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

Cruceanu, Cristiana; Dony, Leander; Krontira, Anthi C.; Fischer, David S.; Roeh, Simone; Di Giaimo, Rossella; Kyrousi, Christina; Kaspar, Lea; Arloth, Janine; Czamara, Darina; Gerstner, Nathalie; Martinelli, Silvia; Wehner, Stefanie; Breen, Michael S.; Koedel, Maik; Sauer, Susann; Sportelli, Vincenza; Rex-Haffner, Monika; Cappello, Silvia; Theis, Fabian J.; Binder, Elisabeth B.

doi:10.1176/appi.ajp.2021.21010095

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

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

/persons/resource/persons262330

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;

/persons/resource/persons128467

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

/persons/resource/persons222059

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

/persons/resource/persons226820

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

/persons/resource/persons262384

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;

/persons/resource/persons98244

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

/persons/resource/persons80291

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

/persons/resource/persons262202

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;

/persons/resource/persons222053

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

/persons/resource/persons222062

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

/persons/resource/persons222056

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

/persons/resource/persons226837

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

/persons/resource/persons222201

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

/persons/resource/persons80495

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

/persons/resource/persons189184

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

/persons/resource/persons80272

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.