title: Microglia processes associate with diffusely injured axons following mild traumatic brain injury in the micro pig.
abstract: BACKGROUND
  Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to early DAI. Additionally, while inflammation is drastically different in rodents compared to humans, pigs and humans share very similar inflammatory profiles and responses.
  
  
  METHODS
  In the current study, we employed a modified central fluid percussion model in micro pigs. Using this model of diffuse mTBI, paired with various immunohistological endpoints, we assessed the potential association between acute thalamic DAI and neuroinflammation 6 h following injury.
  
  
  RESULTS
  Injured micro pigs displayed substantial axonal damage reflected in the presence of APP+ proximal axonal swellings, which were particularly prominent in the thalamus. In companion, the same thalamic sites displayed extensive neuroinflammation, which was observed using Iba-1 immunohistochemistry. The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.
  
  
  CONCLUSIONS
  In aggregate, these studies reveal acute microglial process convergence on proximal axonal swellings undergoing DAI, an interaction not previously recognized in the literature. These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. forrestad@vcu.edu.
authors.forename: Audrey D
authors.initials: AD
authors.lastname: Lafrenaye
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. mtodani@vcu.edu.|Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan. mtodani@vcu.edu.
authors.forename: Masaki
authors.initials: M
authors.lastname: Todani
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. susan.a.walker@vcuhealth.org.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Walker
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. John.Povlishock@vcuhealth.org.
authors.forename: John T
authors.initials: JT
authors.lastname: Povlishock
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001930:Brain Injuries / Q000150:complications*; D020833:Diffuse Axonal Injury / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D018709:Statistics, Nonparametric; D013552:Swine
chemical_list: D016229:Amyloid beta-Peptides; D008840:Microfilament Proteins