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

Exposure to prenatal adversity (e.g., stress, malnutrition) is a major risk factor for lifelong vulnerability to neuropsychiatric and metabolic disorders, and alterations in the function of peripheral hormones in the brain are suggested as a possible and unexplored mechanism. Although insulin is well known for its peripheral metabolic functions, it also influences brain development and emotional regulation, particularly within the medial prefrontal cortex (mPFC). Here, we identify insulin signaling as a key mechanistic link between prenatal stress and long-term alterations in brain function and behavior. Using a validated rat model of prenatal adversity (prenatal food restriction, FR), we found that insulin administration selectively modulates gene expression in FR animals at P0, P21 and P90, affecting pathways involved in neurodevelopment and stress regulation, such as 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. These findings offer novel insight into the neurodevelopmental role of insulin and suggest that insulin signaling may serve as a therapeutic target to mitigate the long-term brain and behavioral consequences of prenatal adversity.