title: Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia.
abstract: BACKGROUND
  Traumatic brain injury (TBI) is associated with a higher incidence of depression. The majority of individuals who suffer a TBI are juveniles and young adults, and thus, the risk of a lifetime of depressive complications is a significant concern. The etiology of increased TBI-associated depression is unclear but may be inflammatory-related with increased brain sensitivity to secondary inflammatory challenges (e.g., stressors, infection, and injury).
  
  
  METHODS
  Adult male BALB/c mice received a sham (n = 52) or midline fluid percussion injury (TBI; n = 57). Neuroinflammation, motor coordination (rotarod), and depressive behaviors (social withdrawal, immobility in the tail suspension test, and anhedonia) were assessed 4 hours, 24 hours, 72 hours, 7 days, or 30 days later. Moreover, 30 days after surgery, sham and TBI mice received a peripheral injection of saline or lipopolysaccharide (LPS) and microglia activation and behavior were determined.
  
  
  RESULTS
  Diffuse TBI caused inflammation, peripheral cell recruitment, and microglia activation immediately after injury coinciding with motor coordination deficits. These transient events resolved within 7 days. Nonetheless, 30 days post-TBI a population of deramified and major histocompatibility complex II(+) (primed) microglia were detected. After a peripheral LPS challenge, the inflammatory cytokine response in primed microglia of TBI mice was exaggerated compared with microglia of controls. Furthermore, this LPS-induced microglia reactivity 30 days after TBI was associated with the onset of depressive-like behavior.
  
  
  CONCLUSIONS
  These results implicate a primed and immune-reactive microglial population as a possible triggering mechanism for the development of depressive complications after TBI.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Fenn
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky.
authors.forename: John C
authors.initials: JC
authors.lastname: Gensel
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, Ohio State University, Columbus, Ohio; Institute for Behavioral Medicine Research, Ohio State University, Columbus, Ohio.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.affiliation: Barrow Neurological Institute at Phoenix Children's Hospital, Department of Child Health, University of Arizona, College of Medicine-Phoenix, Phoenix, Arizona.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, Ohio State University, Columbus, Ohio; Institute for Behavioral Medicine Research, Ohio State University, Columbus, Ohio. Electronic address: jonathan.godbout@osumc.edu.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications*; D003863:Depression / Q000209:etiology* / Q000276:immunology*; D004660:Encephalitis / Q000209:etiology / Q000276:immunology*; D005911:Gliosis; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism*; D009043:Motor Activity; D013997:Time Factors
chemical_list: D008070:Lipopolysaccharides
keywords: Cytokines; depression; fluid percussion injury; lipopolysaccharide; major histocompatibility complex II; microglia