Adolescent Vitamin D Supplementation Reverses Neuroplasticity and Motivational Deficits Induced by Developmental Alcohol Exposure and Early‐Life Stress

Early postnatal ethanol exposure (PNEE) and early-life stress (ELS) are major contributors to persistent deficits in cognition, motivation and emotional regulation. These insults disrupt hippocampal plasticity and increase vulnerability to psychiatric disorders. Vitamin D (VitD), a neuroactive steroid, has emerged as a potential modulator of neurodevelopment and plasticity. We investigated whether adolescent VitD supplementation could mitigate behavioural and neuroplastic impairments resulting from early exposure to ethanol and maternal separation. On postnatal day (PND) 2, 64 Wistar rat pups (male and female) were randomized into eight experimental groups (n = 8 animals per group, with sex balanced across groups): (1) control, (2) VitD, (3) ethanol (EtOH), (4) EtOH + VitD, (5) maternal separation (MS), (6) MS + VitD, (7) EtOH + MS, and (8) EtOH + MS + VitD. EtOH groups received 5 g/kg i.p. ethanol on alternate days from PND 4-10. MS groups were separated from the dam for 3 h/day from PND 2-14. From PND 22-37, VitD groups received 1000 IU/kg/day of cholecalciferol. Behavioural assessments included palatable food intake and reward omission-based task. Brains were processed for doublecortin (DCX) immunohistochemistry and Golgi-Cox analysis. EtOH + MS animals displayed increased latency to eat, reduced food consumption and persistent feeder-directed responding following reward omission. VitD treatment reversed these effects, improving motivational performance and reducing reward omission-induced responding. VitD also restored hippocampal neurogenesis and normalized dendritic complexity and length. Vitamin D supplementation during adolescence mitigates behavioural and neuroplasticity deficits induced by PNEE (corresponding to the third trimester of human brain development) and ELS. These findings support VitD as a promising therapeutic strategy for neurodevelopmental disorders such as foetal alcohol spectrum disorder (FASD).