Sex differences in socioemotional behavior and changes in ventral hippocampal transcription across aging in C57Bl/6J mice

Abstract

Socioemotional health is positively correlated with improved cognitive and physical aging. Despite known sex differences in socioemotional behaviors and trajectory of aging, the interactive effects between sex and aging on socioemotional outcomes are poorly understood. We performed the first comprehensive assessment of sex differences in socioemotional behaviors in C57Bl/6J mice across aging. Compared to males, females exhibited decreased anxiety-like behavior and social preference, but increased social recognition. With age, anxiety-like behavior, cued threat memory generalization, and social preference increased in both sexes. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed transcriptional neuropathology markers in ventral hippocampus and found age-related changes in genes related to activated microglia, angiogenesis, and cytokines. Sex differences emerged in timing, direction, and magnitude of these changes, independent of reproductive senescence in aged females. Interestingly, female-specific upregulation of autophagy-related genes correlated with age-related behavioral changes selectively in females. These novel findings reveal critical sex differences in trajectories of ventral hippocampal aging that may contribute to sex- and age-related differences in socioemotional outcomes.