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

How early growth changes insulin’s influence on the brain

How can poor growth before birth contribute to difficulties with both metabolism and emotional health later on? This study investigates a possible connection: insulin’s actions inside the developing brain. Insulin is best known for regulating blood sugar, but in the brain it also influences processes involved in development, metabolism and immune signaling.

Testing the brain’s response to insulin. The researchers used rats whose growth before birth had been restricted by limiting their mothers’ food intake during pregnancy. They examined the medial prefrontal cortex, or mPFC, a brain region involved in regulating behavior and emotion. At birth, weaning and adulthood, they used RNA sequencing to measure gene activity after an insulin injection. This allowed them to ask whether early growth conditions changed how this brain region responded to the hormone, and whether the response differed between males and females.

Early growth changed that response. Insulin affected different patterns of gene activity according to age, sex and prenatal growth. Some responses seen in control animals were reduced or absent after growth restriction, suggesting altered sensitivity to insulin. In control males, the genes responding to insulin were enriched for genes associated with microglia, the brain’s resident immune cells. This pattern was not detected in growth-restricted males. The broader gene patterns also implicated immune, metabolic and developmental pathways, including Wnt/β-catenin, a system of signals involved in how cells develop and function. These results connect insulin responsiveness with the interaction between brain development and immune biology.

The effects were not a simple reset. Some gene-activity changes triggered by insulin in control animals resembled changes associated with growth restriction. In growth-restricted animals, insulin shifted some altered gene activity in the opposite direction. The response therefore depended on the animal’s developmental history: the same hormone did not produce the same biological effect in every group.

Changing insulin signaling also changed adult behavior. In a separate experiment, the researchers delivered insulin directly into the mPFC of adult rats. This changed responses in tests of exploration and avoidance of a brightly lit space, with effects depending on sex and the test conditions. Growth-restricted animals given insulin spent more time in the lit compartment, consistent with reduced avoidance. Directly manipulating signaling in this brain region therefore affected behavior, extending the evidence beyond a comparison of gene activity.

The study identifies brain insulin signaling as a candidate connection between prenatal growth, immune-related gene activity and later emotional responses. It also shows that some behavioral consequences remained responsive to intervention in adult rats. Establishing which cellular changes produce those effects is the next step toward understanding the mechanism.