IN UTERO KETOGENIC DIET EXPOSURE ALTERS HIPPOCAMPAL CONNECTIVITY AND SEX-SPECIFIC NEUROBEHAVIORAL OUTCOMES IN ADULT MICE

The Developmental Origins of Health and Disease (DOHaD) theory suggests that environmental exposures during critical developmental periods can have lasting effects on health, potentially contributing to the increased prevalence of neurodevelopmental disorders such as autism spectrum disorder. This study investigates the long-term neurobehavioral effects of in utero exposure to a ketogenic diet (KD) in adult mice. Behaviorally, while KD-exposed mice developed normally, females exhibited impaired social discrimination in the 3-chambers test, failing to distinguish between novel and familiar mice. These females also displayed increased grooming and motor coordination deficits on the accelerated rotarod. Using functional Ultrasound Imaging (fUSI), which links cerebral blood flow fluctuation to neural activity, we mapped brain functional connectivity in awake mice. Our findings reveal a distinct "KD fingerprint" characterized by dysconnectivity, particularly a hypoconnectivity, within and between the hippocampi of both male and female mice. Given the hippocampus's roles in social recognition, motor coordination, and stereotyped behaviors, these connectivity alterations align with the observed behavioral phenotypes. These results suggest that in utero KD exposure alters brain connectivity and social behavior, with sex-specific effects highlighting the hippocampus as a region particularly sensitive to early dietary interventions. Further research is needed to elucidate the underlying mechanisms, but our findings underscore the potential for maternal diet to influence offspring neurobehavioral outcomes.