title: Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness.
abstract: BACKGROUND
  Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before.
  
  
  OBJECTIVE
  This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders.
  
  
  METHODS
  A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text.
  
  
  RESULTS
  Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus.
  
  
  CONCLUSIONS
  There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.
authors: Department of Psychosis Studies, Institute of Psychiatry, Neurology and Neuroscience (IoPPN), King's College London, Denmark Hill, London, SE5 8AZ, UK.
authors: Marilia A
authors: MA
authors: Calcia
authors: Psychiatric Imaging Group, Imperial College, MRC Clinical Sciences Centre, Hammersmith Hospital, London, W12 0NN, UK. d.bonsall@csc.mrc.ac.uk.
authors: David R
authors: DR
authors: Bonsall
authors: Psychiatric Imaging Group, Imperial College, MRC Clinical Sciences Centre, Hammersmith Hospital, London, W12 0NN, UK.
authors: Peter S
authors: PS
authors: Bloomfield
authors: Department of Psychiatry and Behavioural Sciences, The University of Texas Health Science Centre at Houston, Houston, TX, 77054, USA.
authors: Sudhakar
authors: S
authors: Selvaraj
authors: Department of Psychiatry and Behavioural Sciences, The University of Texas Health Science Centre at Houston, Houston, TX, 77054, USA.
authors: Tatiana
authors: T
authors: Barichello
authors: Department of Psychosis Studies, Institute of Psychiatry, Neurology and Neuroscience (IoPPN), King's College London, Denmark Hill, London, SE5 8AZ, UK.|Psychiatric Imaging Group, Imperial College, MRC Clinical Sciences Centre, Hammersmith Hospital, London, W12 0NN, UK.
authors: Oliver D
authors: OD
authors: Howes
mesh_terms: D000818:Animals; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D001523:Mental Disorders / Q000276:immunology* / Q000503:physiopathology* / Q000523:psychology; D017628:Microglia / Q000276:immunology*; D011598:Psychoneuroimmunology; D011618:Psychotic Disorders / Q000276:immunology / Q000503:physiopathology / Q000523:psychology; D013315:Stress, Psychological / Q000276:immunology* / Q000503:physiopathology / Q000523:psychology
keywords: Inflammation; Microglia; Neuroinflammation; Psychosis; Stress