Objective To observe the depressive behavior and neuronal damage induced by different doses of corticosterone (CORT) in mice, and to explore the optimal dose for a corticosterone-induced depression model in mice. Methods Forty male C57BL / 6J mice were divided randomly into four groups: control group and low,medium, and high CORT groups (20, 40, and 60 mg / kg, respectively), treated with the corresponding drug dose by subcutaneous injection for 4 weeks. Behavioral changes in mice after corticosterone administration for 3 and 4 weeks were detected by sugar water preference, forced swimming, tail suspension, and open field tests. Morphological changes in neurons in the hippocampal CA1 area and forebrain cortex area were observed by hematoxylin-eosin(HE) and Nissl staining. Serum levels of 5-hydroxytryptamine ( 5-HT) were detected by enzyme-linked immunosorbent assay. Depression-related behavioral changes induced by different doses of corticosterone were compared. Results The bodyweights of mice in all three CORT groups (20, 40, and 60 mg / kg) decreased (P<0. 05) and the preference for sucrose solution decreased (P<0. 01) compared with the findings in the control group. The immobility time in the forced swimming test was prolonged in the CORT 20 and 40 mg / kg groups (P<0. 01) and the immobility time of mice in the tail suspension test was prolonged in the CORT 40 mg / kg group (P<0. 05). The total distance, the length of time spent in the peripheral area was prolonged and the time entering the central area in the open-field experiment were decreased in the CORT 40 and 60 mg / kg groups (P<0. 05), and average speed were decreased in the CORT 40 mg / kg group ( P< 0. 05). In addition, CORT injection result ed in abnormal neuronal cell morphology, cell deformation, and nuclear condensation in the hippocampal CA1 and forebrain cortex areas, to different degrees.Serum 5-hydroxytryptamine levels were reduced in the CORT 40 and 60 mg / kg groups ( P< 0. 05). ConclusionsCORT 20, 40, and 60 mg / kg can induce depression-like behavioral changes and neuronal damage in mice to varying degrees, with the most notable effect at 40 mg / kg. Under experimental conditions, we consider that 40 mg / kg is the best dose for replicating corticosterone-induced depression in model mice.