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

Biol Psychiatry. 2014 Oct 1;76(7):575-84. doi: 10.1016/j.biopsych.2013.10.014. Epub 2013 Oct 25.


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.

Keywords: Cytokines; depression; fluid percussion injury; lipopolysaccharide; major histocompatibility complex II; microglia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / complications*
  • Depression / etiology*
  • Depression / immunology*
  • Encephalitis / etiology
  • Encephalitis / immunology*
  • Gliosis
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microglia / metabolism*
  • Motor Activity
  • Time Factors


  • Lipopolysaccharides