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Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.