Abstract: Objective To explore the role and mechanism of hippocampal microRNA (miR)-98-5p in a chronic social defeat stress (CSDS)-induced mouse model of depression.Methods A total of 40 male C57BL/6J mice, aging 8 weeks, were selected and divided into four groups:a control group, a CSDS group, a CSDS + mimic control treatment group and a CSDS + miR-98-5p mimic treatment group. Except for the control group, mice in the remaining three groups were subjected to CSDS. One week before CSDS, a CSDS + mimic control treatment group and a CSDS + miR-98-5p mimic treatment group were stereotactically injected with mimic-NC or miR-98-5p mimic, respectively, while those in the control group and the CSDS group were given the same amount of normal saline. A series of behavioral tests were conducted to evaluate the depression-like behaviors of mice, including sucrose preference test, tail suspension test, forced swimming test and social interaction test. The expression of inflammatory factors in the hippocampus of each group was examined by ELISA, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. The levels of brain-derived neurotrophic factor (BDNF), phosphorylated-cAMP responsive element-binding protein (p-CREB) and CREB in the hippocampus were measured by Western blot. The expression of dicorticocortin (DCX) and neuronal nuclear protein (NeuN) in the hippocampus was quantified by immunohistochemistry.Results According to behavioral test, compared with the control group, the CSDS group showed significant decreases in sucrose consumption and social interaction time (P<0.01) and increases in immobility time (P<0.01). Furthermore, compared with the CSDS group, the CSDS+miR-98-5p mimic group presented significantly reduced immobility time, as well as increased sucrose consumption and social interaction time (P<0.01). Treatment with miR-98-5p mimic remarkably improved the levels of TNF-α, IL-1β and IL-6 in CSDS-induced mice (P<0.01). Furthermore, miR-98-5p mimic attenuated the neurogenesis in the hippocampus of CSDS-induced mice through activating the BDNF-CREB signal pathway.Conclusions MiR-98-5p mimic can improve CSDS-induced depression-like behavior in mice through targeting BDNF, indicating its protective role in depression.