Prenatal stress reprograms placental signaling and opposes maternal immune activation effects in the fetal brain

Abstract Prenatal psychosocial stress and maternal immune activation (MIA) increase risk for overlapping offspring psychiatric disorders, but whether they influence fetal neurodevelopment through shared or distinct mechanisms is unclear. Positioned at the interface of maternal and fetal physiology, the placenta has a critical role in regulating fetal brain development. Here, we combine mouse placental single-cell RNA sequencing, transcriptomics of matched placentas and fetal brains, maternal cytokine profiling, and human placental RNA-seq to dissect this axis. In mice, chronic stress suppressed interferon signaling across placental immune cells and downregulated oxidative phosphorylation pathway expression in trophoblasts. Stressed dams also mounted a blunted type I interferon response to poly(I:C), resulting in attenuated placental antiviral signaling. Weighted gene co-expression analysis of fetal brains revealed that prenatal stress and MIA regulate overlapping DNA repair, synaptic, and translational networks in opposite directions, with stress promoting signatures of premature maturation and MIA driving replication stress. In human placentas, higher perceived stress was associated with chromatin-regulatory, RNA-metabolic, and extracellular-matrix modules that mirrored the murine stress signature. These findings identify a conserved placental stress-associated transcriptional program and suggest that stress and MIA affect shared neurodevelopmental pathways in opposing directions.