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Objective: To observe the effects of gastrodin on the abnormal behaviors and the expressions of janus kinase 2-signal transducer and transcription activator 3 (JAK2-STAT3) signaling pathway in depression mice model. Methods: Forty male Kunming mice, were randomly divided into normal and model groups. After 4 weeks CUMS stimulation, the behavioral changes of mice were detected in week 6 to verify the modeling effect. The model was then composed of three subgroups: CUMS+saline, CUMS+fluoxetine and CUMS+gastrodin group, CUMS stimulation continued during weeks 7-8. At the same time, three subgroups of mice were injected intraperitoneally. The behavior test was carried out again in week 9. Mouse brain tissue was HE stained and Western blot. Results: The results of week 6 showed that, compared to control group, CUMS stimulation significantly decreased the weight change (P<0.001), increased the immobility time in tail suspension and forced swimming test (P<0.001, P<0.001) and decreased the percentage of sucrose intake(P<0.001). At week 9, the results showed: compared to CUMS+saline group, CUMS+fluoxetine group and CUMS+gastrodin group significantly increased weight change (P<0.001, P<0.001), decreased the immobility time in forced swimming test (P<0.001, P<0.001), decreased immobility the time in tail suspention test (P<0.01, P<0.01) and increased the percentage of sucrose intake(P<0.001, P<0.001). Compared with CUMS+saline group, the expression of JAK2, STAT3 IL-1茁 in CUMS+gastrodin group decreased significantly(P<0.01, P<0.01, P<0.05); The results of HE staining showed that, the morphology of neurons in CUMS+saline group was changed, the cell structure was not clear, the nucleus shrank and dyed deeply, and the morphology of neurons in CUMS+gastrodin group was improved compared to that in CUMS+saline group. Conclusion: Gastrodin could effectively improve the CUMS induced depressive behaviors in mice, and its effect might be related to the expressions of key proteins in JAK2-STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]