Roles and actions of neural inflammation-related molecules in repeated social defeat stress-induced behavioral changes in mice

Abstract

Stress due to social and environmental challenges induces emotional and cognitive disturbances across species, and can be a risk factor for mental illnesses. We previously reported a critical role of prostaglandin (PG) E₂, an inflammation-related bioactive lipid, in behavioral changes induced by repeated social defeat stress in mice. Thus, EP1, a receptor subtype for PGE₂, mediates the attenuation of the prefrontal dopaminergic pathway with repetition of the stress, thereby inducing social avoidance. PGE₂ derived from microglia appears to induce this effect, since COX-1, a PG synthase enriched in microglia, is critical for the induction of social avoidance. These findings implicate PGE₂-mediated microglia-neuron crosstalk in repeated social defeat stress. However, a role of the stress-induced microglial activation and its mechanism remain unclear. Here we show a critical role of Toll-like receptors (TLRs), innate immune receptors, in repeated social defeat stress-induced social avoidance and elevated anxiety as well as concomitant neuronal changes and microglial activation in the medial prefrontal cortex. Furthermore, knockdown of TLRs in microglia in the medial prefrontal cortex abolished the induction of social avoidance. These findings suggest that TLR-mediated microglial activation in the medial prefrontal cortex underlies the induction of social avoidance by repeated social defeat stress. Therefore, our studies pave the way for elucidating a network of neural inflammation-related molecules associated with microglial activation for stress-related pathology as a potential therapeutic target for mental illnesses.