Sex-dependent protective effects of a ketogenic diet following prenatal stress exposure: Evidence from adolescent rats

Exposure to stress during gestation (prenatal stress, PNS) disrupts neurodevelopmental trajectories and increases vulnerability to neuropsychiatric disorders, through dysregulation of different molecular pathways. PNS-induced alterations frequently emerge during adolescence, a highly dynamic maturational period, highlighting a critical window in which therapeutic interventions may modify pathological outcomes. Here, we investigated whether a post-weaning ketogenic diet (KD) could modulate PNS-induced behavioral and molecular alterations in adolescent Sprague-Dawley rats. At weaning offspring from dams exposed to repeated restraint stress during gestation were assigned to a control diet (CD) or KD. Behavioral testing was conducted during adolescence, and prefrontal cortex (PFC) was analyzed for excitatory/inhibitory markers, redox regulators, and inflammatory mediators. PNS induced sociability deficits that were ameliorated by KD. A two-step cluster analysis identified ∼50-55 % of PNS offspring as "vulnerable," whereas KD reduced this proportion to 22 % in males and 12 % in females. At the molecular level, KD exerted sex-dependent effects in the PFC: in males, it enhanced inhibitory interneuron markers and reduced pro-inflammatory transcripts while altering NRF2/KEAP1 redox signaling; in females, it increased NRF2 and partially restored GCLC1, while PNS selectively disrupted inhibitory and excitatory markers. Together, these findings demonstrate that post-weaning KD rescues PNS-induced social deficits and reshapes PFC molecular profiles, engaging sex-specific mechanisms of resilience. In summary, diet-based interventions during adolescence may represent a promising strategy to counteract developmental stress-related vulnerability.