Stress, a risk factor for psychiatric disorders, alters emotional and cognitive behaviors across species. Previous studies in rodents showed that stress induces structural and functional changes of neurons in the medial prefrontal cortex (mPFC), and that such changes in mPFC underlie at least some of stress-induced behavioral changes. However, the molecular mechanism underlying these processes remains elusive. Toll-like receptors (TLR), a group of innate immune molecules, can be activated not only by pathogen-associated ligands, but also by endogenous ligands that are released from cells upon cellular stress or damage. Using repeated social defeat stress in mice, we have found a critical for TLRs in stress-induced behavioral changes. Thus, TLR-deficient mice failed to show social avoidance and elevated anxiety induced by repeated social defeat. Repeated stress attenuated c-Fos expression upon stress, induced atrophy of dendritic arbors, and altered gene expression of neurotransmitter receptors in mPFC, and all of these neuronal changes were impaired in TLR-deficient mice. Notably, TLR expression was enriched in microglia, and repeated stress promoted microglial response to stress in mPFC in a TLR-dependent manner. Therefore, our study suggests a role for TLRs in neuron-microglia crosstalk in mPFC that may underlie stress-related behaviors. In this symposium, I will introduce these recent data and discuss a potential mechanism about how stress activates TLRs and how TLRs mediate stress-induced neuroglia crosstalk.