Distinct mechanisms of transcriptomic habituation to repeated stress in the mouse hippocampus

Chronic stress is a risk factor for neuropsychiatric disorders, making the ability to adapt to repeated stress a crucial determinant of mental health. It remains unclear whether repeated stress exposure leads to habituation or new adaptive responses. Here, we investigated how the transcriptomic response to acute restraint stress changes - in the mouse ventral hippocampus - with repeated exposure. Using bulk RNA-seq across multiple timepoints, we observed widespread transcriptional habituation: stress-induced gene expression was blunted without the emergence of new response profiles or changes in baseline gene expression. Temporally resolved single-nucleus multi-omic profiling (RNA and chromatin accessibility) confirmed that the transcriptional habituation occurs across cell types, revealing cell type-specific patterns. We identify gene clusters whose expression habituates with repeated exposure, which appear primarily related to two distinct mechanisms: an early blunting of cAMP-associated genes chiefly linked to a reduced number of activated cells, and a shortened transcriptional response of corticosterone-associated genes, independent of the number of activated cells. Our study provides a comprehensive resource, accessible as an interactive app, that characterizes the dynamic transcriptomic response to stress in the mouse hippocampus and how it habituates with repeated exposure to stress.