Stimulation of microglia in adolescence produces a long-lasting prophylactic effect on single prolonged stress-induced PTSD-like behavior in adult mice

Abstract

Our previous studies have reported that pre-stimulation of microglia in adult mice by a single injection of low-dose lipopolysaccharide (LPS) one day before stress stimulation prevents the occurrence of PTSD-like behavior induced by single prolonged stress (SPS), which disappears when the time interval between LPS injection and stress stimulation is extended to 10 days. This disappearance can be rescued by repeated LPS injection, suggesting that enhancing the response of microglia may increase stress tolerance. Since microglia exhibit strong functional plasticity during adolescence, we hypothesize that mice administered LPS during this period acquire a strong ability to resist SPS stimulation. As expected, the results showed that a single injection of LPS (100 μg/kg) on post-natal day 28 (PND28) could prevent SPS-induced development of anxiety- and fear-like behaviors and neuroinflammatory responses in the hippocampus and medial prefrontal cortex of adult mice of different ages, including PND70, PND154 and PND266. Both pre-inhibition of microglia by minocycline pretreatment and pre-depletion of microglia by PLX3397 pre-administration were able to abolish the preventive effect of low-dose LPS injection in adolescence on SPS-induced development of neuroinflammatory responses and anxiety- and fear-like behaviors in adult mice of different ages, including PND70, PND154, and PND266. These results suggest that pre-stimulation of microglia during adolescence may enable adult mice to resist harmful stress-induced PTSD-like behaviors in the long term, which could be useful for developing an approach to prevent the occurrence of PTSD from the root by a vaccine-like method.