To explore the neuroendocrine effects of Shugan Decoction in improving depressive-like behaviors.Methods:Rats were randomly divided into normal，model，Western medicine，and Chinese medicine groups using a random number table.A gentle syndrome model was induced by chronic unpredictable mild stress(CUMS).The Western medicine group was treated with fluoxetine hydrochloride，while the Chinese medicine group was treated with Shugan Decoction.Body weight，sucrose preference test，and open field test results were recorded.After intervention，peripheral blood and hypothalamic levels of adrenocorticotropic hormone(ACTH)，cortisol(CORT)，serotonin(5-HT)，and norepinephrine(NE) were measured.The levels of nitric oxide(NO) in the hippocampus and amygdala，brain-derived neurotrophic factor(BDNF)，cyclic adenosine monophosphate response element-binding protein(CREB)，phosphorylated extracellular signal-regulated kinase(p-ERK)，c-fos，c-jun，and phosphorylated CREB(p-CREB) in the hippocampus and cortex were also detected.Additionally，the protein levels of c-fos and c-jun in the amygdala and mRNA expression of BDNF，c-fos，and c-jun in the hippocampus and amygdala were analyzed.Results:On the 21st day of modeling，compared with the model group，both the Western medicine and Chinese medicine groups showed significant increases in body weight，total distance in the open field test，and sucrose preference(P<0.05).The levels of peripheral blood ACTH and CORT were significantly lower，while hypothalamic 5-HT and NE levels were significantly higher in the Western medicine and Chinese medicine groups compared with the model group(P<0.05).Protein levels of c-fos and c-jun in the amygdala and hippocampus in the Western medicine and Chinese medicine groups，cortical c-fos and c-jun in the Western medicine group，and cortical c-fos in the Chinese medicine group were significantly reduced(P<0.05).Phosphorylated ERK(p-ERK) and BDNF in the cortex and hippocampus were significantly increased(P<0.05).The Chinese medicine group showed higher cortical BDNF and hippocampal p-CREB than the Western medicine group(P<0.01 and P<0.05).The mRNA levels of c-fos，c-jun，and NO in the hippocampus，and c-jun mRNA and NO in the amygdala were significantly decreased in both the Western medicine and Chinese medicine groups(P<0.05 or P<0.01).Meanwhile，the mRNA expression of BDNF in the hippocampus and amygdala was significantly elevated(P<0.05).Conclusion:Shugan Decoction significantly improved depressive-like behaviors in rats with a gentle syndrome.Its mechanism involves correcting the abnormal activation of the hypothalamic-pituitary-adrenal(HPA) axis，regulating the levels of 5-HT and NE in the hypothalamus，and affecting BDNF levels through the modulation of c-fos，c-jun，NO，and the MAPK pathway at the protein and mRNA levels，which helps improve neurocellular regeneration and repair.