Early-life stress contributes to depression-like behaviors in a two-hit mouse model

Depression is a common psychological disorder with pathogenesis involving genetic and environmental interactions. Early life stress can adversely affect physical and emotional development and dramatically increase the risk for the development of depression and anxiety disorders.To examine potential early life stress driving risk for anxiety and depression, we used a two-hit developmental stress model，injecting poly(I: C) into neonatal mice on P2-P6 followed by peripubertal unpredictable stress in adolescence.Our study shows that early-life and adolescent stress leads to anxiety and depression-related behavioral phenotypes in male mice. Early-life stress exacerbated depression-like behavior in mice following peripubertal unpredictable stress. We confirmed that early life stress might be involved in the decreased neuronal activity in the medial prefrontal cortex (mPFC) and might be involved in shaping behavioral phenotypes of animals. We found that increased microglia and neuroinflammation in the mPFC of two-hit mice and early life stress further boost microglia activation and inflammatory factors in the mPFC region of mice following adolescent stress.The specific neural circuits and mechanisms by which microglia regulate depression-like behaviors require further investigation.Our findings provide a novel insight into developmental risk factors and biological mechanisms in depression and anxiety disorders.