Prenatal Methyl Nutrient Availability Shapes Mesolimbic Dopaminergic Circuitry and Systemic Inflammation in Wistar Rat Offspring of Both Sexes

ABSTRACT The dopaminergic system constitutes a principal element of the reward neurocircuitry and is responsive to influences encountered early in life. Methylation potential, shaped by nutrients involved in one‐carbon metabolism, intersects with immune signaling and dopaminergic receptor, creating a broader metabolic network through which early life nutrition may alter neurobehavioral outcomes. We have shown that methyl nutrient imbalance between folic acid and choline during pregnancy produces offspring with higher body weight and perturbed methylation potential. However, whether these effects reflect disruptions in the dopaminergic receptor expression and systemic inflammation, and the capacity of betaine (a direct methyl donor) to modify responses across different nutritional contexts remain unknown. To address this, primiparous Wistar rats were randomly assigned to either a recommended vitamin or high folic acid/low choline diet, with or without betaine supplementation during pregnancy, then switched to a control diet during lactation. One female and one male offspring from each dam were followed for 12 weeks post‐weaning under an obesogenic environment. Prenatal micronutrient composition produced distinct patterns of activity in offspring across the light–dark cycle, revealing behavioral signatures of both imbalance and betaine supplementation. Betaine alone reduced body weight and food intake, and provided partial protection against the metabolic consequences of the imbalanced micronutrient diet. Dopaminergic receptor gene expression was responsive to prenatal micronutrient exposure, with treatment sex interactions restricted to the ventral tegmental area (VTA) and betaine modifying receptor patterns across both the VTA and nucleus accumbens. Catechol‐O‐methyltransferase expression was altered consistent with changes in S‐adenosylmethionine and the S‐adenosylmethionine: S‐adenosylhomocysteine ratio across groups. Higher C‐reactive protein concentrations occurred under micronutrient imbalance, but remained unchanged with betaine supplementation. In conclusion, gestational intake of high folic acid and low choline disturbs dopaminergic, metabolic and immune outcomes in offspring, whereas betaine may serve as a potential modulator capable of mitigating these effects. image