title: Accelerated axon outgrowth, guidance, and target reinnervation across nerve transection gaps following a brief electrical stimulation paradigm.
abstract: OBJECTIVE
  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.
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Bhagat
authors.initials: B
authors.lastname: Singh
authors.forename: Qing-Gui
authors.initials: QG
authors.lastname: Xu
authors.forename: Colin K
authors.initials: CK
authors.lastname: Franz
authors.forename: Rumi
authors.initials: R
authors.lastname: Zhang
authors.forename: Colin
authors.initials: C
authors.lastname: Dalton
authors.forename: Tessa
authors.initials: T
authors.lastname: Gordon
authors.forename: Valerie M K
authors.initials: VM
authors.lastname: Verge
authors.forename: Rajiv
authors.initials: R
authors.lastname: Midha
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology*; D004558:Electric Stimulation / Q000295:instrumentation / Q000379:methods*; D051379:Mice; D009416:Nerve Regeneration / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology* / Q000293:injuries* / Q000502:physiology