Dentate gyrus microglial dynamics contributes to high-fat diet-induced depression-like behaviors in mice

High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previous studies have reported that a decline in microglia in the dentate gyrus, following initial microglial activation under stress, is an important mechanism mediating the pathogenesis of depression. As HFD can activate microglia, we hypothesize that dynamic changes in dentate gyrus microglia also mediate the development of depression-like behaviors under chronic HFD exposure. Our results showed that a 12-week HFD induced depression-like behaviors in mice, accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus. The reduction in microglia in the dentate gyrus of mice treated with a 12-week HFD was mediated by initial microglial activation and subsequent microglial damage. Suppressing initial microglial activation with minocycline prevented HFD-induced dentate gyrus microglial damage and decline, as well as the development of depression-like behaviors in HFD-treated mice. Furthermore, administration of lipopolysaccharide (LPS), a classical microglial stimulant that restored the number of microglia in the dentate gyrus of HFD mice, reversed the depression-like behaviors in mice given a 12-week HFD. These findings reveal a dynamic microglial response in the dentate gyrus underlying HFD-induced depression-like behaviors and suggest that modulating microglial dynamics may offer a potential strategy for preventing or treating depression caused by factors associated with high fat intake.