Long-term real-world PM 2.5 exposure induces depression-like behaviors in mice by disrupting nuclear factor erythroid 2-related factor 2-mediated astrocyte-to-microglia communication.

Long-term exposure to ambient fine particulate matter (PM 2.5 ) may increase the risk of neurotoxicity in human populations. However, research studies on the underlying mechanisms of chronic PM 2.5 -induced depression-like behaviors, and potential therapeutical strategies, remain scarce. In the present study, after long-term exposure to real-world PM 2.5 for 15 weeks, male mice displayed depression-like behaviors, which were revealed using the open field and sucrose preference tests. Mechanistically, chronic PM 2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus. Furthermore, PM 2.5 -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 PM 2.5 -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 Nfe 2l2 knockdown. Importantly, the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM 2.5 - 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 PM 2.5 -induced depresson-like behaviors.