DOI: 10.7554/elife.88559.3 ISSN: 2050-084X

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

Mattia Privitera, Lukas M von Ziegler, Amalia Floriou-Servou, Sian N Duss, Runzhong Zhang, Rebecca Waag, Sebastian Leimbacher, Oliver Sturman, Fabienne K Roessler, Annelies Heylen, Yannick Vermeiren, Debby Van Dam, Peter P De Deyn, Pierre-Luc Germain, Johannes Bohacek
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine
  • General Neuroscience

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 (LC-NA) system to the acute stress response in mice. 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, and 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 how NA impacts brain function in health and disease.

More from our Archive