CELL-TYPE-SPECIFIC TRANSCRIPTIONAL RESPONSES TO GLUCOCORTICOID SIGNALING IN HUMAN IPSC-DERIVED NEURAL CULTURES

Mental health disorders rank among the leading causes of disease burden worldwide. The etiology of these conditions involves a complex interplay between genetic and environmental factors, with chronic stress and stressful life events representing major risk contributors. The stress response is coordinated by the hypothalamus–pituitary–adrenal axis, activation of which leads to the secretion of glucocorticoids (GCs). GCs mediate this response primarily through the glucocorticoid receptor (GR), a ubiquitous transcription factor with pronounced tissue- and cell-type-specific activity. While GR-regulated pathways are well characterized in peripheral organs, GR signaling in human neural cells remains to be fully understood.
Here, we investigated GC-induced transcriptional responses in a human-relevant model using surface-attached three-dimensional mixed neural cultures derived from induced pluripotent stem cells (iPSCs). These cultures contain neurons, astrocytes, and oligodendrocytes at both progenitor and mature stages, and express the GR. Cultures were treated with the stress hormone cortisol or the synthetic GR agonist dexamethasone, followed by immunocytochemistry, qPCR, and single-cell RNA sequencing to assess GR activation.
We observed robust induction of canonical GR bona fide target genes across neural populations, alongside pronounced cell-type- and ligand-specific transcriptional signatures. These results highlight heterogeneity in GR signaling within complex human neural systems and suggest that differential transcriptional responses may contribute to stress-related vulnerability or resilience.
Overall, this work provides insight into how stress hormones shape molecular programs in human brain cells and establishes a framework for studying mechanisms relevant to stress-related psychiatric disorders and therapeutic target discovery.