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

MPS-Authors
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Cruceanu,  Cristiana
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Dony,  Leander
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Roeh,  Simone
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Di Giaimo,  Rossella
Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society;

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Kyrousi,  Christina
Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society;

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Kaspar,  Lea
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Arloth,  Janine
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Czamara,  Darina
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Gerstner,  Nathalie
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Martinelli,  Silvia
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Wehner,  Stefanie
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Koedel,  Maik
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Sauer,  Susann
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Sportelli,  Vincenza
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Rex-Haffner,  Monika
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Cappello,  Silvia
Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society;

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Binder,  Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Cruceanu, C., Dony, L., Krontira, A. C., Fischer, D. S., Roeh, S., Di Giaimo, R., et al. (2022). Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study. AMERICAN JOURNAL OF PSYCHIATRY, 179(5), 375-387. doi:10.1176/appi.ajp.2021.21010095.


Cite as: https://hdl.handle.net/21.11116/0000-000A-AA3D-3
Abstract
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.