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Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study
Cristiana Cruceanu1, Leander Dony1, Anthi C Krontira1
1Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany (Cruceanu, Dony, Krontira, Roeh, Kaspar, Arloth, Czamara, Gerstner, Martinelli, Wehner, Koedel, Sauer, Sportelli, Rex-Haffner, Binder);International Max Planck Research School for Translational Psychiatry, Max Planck Institute of Psychiatry, Munich (Dony, Krontira, Kaspar, Gerstner);Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany (Dony, Fischer, Arloth, Theis);TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany (Fischer);Max Planck Institute of Psychiatry, Munich (Di Giaimo, Kyrousi, Cappello);Department of Biology, University of Naples Federico II, Naples, Italy (Di Giaimo);First Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, and University Mental Health, Neurosciences, and Precision Medicine Research Institute "Costas Stefanis," Athens, Greece (Kyrousi);Department of Psychiatry, Department of Genetics and Genomic Sciences, Seaver Autism Center for Research and Treatment, and Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York (Breen);School of Life Sciences Weihenstephan and Department of Mathematics, Technical University of Munich, Munich (Theis);Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (Binder).
Objective:
A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids 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 developing brain.
Methods:
The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development.
Results:
The GR was expressed in all cell types, with increasing 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 significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid 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 glucocorticoid 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.
Insights
Prenatal exposure to glucocorticoids can disrupt fetal brain development by affecting neuronal maturation. Cerebral organoids reveal that glucocorticoid receptor activation in neurons is linked to behavioral disorders, highlighting risks from in utero exposures.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Glucocorticoid receptor (GR) activation is crucial for organ development, but prenatal exposure can negatively impact brain development.
- Mechanisms of GR's cell-type-specific effects on the developing human brain remain unclear.
Purpose of the Study:
- To investigate the impact of prenatal glucocorticoid exposure on the developing human brain using induced human pluripotent stem cell (hiPSC)-derived cerebral organoids.
- To determine the suitability of cerebral organoids as a model for studying glucocorticoid effects on neurodevelopment.
Main Methods:
- Activation of the glucocorticoid receptor (GR) using dexamethasone in cerebral organoids.
- Single-cell transcriptomics analysis to map gene expression changes across developmental stages.
Main Results:
- GR is expressed in all cerebral organoid cell types, increasing with development.
- GR activation affects neuronal differentiation and maturation pathways.
- Neurons uniquely show GR-regulated genes associated with behavioral phenotypes and disorders, validated across multiple hiPSC lines.
Conclusions:
- Excessive prenatal glucocorticoid exposure may impair neuronal maturation, increasing susceptibility to neurodevelopmental disorders.
- Cerebral organoids serve as a valuable model for studying glucocorticoid impacts on early human brain development.
