Abstract Stress-related psychiatric disorders impact the quality of life of half a billion people around the world. However, our understanding of the molecular mechanisms responsible for stress-response regulation remain unclear. Here, we report the largest and most comprehensive characterization of the adult male mouse hippocampus, under baseline and acute stress condition, using single-cell RNA sequencing. We further used genetically modified knockout lines for the glucocorticoid and mineralocorticoid receptors (GR and MR); two transcription factors which are pivotal regulators of the central stress-response. We found previously unknown, cell-type specific, molecular signatures of a single prolonged social defeat stress response and identified Nrgn and SgK1 as key regulators in stress-responsive glutamatergic neurons, oligodendrocytes, astrocytes, and endothelial cells. Intriguingly, GR or MR deletion, specifically in glutamatergic or GABAergic neurons, led to distinct and cell-type specific transcriptional signatures after stress exposure. This study significantly advances our understanding of the molecular and cellular network underlying the central response to stressful stimuli.
Donno et al. (Mon,) studied this question.