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Clinical studies and animal models of chronic stress have reported that symptom severity is correlated with innate immune responses and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation (mPFC; medial Prefrontal Cortex). Despite increasing evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress\u2010related mental disorders, how microglia may modulate neuronal homeostasis in response to chronic stress has not been defined. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial\u2010induced inflammatory responses are regulating neuronal plasticity associated with psychosocial stress. Specifically, we show that chronic stress induces a rapid activation and proliferation of microglia as well as macrophage infiltration in the mPFC, and these processes are spatially related to neuronal activation. Moreover, we report a significant association of microglial inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuronal plasticity. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non\u2010penetrant PLX73086) we highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression.<\/jats:p>","DOI":"10.1002\/glia.24464","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T05:42:29Z","timestamp":1694065349000},"page":"111-132","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Chronic psychosocial stress triggers microglial\u2010\/macrophage\u2010induced inflammatory responses leading to neuronal dysfunction and depressive\u2010related behavior"],"prefix":"10.1002","volume":"72","author":[{"given":"Alexandros G.","family":"Kokkosis","sequence":"first","affiliation":[{"name":"Department of Pharmacological Sciences 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