Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study

Objective: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with distur-bances influencing many health outcomes. In utero, glu-cocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the devel-oping brain. Methods: The GR was activated with the synthetic gluco-corticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. Results: The GR was expressed in all cell types, with in-creasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation-and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were signifi-cantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocor-ticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. Conclusions: These findings suggest that excessive gluco-corticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.