INTRODUCTION: Mental health disorders are leading contributors to the global disease burden, with chronic stress and stressful life events acting as major risk factors in disease etiology. The molecular mechanisms of the underlying pathology are not fully understood, limiting the development of innovative treatments. The stress response is mediated by glucocorticoids, which induce systemic physiological changes via the glucocorticoid receptor (GR), a ubiquitous transcription factor acting in a tissue- and cell-specific manner. Molecular pathways affected by altered GR signaling are well recognized in peripheral organs. However, the response to GR stimulation in the brain remains be elucidated.

AIM(S): Our research aims to uncover cell-type-specific pathways regulated by GR signaling in the context of human genetics and their implications in stress-related disorders.

METHOD(S): To this end, we exploited human induced pluripotent stem cells differentiated into surface-attached tridimensional mixed cultures of neural cells. Mixed cultures were treated with GR agonists (2.5 µM cortisol or 100 nM dexamethasone) and analysis of GR bona fide target genes was performed.

RESULTS: Immunocytochemical staining and qPCR analyses confirmed the presence of cortical neurons, astrocytes, and oligodendrocytes in both mature and progenitor states, along with GR expression in each cell type. The patterns of GR-activated transcription were characterized and compared with a large collection of GR-dependent transcriptional signatures. Further analysis revealed cell-type-specific components of the response.

CONCLUSIONS: This study offers deeper insights into the molecular underpinnings of stress-related psychiatric disorders and may support the identification of novel therapeutic targets.

FINANCIAL SUPPORT: This work was supported by NCN OPUS grant GRtraits nr 2022/45/B/NZ5/03188.