Ketogenic diet attenuates late gestational sleep deprivation-induced aggression in adult offspring mice

Sleep deprivation (SD) during late gestation is an important risk factor for neurodevelopmental disturbances and may contribute to long-lasting alterations in adult behavior. The ketogenic diet (KD) has been reported to influence stress-related neurobiological processes. In this study, we examined whether post-weaning KD modulates aggressive behaviors in adult mice exposed to late gestational SD, together with changes in hypothalamic neuronal morphology and metabolic profiles. Behavioral analyses showed that KD was associated with reduced defensive aggression in normal adult male and female mice, while proactive aggression was not significantly altered. In SD-exposed offspring, prenatal SD was associated with increased defensive aggression in both sexes and a selective elevation of proactive aggression in males. These behavioral changes were attenuated following KD intervention. Golgi staining revealed that SD was associated with reduced dendritic spine density in the ventromedial hypothalamus of male offspring. This structural alteration appeared less pronounced in KD-fed mice, whereas no significant changes were observed in females. LC-MS-based metabolomic analyses further indicated that SD was associated with disturbances in hypothalamic metabolic pathways, including metabolites related to inflammatory and oxidative stress processes. These metabolic alterations were partially corrected in KD-treated groups. Together, these findings suggest that prenatal SD exposure is associated with persistent alterations in stress-related aggressive behaviors in adulthood. KD was associated with modulation of these behavioral outcomes, potentially in conjunction with changes in hypothalamic metabolic profiles and synaptic structure. These results provide preliminary evidence that dietary interventions may influence the behavioral consequences of early life stress.