Abstract: Long-term exposure to ambient fine particulate matter (PM2.5) may increase the risk of neurotoxicity in human populations. However, research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors, and potential therapeutical strategies, remain scarce. In the present study, after long-term exposure to real-world PM2.5 for 15 weeks, male mice displayed depression-like behaviors, which were revealed using the open field and sucrose preference tests. Mechanistically, chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction–oxidation balance in the mouse hippocampus. Furthermore, PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling. Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication; this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown. Importantly, the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication. Together, our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication, and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors. 

Key words: air pollution, astrocyte-to-microglia communication, depression-like behaviors, fine particulate matter (PM2.5), neurotoxicity, nuclear factor erythroid 2-related factor 2, oxidative stress, procyanidins