MATERNAL DIETARY IMBALANCE BETWEEN OMEGA-6 AND OMEGA-3 FATTY ACIDS INDUCES SHORT- AND LONG-TERM SEX-SPECIFIC NEURODEVELOPMENTAL ALTERATIONS

A maternal high-fat diet (mHFD) enriched in Omega (n)-6 fatty acids can promote intrauterine milieu inflammation and disrupt neurodevelopment by altering neurogenesis, synaptogenesis and microglial maturation, ultimately increasing offspring’s vulnerability to psychiatric disorders. We investigated the impact of a n-6^high/n-3^low mHFD on neurodevelopment and whether prenatal dietary Omega-3 supplementation, by restoring a physiological n-6/n-3 ratio, may prevent such effects.
Female C57BL/6 mice received either an HFD (58% fat; n-6/n-3=120) or a control diet (CD:11% fat; n-6/n-3=7) for 4 weeks. Half females were then supplemented with Omega-3 (n-6/n-3=1) for 6 weeks, until delivery. To evaluate the detrimental effects of n-6^high/n-3^low diet, we assessed embryonal brain fatty acid composition and adolescent emotional behavior, neuroendocrine stress response by measuring plasma corticosterone levels via Enzyme-Linked Immunosorbent Assay, and microglial phagocytic activity through Fluorescence-Activated Cell Sorting.
In utero mHFD exposure drastically affected embryonal brain composition by increasing n-6 and reducing n-3 levels, prenatal Omega-3 supplementation prevented this alteration. mHFD also showed long-term and sex-dependent effects in the adolescent offspring. Males exhibited decreased neuroendocrine reactivity, as shown by a reduced corticosterone peak after stress exposure and reduced behavioral inhibition, manifested by a decreased latency in the novelty-suppressed feeding test and time spent in closed arms of the elevated plus maze. By contrast, females showed increased corticosterone levels and a deficit in microglial activation.
Overall, data indicate that a dysbalanced (n-6^high/n-3^low) mHFD disrupts offspring neurodevelopment, resulting in sex-dependent neurobehavioral and neuroendocrine alterations. These effects implicate microglial reactivity and glucocorticoid-driven pathways as key mediators of long-term vulnerability.