摘要Neuroinflammation is crucial for the pathogenesis of major depression.Preclinical studies have shown the potential of anti-inflammatory agents,specifically costunolide(COS),correlate with antidepressant effects.In this study,we investigated the molecular mechanisms underlying the antidepressant actions of COS.Chronic restraint stress(CRS)was induced in male mice.The mice were treated with either intra-DG injection of COS(5 μM,1μL per side)or COS(20 mg/kg,i.p.)for 1 week.We showed that administration of COS through the both routes significantly ameliorated the depressive-like behavior in CRS-exposed mice.Furthermore,administration of COS significantly improved chronic stress-induced adult hippocampal neurogenesis deficits in the mice through attenuating microglia-derived neuroinflammation.We demonstrated that COS(5 μM)exerted anti-neuroinflammatory effects in LPS-treated BV2 cells via inhibiting microglial Akt/mTOR/NF-κB pathway;inactivation of mTOR/NF-κB/IL-1β pathway was required for the pro-neurogenic action of COS in CRS-exposed mice.Our results reveal the antidepressant mechanism of COS that is normalizing neuroinflammation to improve neurogenesis deficits,supporting anti-inflammatory agents as a potential therapeutic strategy for depression.