<p>Recurrent major depression is associated with increased morbidity, suicidal behaviors and increasing neurocognitive deficits. Microglia-mediated neuroinflammatory processes deeply participate in the physiopathology of depression. In response to stress, microglia can develop trained immunity mediated by epigenetic reprogramming, which can enhance the neuro-inflammatory response to subsequent insults. Here, we investigate whether, in animal models, previous depressive-like behaviors are associated with microglial trained immunity, which increases the susceptibility of mice to stress, resulting in the reocurrence of depressive-like behaviors. In the hippocampus and after recovery of initial chronic mild stress (CMS)-induced depressive behaviors, this study discovered increased and persistent chromatin accessibility and H3K4me3 marks in genes related to proinflammatory response, but without sustaining microglial activation and neuroinflammation. Furthermore, the initial CMS induced increased H3K4me3 deposition on the promotor region of NLRP3, inducing impairments in the adult hippocampal neurogenesis and stress sensitization when mice are re-exposed to subthreshold stress (reCMS) for 2 weeks, resulting in the reocurrence of depressive-like behaviors, which could be reversed through specific knockdown of NLRP3 in hippocampal microglia. Blockade of H3K4me3-mediated NLRP3 activation via the H3K4me3 inhibitor rescued neurogenesis impairment induced by initial CMS, and ameliorated the enhanced susceptibility of mice to stress re-exposure. Collectively, initial CMS induced a NLRP3-dependent trained immunity of microglia, which was mediated by epigenetic reprogramming, facilitating the susceptibility of mice to subsequent stress, thereby contributing to the reocurrence of depressive-like behaviors. Our findings might provide a perspective strategy for the prevention and treatment of depression recurrence.</p>