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 journalArticle

98 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)575-584
Number of pages10
JournalBiological Psychiatry
Volume76
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Microglia
Depression
Lipopolysaccharides
Wounds and Injuries
Traumatic Brain Injury
Diffuse Brain Injury
Anhedonia
Hindlimb Suspension
Percussion
Major Histocompatibility Complex
Ambulatory Surgical Procedures
Population
Young Adult
Cytokines
Inflammation
Injections
Incidence
Brain

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry
  • Medicine(all)

Cite this

Immune activation promotes depression 1 month after diffuse brain injury : A role for primed microglia. / Fenn, Ashley M.; Gensel, John C.; Huang, Yan; Popovich, Phillip G.; Lifshitz, Jonathan; Godbout, Jonathan P.

In: Biological Psychiatry, Vol. 76, No. 7, 2014, p. 575-584.

Research output: Contribution to journalArticle

Fenn, Ashley M. ; Gensel, John C. ; Huang, Yan ; Popovich, Phillip G. ; Lifshitz, Jonathan ; Godbout, Jonathan P. / Immune activation promotes depression 1 month after diffuse brain injury : A role for primed microglia. In: Biological Psychiatry. 2014 ; Vol. 76, No. 7. pp. 575-584.
@article{18faea50fe9b41219d29d33233608860,
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.",
keywords = "Cytokines, Depression, Fluid percussion injury, Lipopolysaccharide, Major histocompatibility complex II, Microglia",
author = "Fenn, {Ashley M.} and Gensel, {John C.} and Yan Huang and Popovich, {Phillip G.} and Jonathan Lifshitz and Godbout, {Jonathan P.}",
year = "2014",
doi = "10.1016/j.biopsych.2013.10.014",
language = "English (US)",
volume = "76",
pages = "575--584",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "7",

}

TY - JOUR

T1 - Immune activation promotes depression 1 month after diffuse brain injury

T2 - A role for primed microglia

AU - Fenn, Ashley M.

AU - Gensel, John C.

AU - Huang, Yan

AU - Popovich, Phillip G.

AU - Lifshitz, Jonathan

AU - Godbout, Jonathan P.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Cytokines

KW - Depression

KW - Fluid percussion injury

KW - Lipopolysaccharide

KW - Major histocompatibility complex II

KW - Microglia

UR - http://www.scopus.com/inward/record.url?scp=84922638429&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922638429&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2013.10.014

DO - 10.1016/j.biopsych.2013.10.014

M3 - Article

VL - 76

SP - 575

EP - 584

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 7

ER -