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.

Automated summary

Objective: Maintaining a balanced activation of glucocorticoid receptor (GR) is crucial for organ formation. Excessive glucocorticoid exposure during pregnancy has been associated with negative outcomes in brain development, but the underlying mechanisms remain unclear. In this study, an in vitro model using induced human pluripotent stem cell (hiPSC)-derived cerebral organoids was used to investigate the impact of prenatal glucocorticoid exposure on the developing brain. The results showed that GR was expressed in all cell types and its activation affected various pathways, including differentiation and maturation, in neurons and progenitor cells. Neurons exhibited differential gene expression associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated in cerebral organoids from different hiPSC lines. These findings suggest that excessive glucocorticoid exposure in utero could interfere with neuronal maturation and increase susceptibility to neurodevelopmental disorders. Cerebral organoids have great potential for studying the effects of glucocorticoids on early human brain development.