Abstract Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here we combine RNA-sequencing with selective pharmacological, chemogenetic and optogenetic manipulations to isolate the contribution of the locus coeruleus - noradrenaline (LN-NA) system to the acute stress response. We reveal that NA-release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 ( Ppp1r3c , Ppp1r3d , Ppp1r3g ) and type II iodothyronine deiodinase ( Dio2 ). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC mediated hippocampal function, and offer new molecular targets for understanding LC function in health and disease.

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression