671. PRENATAL STRESS EXPOSURE SHAPES CORTICOGENESIS THROUGH CELL FATE AND GENE REGULATORY NETWORKS WITH IMPLICATIONS FOR NEURODEVELOPMENTAL DISORDERS

Abstract Background Early perinatal development is a critical period for the placenta-brain axis, whereby maternal exposures can fundamentally alter the course of fetal health. Activation of the glucocorticoid receptor (GR) system is one factor mediating stress effects, through transcriptional and epigenetic dysregulation – which can have profound effects on child health risk and resilience. Aims & Objectives We modeled critical periods of human corticogenesis using brain organoids, and placenta organoids to model maternal-fetal transmission. Method We profiled thousands of cells following glucocorticoid receptor activation with endogenous and synthetic corticosteroids, using single-cell transcriptomic and chromatin accessibility analyses, to understand gene-level responses and to build gene-regulatory networks of specific cell population effects. High-content confocal microscopy revealed protein, and cell morphology-level effects. Results Chronic GR activation in cerebral organoids induced a robust differential response from transcription factors involved in neuronal cell fate regulation: SOX2, PAX6, and TBR1. Lineage analyses altered inhibitory neuron fate commitments, through modulation of lineage driver genes. In-vitro findings were supported by ex-vivo human fetal brain data. Multi-modal machine learning investigations identified activation of gene regulatory networks and epigenetic regulation of key developmental transcription factors like PBX3, ZBTB16, and HSD11B2, highlighting the importance of critical developmental periods of exposure. Investigation of placenta developmental pathways of stress response underscored this gatekeeper’s role in coordinating pathways of neurodevelopmental health. Discussion & Conclusions Prenatal glucocorticoid overexposure has a lasting effect on neuron type distribution and consequently brain architecture, while the placenta mirrors critical periods of exposure vulnerability. Through these mechanisms of dysregulation of the placenta-brain axis, maternal stress or pharmacology exposure could lead to lasting fetal neurodevelopmental and mental illness vulnerability or resilience mechanisms.