosystems Integration Facility, Electrical and Computer Engineering, University of Calgary;
  • 3 Center for Neuroscience, University of Alberta, Edmonton, Alberta; and
  • 4 Cameco MS Neuroscience Research Center, Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Canada
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Object

Regeneration of peripheral nerves is remarkably restrained across transection injuries, limiting recovery of function. Strategies to reverse this common and unfortunate outcome are limited. Remarkably, however, new evidence suggests that a brief extracellular electrical stimulation (ES), delivered at the time of injury, improves the regrowth of motor and sensory axons.

Methods

In this work, the authors explored and tested this ES paradigm, which was applied proximal to transected sciatic nerves in mice, and identified several novel and compelling impacts of the approach. Using thy-1 yellow fluorescent protein mice with fluorescent axons that allow serial in vivo tracking of regeneration, the morphological, electrophysiological, and behavioral indices of nerve regrowth were measured.

Results

The authors show that ES is associated with a 30%–50% improvement in several indices of regeneration: regrowth of axons and their partnered Schwann cells across transection sites, maturation of regenerated fibers in gaps spanning transection zones, and entry of axons into their muscle and cutaneous target zones. In parallel studies, the authors analyzed adult sensory neurons and their response to extracellular ES while plated on a novel microelectrode array construct designed to deliver the identical ES paradigm used in vivo. The ES accelerated neurite outgrowth, supporting the concept of a neuron-autonomous mechanism of action.

Conclusions

Taken together, these results support a robust role for brief ES following peripheral nerve injuries in promoting regeneration. Electrical stimulation has a wider repertoire of impact than previously recognized, and its impact in vitro supports the hypothesis that a neuron-specific reprogrammed injury response is recruited by the ES protocol.

Abbreviations used in this paper: BDNF = brain-derived neurotrophic factor; cAMP = cyclic adenosine monophosphate; CMAP = compound muscle action potential; DRG = dorsal root ganglion; ES = electrical stimulation; FB = fast blue; GFAP = glial fibrillary acidic protein; MEA = microelectrode array; PBS = phosphate-buffered saline; SC = Schwann cell; YFP = yellow fluorescent protein.

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Contributor Notes

* Mr. Singh and Dr. Xu contributed equally to this study.

Address correspondence to: Douglas W. Zochodne, M.D., F.R.C.P.C., Department of Clinical Neurosciences and the Hotchkiss Brain Institute, 168 Heritage Medical Research Building, 3330 Hospital Drive NW, University of Calgary, Alberta, Canada T2N 4N1. email: dzochodn@ucalgary.ca.

Please include this information when citing this paper: published online December 9, 2011; DOI: 10.3171/2011.10.JNS11612.

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