Adolescent microglia stimulation produces long-lasting protection against chronic stress-induced behavioral abnormalities in adult male mice.

Our previous studies had reported that microglia activation one day before stress exposure prevented the behavioral abnormalities induced by chronic stress in adult mice, and a 10-day interval between microglia stimulation and stress exposure can abolish the prophylactic effect of LPS preinjection on the behavioral abnormalities induced by chronic stress, which, however, could be rescued by repeated LPS injection. This suggests that increased stimulation of microglia results in animals developing a strong ability to prevent deleterious stress stimuli. Because microglia in the adolescent brain exhibit flexible immunological plasticity, we hypothesize that a single low-dose LPS injection during adolescence may provide long-lasting protection against behavioral abnormalities induced by chronic stress in adult mice. As expected, our results showed that a single injection of LPS (100 μg/kg) at post-natal day 28 (PND 28) prevented the development of abnormal behaviors and shifted neuroinflammatory responses toward an anti-inflammatory phenotype in adult mice treated with CSDS at their different stages of the age (PND 56, 140, and 252). Moreover, pretreatment with minocycline or PLX3397 to inhibit microglial activation abolished the prophylactic effect of LPS preinjection after PND 28 on behavioral abnormalities and neuroinflammatory responses induced by CSDS in adult mice at their different stages of the age, PND 56, 140, and 252. These results indicate that stimulation of microglia in adolescence may confer long-lasting protection against neuroinflammatory responses and behavioral abnormalities induced by chronic stress in adult mice. This may offer the potential for the development of a "vaccine-like strategy" to prevent mental disorders.