Objective To explore the difference of chronic restrain stress (CRS) and chronic unpredictable mild stress (CUMS) model in the neuronal/immune system in 45 male C57BL/6 mice through evaluating behavioral alteration, the hippocampus and the spleen structure and related factor expressions，so as to provide certain references for the pathogenesis of depression and early drug screening for antidepressants. Methods Totally 45 mice were randomly divided into control group，CRS group，and CUMS group．After 6 weeks of stress exposure, Behavioral assessment experiments were carried out to detect the behavior changes of mice. HE staining was to examine structural changes in hippocampus and spleen; The Nissl staining was used to explore neuron damage in hippocampus; In addition, the Real-time PCR was used to detect the gene expression of brain derived neurotrophic factor(BDNF),5-hydroxytrypamine transporter(5-HTT), indoleamine 2, 3 dioxygenase 1（IDO1）in hippocampus and inflammation factor IL-1β, IL-6 in spleen. Results Compared with the control group, CRS group had no significant difference in the number of crossing and rearing. However, it was contrary to the CUMS groups; The immobility of tail suspension and forced swimming test were significant increased in both groups; Both stress had a similar damage effect on hippocampus and spleen structure, while CUMS group of hippocampus neuron damage was more serious; Only CUMS group had significant change in the level of gene expression decreased in BDNF and 5-HTT and elevated in IDO1 expression levels; The spleen gene expression levels of IL-1β and IL-6 were significantly increased in CUMS group, while the spleen gene expression levels of IL-6 had no significant change in CRS group. Conclusion The results show that both CRS and CUMS can induce depressive-like behaviors in C57BL/6 mice. From the perspective of neuro-immunology observation, depression symptoms in CUMS model tend to be more obvious. This suggestes that CUMS model may be a better model of depression.