Chronic stress abnormalize microglial-vascular interaction via AT1R signaling and microglia activation to drive depression-like behaviors

Abstract

Depression entails a range of pathological processes in the brain, typically characterized by microglia activation, 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, marked 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 vascular-contacted microglia. These vascular-contacted microglia 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 microglia activation under chronic stress are critical mediators for the altered microglial-vascular contact situation, 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 microglia activation, leads to depression, forging a new link between chronic stress and depression.