Stress is a risk factor for mental illness. Acute stress activates the sympathetic nervous system and HPA axis as a survival mechanism whereas prolonged and excess stress induces cognitive decline and behavioral abnormalities. For instance, repeated social defeat stress, an animal model of depression, induces behavioral changes such as social avoidance.
We previously reported that prostaglandin E₂ which is derived from microglia suppresses mesocortical dopaminergic pathway to induce social avoidance. However, we still do not know whether or how stress activates microglia, or whether microglial activation plays a role in stress-induced behavioral changes.
To identify a molecule which is induced by repeated social defeat stress in the medial prefrontal cortex (mPFC), we performed transcriptome analysis. Repeated social defeat stress upregulated S100A8 and S100A9 in the mPFC. These molecules form a heterodimer to exert their function. Intracellularly, S100A8/A9 migrates phagocytes in a calcium dependent manner. Extracellularly, S100A8/A9 activates Toll-like receptor 4 (TLR4). In this symposium, I will introduce the roles of TLRs in repeated stress-induced behavioral changes and the latest findings on inflammation-like responses.