title: Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes.
abstract: BACKGROUND
  Diffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the central fluid percussion injury (cFPI) TAI model in mice, the neuroinflammatory and astroglial response and behavioral changes are unknown.
  
  
  METHODS
  Twenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).
  
  
  RESULTS
  At all post-injury time points, β-amyloid precursor protein (β-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood-brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.
  
  
  CONCLUSIONS
  Traumatic axonal injury TAI resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting TAI.
authors.affiliation: Department of Neuroscience, Division of Neurosurgery, Uppsala University, Uppsala 751 85, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Ekmark-Lewén
authors.forename: Johanna
authors.initials: J
authors.lastname: Flygt
authors.forename: Olivia
authors.initials: O
authors.lastname: Kiwanuka
authors.forename: Bengt J
authors.initials: BJ
authors.lastname: Meyerson
authors.forename: Anders
authors.initials: A
authors.lastname: Lewén
authors.forename: Lars
authors.initials: L
authors.lastname: Hillered
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001522:Behavior, Animal / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology / Q000523:psychology; D002452:Cell Count; D020833:Diffuse Axonal Injury / Q000473:pathology* / Q000523:psychology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology; D016896:Treatment Outcome; D014746:Vimentin / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D014746:Vimentin
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