Distinct molecular mechanisms of stress habituation in the mouse hippocampus [bulk ATAC-seq]

We explore how the tightly regulated molecular response triggered by acute restraint stress becomes altered after repeated restraint exposure. Transcriptomic sampling of the mouse hippocampus at multiple time points revealed that repeated stress leads to widespread habituation, damping stress-induced gene expression of all stress-responsive genes. However, we find no evidence for the emergence of new response profiles or alterations in baseline gene expression. Using single-cell multi-omics, we show that these findings hold true across cell types, and we reveal cell type specific patterns of habituation. Transcriptomic and chromatin accessibility profiles identify two distinct mechanisms that contribute to the observed habituation patterns: an early cAMP-associated mechanism that is related to blunted transcription after chronic stress, and a late corticosterone-dependent mechanism that is linked to a shortened transcriptional response. Restraint stress involves placing the mice in a 50 ml Falcon tube with a large air hole for 1h30. Chronically stressed animals were subjected to daily restraint for 10 consecutive days at varying time of day before the final (acute) stress exposure, while handling animals were handled gently (lifting the animals by the tail, simulating the handling method used before restraint stress). Following this treatment, animals were single-housed 24 hours before being subjected once again to the same restraint stress, and the samples were collected 45min following stress initiation (time point 0min indicates an absence of acute stress, i.e. homecage animals). All stress exposures were carried out between 10:00 and 17:00 in the animals’ active phase (i.e. reverse light cycle).