Single-cell characterization of the adult male hippocampus suggests a prominent, and cell-type specific, role for Nrgn and Sgk1 in response to a social stressor.

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.