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dc.contributor.author
Floriou Servou, Amalia
dc.contributor.supervisor
Bohacek, Johannes
dc.contributor.supervisor
Helmchen, Fritjof
dc.contributor.supervisor
Zeilhofer, Hanns-Ulrich
dc.contributor.supervisor
Karayannis, Theofanis
dc.date.accessioned
2021-07-09T12:41:12Z
dc.date.available
2020-07-07T15:25:09Z
dc.date.available
2020-07-08T05:51:56Z
dc.date.available
2021-07-09T12:41:12Z
dc.date.issued
2020
dc.identifier.uri
http://hdl.handle.net/20.500.11850/425024
dc.identifier.doi
10.3929/ethz-b-000425024
dc.description.abstract
All organisms have evolved elaborate systems to mount a stress response, which increases the chances of survival in dangerous situations. The response to acute stress encompasses a myriad of neurochemicals, the stress-mediators, that act in concert throughout the brain and body. One of the most crucial aspects of the stress response is the mobilization and reallocation of energy resources. The brain is the organ that first perceives potential threats and coordinates the stress response, yet the stress response also impacts the brain itself, changing its function and metabolic activity. One brain area with a key role in the stress response is the locus coeruleus (LC), the largest noradrenergic cell population in the central nervous system, located in the pons of the brainstem. The LC sends diffuse projections to the entire brain, thus providing the main supply of norepinephrine (NE) in the brain, and controlling basic functions such as arousal, cognition and vigilance. Theories have proposed that LC activation mediates a rapid shift in the functional connectivity of the brain, to strengthen connections that promote a higher state of alertness, and enhance threat detection. However, causal evidence that the LC is able to directly exert this effect on large-scale brain function was missing. Here, we chemogenetically activated the mouse LC while performing resting-state functional magnetic resonance imaging (fMRI), an approach we termed chemo-connectomics. Our results showed an increase in brain-wide connectivity, and a rapid reconfiguration of the functional connectome that enhanced brain networks tasked with salience processing and threat detection. Even though this experiment was performed in anesthetized mice, these findings mirror the effects observed in fMRI scans of awake human subjects presented with emotionally aversive stimuli. Moreover, we provided clues that alpha1 and beta1 adrenergic receptors might be involved in these effects, by correlating the changes in functional connectivity to the distribution of adrenergic receptors at the mRNA level. These results highlight the role of LC in the stress response, as well as the potential of neuromodulators in regulating whole-brain states. The release of stress-mediators in response to acute stress also affects the brain on a molecular level, in part through the recruitment of intracellular signaling cascades and the regulation of gene expression. Although a large body of literature has focused on such molecular changes in the context of stress-triggered neuropsychiatric disorders, the molecular events that affect cellular function to mediate the healthy, default response to acute stress have not been characterized in detail. Here, we used a multi-omic approach to investigate the molecular response to acute stress in the mouse brain. We focused on the hippocampus (HC), since this area – owing to its connectivity and molecular composition – is at the heart of the stress response. First, we showed that the dorsal (dHC) and ventral HC (vHC), are inherently different at the transcriptome and proteome level. Hence, we performed our analysis in those two regions separately, after an acute swim stress paradigm. We first used phosphoproteomics to identify the signaling events that initiate the cellular response to stress. In addition, we characterized the transcriptional changes that take place over time, as well as the changes on the translatome of excitatory and inhibitory neurons. We found that stress-induced changes in protein phosphorylation and in gene expression are widespread and rapid, but tightly regulated, as they terminate within a few hours after the initiation of stress. Altogether, these results provide the most detailed characterization of the molecular stress response to date, and will hopefully provide a starting point for understanding where the healthy stress-response might be derailed in cases of stress-induced psychopathology.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.rights.uri
http://rightsstatements.org/page/InC-NC/1.0/
dc.subject
brain
en_US
dc.subject
Neuroscience
en_US
dc.subject
neuromodulation
en_US
dc.subject
Locus coeruleus
en_US
dc.subject
hippocampus
en_US
dc.subject
stress response
en_US
dc.subject
Omics technologies
en_US
dc.subject
chemogenetics
en_US
dc.title
The Acute Stress Response in the Brain: From Neuromodulation to Molecules
en_US
dc.type
Doctoral Thesis
dc.rights.license
In Copyright - Non-Commercial Use Permitted
dc.date.published
2020-07-08
ethz.size
157 p.
en_US
ethz.code.ddc
DDC - DDC::5 - Science::570 - Life sciences
en_US
ethz.identifier.diss
26703
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02542 - Institut für Neurowissenschaften / Institute for Neuroscience::09499 - Bohacek, Johannes / Bohacek, Johannes
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02542 - Institut für Neurowissenschaften / Institute for Neuroscience::09499 - Bohacek, Johannes / Bohacek, Johannes
en_US
ethz.date.deposited
2020-07-07T15:25:20Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.date.embargoend
2021-07-08
ethz.rosetta.installDate
2020-07-08T05:52:27Z
ethz.rosetta.lastUpdated
2024-02-02T14:17:45Z
ethz.rosetta.versionExported
true
ethz.COinS
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