The locus coeruleus noradrenergic system in stress: Shaping the pupillary and transcriptomic stress response
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Author
Date
2023Type
- Doctoral Thesis
ETH Bibliography
yes
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Abstract
In an ever-changing environment, we are constantly presented with new challenging and stressful situations. Within all organisms, specific molecular, physiological and behavioral adaptations have evolved to perceive, assess and execute appropriate stress responses. A rapid and adequate response not only increases the chance of immediate survival, but also promotes long-term adaptations to improve future outcomes. However, maladaptation to stress has also been associated with the development of various neurological disorders,
such as depression, anxiety and post-traumatic stress disorder. A better understanding of the underlying mechanisms is therefore essential to fully grasp how stress responses lead to maladaptation. Various systems across peripheral and central organs have evolved to mediate responses to stress. The central nervous system mainly governs the perception, assessment and execution of stress responses. This includes the complementary actions of various brain areas and neurotransmitter systems; however, the locus coeruleus (LC) noradrenergic system has been proven to play a key role in facilitating responses to stress.
Here, I present our research on the LC noradrenergic system and how it shapes pupillary and molecular responses in mice. First, we demonstrate how pupillometry, the measurement of pupil diameter, can be easily applied to rodents and how it can complement electric, chemogenetic and optogenetic manipulations of the locus coeruleus. Thus, pupillometry provides a rapid, non-invasive and translationally relevant tool to facilitate locus coeruleus research. Secondly, long-term adaptations to stress are based on molecular changes in the brain; however, the role of noradrenaline (NA) in this is still barely understood. To this end,
we investigated and characterized how stress-dependent activation of the LC-NA system affects transcriptomic responses in the hippocampus, a stress-sensitive projection region of the LC. By combining RNA-sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations of the LC-NA system, we show that NA-release during stress exposure reliably regulates a set of genes in the hippocampus via β-adrenergic receptors.
The identity of the gene set suggests LC-mediated mobilization of astrocytic energy and thyroid hormone metabolism as essential mediators of LC function in the hippocampus. I further expand on current models of LC function and propose that these astrocytic pathways underlie LC-mediated facilitation of long-term adaptations to stress and thus offer prominent targets for further research investigating the role of the LC-NA system in health and disease. Show more
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https://doi.org/10.3929/ethz-b-000614356Publication status
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Publisher
ETH ZurichOrganisational unit
09499 - Bohacek, Johannes / Bohacek, Johannes
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ETH Bibliography
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