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

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)375-387
Number of pages13
JournalAmerican Journal of Psychiatry
Volume179
Issue number5
DOIs
StatePublished - 1 May 2022
Externally publishedYes

Keywords

  • Biology
  • Brain
  • Child/Adolescent Psychiatry
  • Development
  • Glucocorticoid Receptor
  • Neurodevelopmental Disorders
  • Pre/Peri/Postnatal Issues
  • Stress
  • Translational Research

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