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Prolonged exposure to stress can affect mood and cognition and lead to mood disorders. Research on stress-associated mood disorders is important in modern society as people are increasingly exposed to unavoidable stressors. We used a mouse model with 2 weeks of exposure to electric foot shock and restraint, to determine the effect of Fraxinus rhynchophylla Hance (FX) extract on chronic stress-induced depression. We measured the effect of FX extract using various physiological, behavioral, and biochemical measures. FX extract ameliorated chronic stress-induced body and relative liver weight loss and improved depressive-like behaviors in the open field and forced swim tests. In addition, plasma cortisol and serotonin levels in stress-induced mice following FX treatment were similar to normal mice, and the elevation of proinflammatory cytokines was prevented. Moreover, FX treatment increased the expression of phosphorylated cyclic adenosine-3′,5′-monophosphate response element-binding protein (pCREB)/brain-derived neurotrophic factor (BDNF). Further experiments confirmed the efficacy of FX extract by showing similar results using esculin and esculetin, compounds extracted from FX. Taken together, these results indicate that FX extract has an antidepressant effect on chronic stress-induced depression by associating signaling with neuroinflammation and neurogenesis. [ABSTRACT FROM AUTHOR]