Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression
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Date
2024
Publication Type
Journal Article
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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 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 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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published
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Volume
12
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Publisher
eLife Sciences Publications
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Subject
transcriptome; noradrenaline; locus coeruleus; hippocampus; stress; optogenetics; Mouse
Organisational unit
09499 - Bohacek, Johannes / Bohacek, Johannes
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Funding
172889 - Dissecting stress-induced molecular changes in circuits underlying anxiety (SNF)
204372 - A molecular roadmap to the acute stress response in health and disease (SNF)
ETH-20 19-1 - A cross‐disciplinary, data‐driven approach to predict stress resilience from large‐scale behavioral, molecular and neural activity data (ETHZ)
204372 - A molecular roadmap to the acute stress response in health and disease (SNF)
ETH-20 19-1 - A cross‐disciplinary, data‐driven approach to predict stress resilience from large‐scale behavioral, molecular and neural activity data (ETHZ)