【Abstract】Objective To observe the changes of depressive behavior and neuronal damage induced by different doses of corticosterone (CORT) in mice, and to explore the best dose of corticosterone-induced depression model in mice. Methods Forty male C57BL/6J mice were randomly divided into four groups: normal control group and corticosterone group (low, medium and high, 20, 40 and 60 mg/kg), and the corresponding drug intervention lasted for 4 weeks. The behavioral changes of mice after subcutaneous injection of corticosterone for 3 and 4 weeks were detected by sugar water preference test, forced swimming test, tail suspension test and open field test. Hematoxylin-eosin staining (HE) and Nissl staining were used to observe the morphological changes of neurons in hippocampal CA1 area and forebrain cortex area of mice. Enzyme-linked immunosorbent assay (ELISA) was used to detect the content of 5- hydroxytryptamine (5-HT) in serum. To compare the behavioral changes of depression in mice induced by different doses of corticosterone. Results Compared with the control group, the weight of mice in corticosterone dosage groups (20 mg/kg, 40 mg/kg and 60 mg/kg) decreased (P < 0.05) and the preference of sucrose solution decreased (P < 0.01). The immobility time of forced swimming mice in corticosterone 20 mg/kg and 40 mg/kg groups was prolonged (P < 0.01). The immobility time of mice in the 40 mg/kg corticosterone group was prolonged (P < 0.05). The total distance, the average speed and the times of entering the central area of the open-field experimental mice in the corticosterone 40 mg/kg and 60 mg/kg groups decreased (P < 0.05), and the stay time in the peripheral area of the mice was prolonged (P < 0.05). In addition, corticosterone injection resulted in incomplete neuronal cell morphology, cell deformation and nuclear condensation in hippocampal CA1 area and forebrain cortex area of mice in different degrees. The level of 5-HT in serum of 40 mg/kg and 60 mg/kg corticosterone decreased (P < 0.05). Conclusion Corticosterone at 20 mg/kg, 40 mg/kg and 60 mg/kg can induce depression-like behavioral changes and neuronal damage in mice to varying degrees, and the effect of corticosterone at 40 mg/kg is more obvious. Under the experimental conditions, it is preliminarily considered that 40 mg/kg is the best dose to replicate the depression model induced by corticosterone in mice.