Chronic stress disrupts microglial-vascular interaction via AT1R signaling and altered microglial state to drive depression-like behaviors

Depression entails a range of pathological processes in the brain, typically characterized by altered microglial state, neural dysfunction, and vascular dysregulation. While it is well established that activated microglia inflict damage to neurons through direct and indirect microglia-neuron interactions, their interaction with vasculature and the associated regulation of vascular structure and function in depression remain poorly understood. Here, using a mouse model of depression induced by chronic unpredictable stress (CUS), we find that in stressed mice, activated microglia present reduced motility and decreased contact area with vasculature, which is accompanied by pathological vascular structure and function, characterized by reduced vessel density, narrowed vascular diameters, and sluggish blood flow velocity. We observe that vascular structure in the stressed mice is rapidly modified by the vessel-associated microglia (VAM). These VAM show upregulated angiotensin II type 1 receptor (AT1R) expression, which is not present in the vascular-uncontacted microglia. Furthermore, we demonstrate that AT1R signaling together with altered microglial state under chronic stress are critical mediators for the altered microglia-vascular interactions, vascular dysregulation, as well as the depression-like behaviors. Together, our findings reveal that under CUS, the aberrant microglial-vascular interaction, including the dysregulated microglial vasoregulation arising from AT1R signaling and altered microglial state, leads to depression, forging a new link between chronic stress and depression.