Glucocorticoid Signaling in PSC-Derived Neural Systems to Elucidate Mechanisms of Stress-Induced Psychiatric...

Glucocorticoids are major regulators of human neural development and stress adaptation, yet their transcriptional effects across experimental paradigms remain poorly integrated. This review synthesizes evidence from 13 studies employing human induced pluripotent stem cell (hiPSC)-derived neural models exposed to cortisol or dexamethasone, including neural progenitors, neurons, astrocytes, and brain organoids. When available, transcriptomic datasets from these studies were reanalyzed under standardized criteria to directly compare acute and chronic GC exposure. This comparative approach revealed that GCs modulate shared pathways related to neurogenesis, cytoskeletal organization, immune signaling, and stress response, while the duration of exposure critically shapes the underlying transcriptional architecture. Acute stimulation predominantly upregulated canonical GR targets such as FKBP5, ZBTB16, and TSC22D3 involved in early stress response and feedback control, whereas chronic exposure induced sustained remodeling of genes including MT2A, RASFAF4, and DPYSL5 linked to oxidative stress regulation and neuronal structure. A conserved downregulated core comprising NFIA, NFIB, and CCL2 was shared across paradigms, reflecting persistent suppression of glial differentiation and inflammatory signaling. Together, these findings delineate distinct yet convergent transcriptional programs governed by GC exposure, providing mechanistic insight into how temporal dynamics of glucocorticoid signaling may contribute to altered neurodevelopmental trajectories and increased vulnerability to stress-related psychiatric disorders.