〔Abstract〕 Objective To investigate the depressive-like behavior and expression of hippocampal brain-derived neurotrophic factor(BDNF) in different sexual cycles of female mice and the effect of estrogen deprivation and supplementation on depressive-like behaviors and BDNF expression, and to elucidate the role of estrogen in the pathogenesis and therapy of depression. Methods Female C57 mice were screened for proestrus and diestrus by using vaginal smear staining. The forced swim was used to evaluate the depressive-like behavior of these two groups of female mice. Real-time PCR and Western blot were used to detect the expression levels of total BDNF mRNA and protein in the hippocampus of these two groups. Sucrose preference test was used to examine the depressive-like behaviors of female mice after OVX mediated estrogen deprivation under basal and chronicunpredictable stress condition. The effect of estrogen deprivation and supplementation on depression-like behaviors and hippocampal total BDNF mRNA expression of female mice were detected by sucrose preference test, forced swim test and Real-time PCR under stress condition respectively. Results The forced swim test results showed that the immobility time of diestrus was significantly more than that of proestrus(P<0.05). Real-time PCR and Western blot results showed that the total mRNA and protein expression levels of hippocampal BDNF in the diestrus were significantly lower than those in the proestrus(allP<0.05). The sucrose preference results showed that under the basic condition, the sucrose preference of OVX mice was not significantly changed compared with the sham operation control group(P>0.05), under stress condition, the sucrose preference of OVX mice was significantly reduced(P<0.05). Sucrose preference test and forced swim test results showed that estrogen supplementation could significantly reverse the decreased sucrose preference and increased immobility time induced by estrogen deprivation under the stress condition. Real-time PCR results showed that total BDNF mRNA level in the hippocampus of female OVX mice was significantly reduced(P<0.05) compared to the sham operation group, However, the total mRNA level of hippocampal BDNF was significantly restored after exogenous estrogen supplementation(P<0.05). Conclusion Sexual cycles of female mice can affect depression-like behavior and hippocampal total BDNF mRNA expression significantly, estrogen deprivation can enhance the susceptibility to the CUS induced depression-like behaviors, and estrogen supplementation can reverse the depression-like behavior and reduce hippocampal BDNF expression.