Comparative Analysis of Prenatal Stress Models: Placental andNeurodevelopmental Outcomes in Mice

Prenatal stress affects offspring development. The placenta, an important maternal-fetal mediator, is susceptible to prenatal stress, and its biology affects fetal neurodevelopment, particularly ventral forebrain. Ventral forebrain developmental disruption is linked to neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Currently, multiple mouse models are used to study these links. However, each model may induce unique effects in both placental and neurodevelopmental outcomes, which are rarely studied. To explore this, pregnant mice were exposed 3 times daily to one of three stress models: repeated restraint stress (RS), chronic unpredictable stress (CUS), or repeated footshock stress (FS) beginning at embryonic day (E)12. At E14 or E18, placenta and embryonic brain were collected, and qPCR and brain stereological measurements were performed. Placental immune and ventral forebrain GABAergic gene expression was impacted more at E14, with many changes not apparent by E18, suggesting an acute dysregulated state. Different models had both unique and overlapping effects. E18 analyses suggested adaptation to stress over time, with overall suppression or lack of placental immune factor changes, fewer deviations in the brain, and correlations between placenta and brain, particularly in females. Chronic unpredictable stress showed the most changes at E18. These findings suggest that, while each model has unique effects, as stress exposure progresses, placental immune functioning may promote the normalization of brain GABAergic systems, particularly in females. Further understanding the placenta-brain axis may be valuable in delineating mechanisms that increase and decrease risk of neurodevelopmental disorders.