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

Bilbo, S.; Patton, M.; Sun, W.; Stanley, L.; Paredes, A.; Kang, J. Y.; Schettewi, Z.; Horvath, B.; Dziabis, J. E.; Devlin, B.; Vaidyanathan, T. V.

doi:10.64898/2026.05.10.723768

bioRxiv · 10.64898/2026.05.10.723768

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

Bilbo, S.·Patton, M.·Sun, W.·Stanley, L.·Paredes, A.·Kang, J. Y.·Schettewi, Z.·Horvath, B.·Dziabis, J. E.·Devlin, B.·Vaidyanathan, T. V.

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Abstract

Maternal nutrition shapes offspring brain development and influences neurodevelopmental disorder risk, but the underlying mechanisms remain unclear. In mice, maternal high-fat diet exposure disrupted microglia-serotonin interactions during a critical postnatal period, producing persistent, sex-specific mesolimbic alterations. Male but not female offspring showed increased serotonergic fiber density in the nucleus accumbens (NAc), coincident with reduced microglial phagocytosis of serotonergic projections. Microglial 5-HT2C receptor signaling is a key regulator of this process. Viral over expression in microglia, mimicking diet-induced upregulation, was sufficient to cause serotonergic hyperinnervation. By adulthood, male offspring displayed increased NAc serotonin release and projection-specific changes in dorsal raphe physiology. These circuit alterations accelerated reward-motivated learning, a phenotype reproduced by chemogenetic activation of NAc-projecting serotonergic neurons. Together, these findings reveal a novel 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 serotonergic dysfunction.

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Bilbo, S., Patton, M., Sun, W., Stanley, L., Paredes, A., Kang, J. Y., Schettewi, Z., Horvath, B., Dziabis, J. E., Devlin, B., Vaidyanathan, T. V.. 2026-05-13. Maternal high-fat diet drives sex-specific microglia remodeling of serotonergic reward circuits. https://doi.org/10.64898/2026.05.10.723768

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