Early-life stress and inflammation: A systematic review of a key experimental approach in rodents.

Ethan G Dutcher,Menna R Clatworthy,Mary-Ellen Lynall,E.A Claudia Pama,Shahid Khan,Jeffrey W Dalley,Edward T Bullmore,Trevor W Robbins

doi:10.1177/2398212820978049

Abstract

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.

Highlights

Early-life stress (ELS), synonymous in the human literature with childhood maltreatment (Danese et al, 2007; Hodel et al, 2015), is associated with many adverse neuropsychiatric and physical health outcomes later in life
We sought to establish a clearer picture of the effects of ELS on the innate immune system by surveying cytokine and microglia findings in the most widely used animal model of ELS
repeated maternal separation (RMS) is considered to have etiological validity as an analogue of human ELS because it occurs in a period of early life analogous to early childhood in humans, and its effects are mediated by reduced parental attendance to emotional and physical needs, just as they are in caregiver neglect, the most prevalent form of human childhood maltreatment (Schmidt et al, 2011; Semple et al, 2013)

Summary

Introduction

Early-life stress (ELS), synonymous in the human literature with childhood maltreatment (Danese et al, 2007; Hodel et al, 2015), is associated with many adverse neuropsychiatric and physical health outcomes later in life. A large meta-analysis concluded that among patients who suffer from depressive disorders, a history of ELS is associated with an increased number of depressive episodes, increased duration of the current depressive episode, and decreased responsiveness to treatment (Nanni et al, 2012). A recent meta-analysis of bipolar disorder patients concluded that a history of childhood maltreatment is associated with earlier disorder onset, increased severity and number of depressive and manic episodes, and increased risk of suicide attempts, anxiety disorders including PTSD, substance

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