Insulin modulates mPFC gene expression and emotional behavior in a sex-specific manner following fetal growth restriction.

Prenatal adversity, such as exposure to stress and malnutrition, increases lifelong vulnerability to neuropsychiatric and metabolic disorders, in part through long-lasting alterations in neuroendocrine and immune signaling that shape brain development and behavior. Insulin, beyond its peripheral metabolic actions, acts as an immunometabolic signal in the brain, yet its contribution to the neurobehavioral consequences of fetal growth restriction (FR) remains poorly understood. Here, using a validated rat model of FR, we investigated how insulin modulates medial prefrontal cortex (mPFC) gene expression across development (P0, P21, P90) and whether mPFC insulin signaling influences adult emotional behavior. RNA sequencing revealed that insulin regulates distinct, sex-specific transcriptional programs in the mPFC, with reduced insulin responsiveness following FR and enrichment of microglia-associated genes among insulin-regulated transcripts in control males. Across conditions, insulin partially recapitulated FR-associated transcriptional signatures, and altered pathways involved in immune responses, metabolism, and neurodevelopment, including the Wnt/β-catenin signaling. Targeted insulin infusion into the mPFC of adult animals reversed behavioral phenotypes induced by FR in a sex- and context-dependent manner, decreasing emotional reactivity to environmental cues. Together, these findings identify insulin signaling as a developmentally dynamic, sex-specific modulator of neuroimmune gene networks in the mPFC following prenatal adversity, and highlight immunometabolic pathways as potential targets to mitigate the long-term behavioral consequences of poor fetal growth.