Immune activation promotes depression 1 month after diffuse brain injury: A role for primed microglia

Ashley M. Fenn, John C. Gensel, Yan Huang, Phillip G. Popovich, Jonathan Lifshitz, Jonathan P. Godbout

Research output: Contribution to journalArticlepeer-review

206 Scopus citations


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.

Original languageEnglish
Pages (from-to)575-584
Number of pages10
JournalBiological Psychiatry
Issue number7
StatePublished - 2014

Bibliographical note

Publisher Copyright:
© 2014 Society of Biological Psychiatry.


  • Cytokines
  • Depression
  • Fluid percussion injury
  • Lipopolysaccharide
  • Major histocompatibility complex II
  • Microglia

ASJC Scopus subject areas

  • Biological Psychiatry


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