Characterization of postnatal brain injury and behavioural deficits in a rat model of placental insufficiency-induced fetal growth restriction

Abstract: Fetal growth restriction (FGR) is a significant pregnancy complication strongly associated with neurodevelopmental deficits in infants. Effective treatments to support brain development are currently lacking. Detailed characterization of structural and functional brain abnormalities caused by FGR can aid the development of targeted therapies. This study aimed to comprehensively characterise brain development at anatomical, cellular and functional levels in a rat model of placental-insufficiency-induced FGR, using the reduced uterine perfusion pressure (RUPP) method. Pregnant Sprague–Dawley rats underwent partial occlusion of the lower abdominal aorta and bilateral ovarian arteries at embryonic day 14. Sham-operated dams served as controls. Offspring were weighed until postnatal day (P)66–67 and underwent behavioural testing; a subset of animals was assessed by histology and MRI at P20. Offspring born from RUPP dams showed an FGR phenotype characterised by decreased body weight without catch-up growth. RUPP pups exhibited reduced brain weight and volume, cortical thinning and altered cortical organization. Additionally, aberrant myelination, and increased immune reactivity and morphological changes of microglia were observed in RUPP pups. These neurological impairments were accompanied by delayed eye opening, increased number of ultrasonic vocalizations, and motor deficits that persisted into adulthood. This is the first study to demonstrate that RUPP in rats leads to FGR-induced neurological impairments and lasting behavioural abnormalities in the offspring, highlighting the long-term vulnerability of FGR rather than its being an acute perinatal event. This model is valuable for advancing understanding of brain injury in affected infants and for developing novel therapies aimed at improving neurodevelopmental outcomes. (Figure presented.). Key points: Fetal growth restriction (FGR) is a common pregnancy complication linked to long-term brain and neurodevelopmental deficits in infants. The reduced uterine perfusion pressure (RUPP) in rats mimics FGR in the offspring, causing FGR-related brain injury and behavioural abnormalities. RUPP pups show reduced body and brain weight, thinner cerebral cortex, abnormal distribution of key interneurons, aberrant myelination, disrupted oligodendrocyte maturation and signs of neuroinflammation. RUPP offspring also display neurodevelopmental delays and motor deficits that persist into adulthood, comparable to what is seen in FGR infants. The RUPP model is valuable for studying how FGR affects the brain and for developing targeted therapeutic approaches to improve long-term outcomes in affected infants.