Chronic psychosocial stress induces microglial activation and inflammatory responses that lead to neuronal dysfunction and depressive-like behavior

Abstract Repeated stress can lead to the development of anxiety and is considered a risk factor for major depressive disorder (MDD). Clinical studies and animal models of repeated and chronic stress have reported that symptom severity is correlated with microglial activation and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation. Despite mounting evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, whether microglial activation modulates neuronal homeostasis in response to chronic stress has been debated. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial activation and related inflammatory responses are regulating neuronal plasticity associated with depressive-like behavior. Specifically, we show that chronic stress induces a swift activation and proliferation of microglia as well as macrophage infiltration in the mPFC, which are spatially related to neuronal activation. Moreover, we report a remarkable association of microglial spectrum of reactivity and concomitant inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and significant neuronal plasticity deficits associated with depressive-like behavior. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we determine the contributions of microglial and infiltrating macrophages in the depression pathophenotype. Our findings highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations of depression in response to chronic stress by promoting neuroinflammation and neuronal deficits in mPFC.