Time-restricted feeding (TRF), which limits food intake to specific time windows, protects against metabolic dysfunction and inflammation. Given TRF's potential benefits, it has been increasingly adopted as a simple dietary intervention. However, limited work has explored whether TRF impacts brain and behavior, and whether its effects are sex-dependent. Since brain inflammation can regulate mood-related behaviors, we hypothesized that TRF would dampen neuroimmune reactivity and protect against associated behavioral changes in adult mice. To test this, male and female mice were either fed during their active (dark) phase for 10 h (TRF) or had unrestricted access to food throughout the day (ad libitum). After five weeks, TRF reduced anxiety-like behaviors in an open field task and in the elevated plus maze in both sexes. TRF females also showed greater sociability in a social exploration task. Next, mice were injected with lipopolysaccharide (LPS) or saline to determine whether TRF protects against impairments in mood elicited by an immune challenge. 24 h post administration, TRF rescued LPS-induced behavioral despair in females but not males. TRF also attenuated LPS-induced hippocampal expression of pro-inflammatory cytokines and some morphological changes in microglia, the brain's immune cell. These findings suggest TRF exerts sex-specific effects on behaviors and neuroimmune functions. Overall, adult female mice were more sensitive to TRF, with greater behavioral and neuroimmune changes than males.
