SUPR
Prenatal stress and pharmacology effects on development
Dnr:

NAISS 2024/23-401

Type:

NAISS Small Storage

Principal Investigator:

Cristiana Cruceanu

Affiliation:

Karolinska Institutet

Start Date:

2024-06-28

End Date:

2025-07-01

Primary Classification:

30105: Neurosciences

Allocation

Abstract

The brain undergoes important growth and plasticity during prenatal development, and altered activation of the glucocorticoid receptor (GR) system is one of the factors mediating stress effects during this time, likely through transcriptional dysregulation. To investigate these processes in a human-specific in vitro system, we use induced pluripotent stem cell-derived 3-dimensional brain organoids. To determine cell-type specific GR activation response, we profile the transcriptomes and epigenomes of thousands of individual cells using single-cell RNAseq and ATACseq analyses in wild-type conditions or following glucocorticoids exposure. Subsequently, we use immunofluorescence to better understand protein, and cell morphology-level long-term effects on cell-type population dynamics. With this approach, we found that prolonged glucocorticoids exposure in cerebral organoids can activate a robust cell-type-specific differential response of key transcription factors involved in neuronal cell fate regulation, including SOX2, PAX6, TBR1 and GAD1. Lineage analyses identified an over-commitment toward inhibitory neurons, whereby glucocorticoids acted directly on lineage driver genes and directed the likelihood of individual cells’ commitment to this neuronal lineage. in vitro findings were consistent across diverse genetic backgrounds, and were supported by in vivo human fetal brain data. In conclusion, cerebral organoids show responsiveness to GR activation consistent with in vivo data, including a cell-type specific transcriptional regulatory response through key lineage drivers capable of shifting lineage commitment. The likely outcome of aberrant overexposure is a lasting shift in neuronal type distribution and developing brain architecture. This work sheds light on the mechanisms by which environmental stimuli like maternal stress-mediated elevated glucocorticoids could lead to subtle changes in brain development and ultimately vulnerability to mental illness.