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

Privitera, M.; von Ziegler, L. M.; Floriou-Servou, A.; Duss, S. N.; Zhang, R.; Leimbacher, S.; Sturman, O.; Waag, R.; Roessler, F.; Heylen, A.; Vermeiren, Y.; Van Dam, D.; De Deyn, P. P.; Bohacek, J.

doi:10.1101/2023.02.02.526661

bioRxiv · 10.1101/2023.02.02.526661

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

Privitera, M.·von Ziegler, L. M.·Floriou-Servou, A.·Duss, S. N.·Zhang, R.·Leimbacher, S.·Sturman, O.·Waag, R.·Roessler, F.·Heylen, A.·Vermeiren, Y.·Van Dam, D.·De Deyn, P. P.·Bohacek, J.

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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 (LC-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 {beta}-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.

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Privitera, M., von Ziegler, L. M., Floriou-Servou, A., Duss, S. N., Zhang, R., Leimbacher, S., Sturman, O., Waag, R., Roessler, F., Heylen, A., Vermeiren, Y., Van Dam, D., De Deyn, P. P., Bohacek, J.. 2023-02-02. Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression. https://doi.org/10.1101/2023.02.02.526661

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