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Our previous study demonstrated that gypenosides produced antidepressant-like effects in mice exposed to chronic mild stress in a brain-derived neurotrophic factor-dependent manner. However, whether other mechanisms are involved in the antidepressant-like effects of gypenosides is not clear. miR-124 is one of the most abundant microRNAs in the hippocampus, and its dysregulation is related to the pathophysiology of depression. The glucocorticoid receptor is dysfunctional in depression, and it is a direct target of miR-124. Therefore, the present study used corticosterone-induced mice as a model to evaluate the role of miR-124 on the antidepressant-like effects of gypenosides. miR-124 agomir was intracerebrally injected prior to administration of gypenosides and corticosterone injection. Sucrose preference and forced swimming tests were performed 21 days later. Proteins related to glucocorticoid receptors and brain-derived neurotrophic factor-tyrosine receptor kinase B signaling in the hippocampus were evaluated. Our results demonstrated that gypenosides reversed the chronic corticosterone injection-induced decreased sucrose preference and increased immobility time. In contrast, this effect was antagonized by miR-124 injection. In addition, gypenosides increased glucocorticoid receptor and tyrosine receptor kinase B expression in the hippocampus, which activated brain-derived neurotrophic factor signaling. miR-124 also blocked these effects. In conclusion, this study demonstrated that a reduction in miR-124 was required for the antidepressant-like effects of gypenosides induced by chronic corticosterone injection in mice. [ABSTRACT FROM AUTHOR]