Maternal high-fat diet drives sex-specific microglia remodeling of serotonergic reward circuits

Maternal nutrition shapes offspring brain development and influences lifelong risk for neurological disorders, yet the circuit-level mechanisms linking maternal metabolic state to offspring behavior remain poorly defined. Here we show that maternal high-fat diet (mHFD) disrupts microglia-serotonin interactions during a critical postnatal window to drive persistent, sex-specific alterations in mesolimbic circuitry. In mice, mHFD selectively increased serotonergic fiber density in the nucleus accumbens (NAc) of male, but not female, offspring at postnatal day 14, coincident with reduced microglial phagocytosis of serotonin (5-HT) projections. This early-life hyperinnervation persisted into adulthood, where male offspring exhibited elevated NAc 5-HT release and projection-specific changes in dorsal raphe neuron activity. Functionally, these circuit alterations were associated with accelerated reward-motivated learning, a phenotype recapitulated by chemogenetic activation of NAc-projecting 5-HT neurons. Together, these findings reveal a microglia-centric mechanism by which maternal diet programs serotonergic circuit assembly and behavior in a sex-specific manner, providing a potential link between early-life metabolic inflammation and lifelong neural function.