In this study, we hypothesized that TNF-α activated astrocytes to progress to the A1 type by binding to its pro-inflammatory specific receptor, TNFR1, to induce the development of depression-like behavior in chronic unpredictable mild stress (CUMS) mice, whereas Rho could “block” the process of this pathophysiology, by acting as an antidepressant. Here, TNFRSF1A is linked to major depressive disorder.