The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

Abstract

Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal-fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain.

Figure 1

Morphology of the maternal–fetal interface: navigating a complex interaction between maternal and fetal compartments. Mid-sagittal schematic depicting the intricate arrangement of maternal tissue (blue), fetally derived trophoblasts (all five subtypes in purple), and fetal endothelial cells (tan) within the three major functional zones of the mature mouse placenta. The decidua, the most superficial layer from the maternal side (top), comprises maternal uterine and immune cells, as well as specialized glycogen-storing cells from the trophoblast lineage. The decidua is traversed by the maternal spiral arteries, veins, and the fetally derived endovascular trophoblasts that line it. The arrow indicates the direction of maternal blood flow. Bordering the decidua is the junctional zone (basal plate in humans), where maternal vasculature penetrates a layer of trophoblast giant cells and spongiotrophoblasts (extravillous cytotrophoblasts in humans) that secrete hormones to modulate maternal–fetal cross-talk, angiogenesis, and tissue remodeling. Finally, in the labyrinth zone (chorionic villous in humans), cytotrophoblasts and syncytiotrophoblasts residing between maternal blood spaces and fetal endothelial cells (inset) prevent direct blood contact while facilitating selective and essential nutrient/waste exchange. Environmental stimuli such as maternal stress can disrupt vital aspects of placental organogenesis and function, including decidual immune tolerance, vascularization and utero-placental blood flow, trophoblast hormone secretion, and nutrient exchange within the labyrinth zone. The neurodevelopmental consequences of stress depend on the maturational state of the entire maternal–placental–fetal unit at the time of exposure. Although implantation occurs early in gestation (embryonic day 4.5 in mice and the second week in humans), placental maturation and expansion continues throughout gestation, leaving this fetal lifeline and the somatic and germ cells it sustains continuously vulnerable to maternal stress signals.

Figure 2

Insulin signaling as potential common programmatic placental pathway. A simplified schematic depicting the predicted impairment of insulin signaling within placentas complicated by diverse fetal exposures. In diabetes, obesity, and pre-eclampsia, changes in insulin receptor (InsR) localization, kinase activity, and substrate availability lead to placenta insulin resistance. Maternal stress and infection are predicted to also elicit insulin resistance, owing to the inhibitory effects of cytokines on insulin action. Predicted programmatic effects of placenta insulin resistance depend on exposure timing. In early pregnancy, InsRs are localized to maternal-facing trophoblasts and predominately regulate expression of genes related to metabolism of lipids and fatty acids. Such changes may have an impact on placental growth, trophoblast survival, and hormone secretion in early pregnancy. Later in gestation, their expression is restricted to the fetal endothelial cells where insulin communicates fetal demand for growth, cell proliferation, and cell survival.