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Dissecting stress-induced molecular changes in circuits underlying anxiety

English title Dissecting stress-induced molecular changes in circuits underlying anxiety
Applicant Bohacek Johannes
Number 172889
Funding scheme Project funding (Div. I-III)
Research institution Brain Research Institute Universität Zürich / ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2018 - 31.12.2021
Approved amount 586'082.00
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Keywords (10)

mice; chemogenetics; transcriptome; noradrenaline; anxiety; hippocampus; serotonin; stress; optogenetics; behavior

Lay Summary (German)

Lead
Extreme Stresssituationen können Angststörungen und affektive Störungen auslösen, an denen viele hundert Millionen Menschen weltweit leiden. Die medikamentöse Behandlung zielt in erster Linie auf die Neurotransmittersysteme von Noradrenalin und Serotonin ab, doch diese Medikamente sind oft unwirksam, haben unerwünschte Nebenwirkungen und ihre Wirkungsmechanismen sind unklar. Da Stress auch im Tiermodell zu Angstzuständen führt und auf ähnlichen neuronalen und molekularen Faktoren beruht, nutzt dieses Forschungsprojekt die modernsten genetischen und technischen Möglichkeiten um den Zusammenhang zwischen Stress, Angst, Serotonin und Noradrenalin im Mausmodell zu untersuchen.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Unsere Forschung hat gezeigt, dass Stresssituationen die Angstzustände auslösen in verschiedenen Hirnregionen zu starken Änderungen der Genaktivität führen. Durch neueste Sequenziermethoden können diese Änderungen in Ihrer Gesamtheit erfasst und quantifiziert werden. Wir nutzen diese Möglichkeiten um zu testen, wie die selektive Stimulation von Noradrenalin- und/oder Serotoninausschüttung im Gehirn diese Genaktivität beeinflusst, und ob das Stilllegen dieser Neurotransmitter die negativen Konsequenzen von Stress auf Angst verhindern kann. Wir benutzen dafür modernste neurogenetische Methoden um mittels gezielt steuerbaren Designerrezeptoren hochspezifische Aktivierung oder Hemmung von serotonergen und/oder noradrenergen Neuronen zu erzielen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Die am häufigsten verwendeten Medikamente zur Behandlung von Angststörungen sind in circa 40% der Patienten unwirksam und haben oft starke Nebenwirkungen. Ein besseres mechanistisches Verständnis der molekularen Veränderungen bei Angststörungen ist daher extrem wichtig, um neue Therapieansätze zu entwickeln. In diesem Projekt versuchen wir kausale Zusammenhänge zwischen stressbedingter Serotonin/Noradrenalinausschüttung und Angstzuständen zu erkennen, und hoffen neue molekulare Ansatzpunkte zur Therapie von Angststörungen zu finden.

Direct link to Lay Summary Last update: 21.09.2017

Responsible applicant and co-applicants

Employees

Name Institute

Collaboration

Group / person Country
Types of collaboration
Prof. Nicole Wenderoth, Neural Control of Movement, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Hanns Ulrich Zeilhofer, Neuropharmacology, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Bruno Weber, xperimental Imaging & Neuroenergetics, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Peter De Deyn, Biomedical Sciences and Medicine, University of Antwerp Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ferdinan von Meyenn, Nutrition and Metabolic Epigenetics, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
49th meeting of the European Brain And Behavior Society Talk given at a conference Chasing stress down a multi-omic rabbit hole 04.09.2021 Lausanne, Switzerland Bohacek Johannes;
Swiss Stress Network Annual Meeting Talk given at a conference The molecular signature of a healthy stress response. 26.01.2021 Virtual Event, Switzerland Bohacek Johannes;
Blue Spot Seminar Series Individual talk The locus coeruleus-noradrenergic system in the multi-omic era. 12.10.2020 Los Angeles (virtual talk), United States of America Bohacek Johannes;
European 3Rs Webinar Talk given at a conference BEHAVE: A toolkit for deep-behavior profiling of laboratory rodents. 22.09.2020 Bern (virtual talk), Switzerland Bohacek Johannes;
Paris Brain Institute, ICM Seminar Individual talk Multi-omic dissection of the locus coeruleus-noradrenergic system. 07.09.2020 Paris (virtual meeting), France Bohacek Johannes;
Paris Brain Institute, ICM Seminar Individual talk Multi-omic dissection of the locus coeruleus-noradrenergic system 07.09.2020 Paris (virtual talk), France Bohacek Johannes;
Alzheimer's Association International Conference Talk given at a conference The locus coeruleus: nexus of behavioral and cognitive problems in dementia 26.07.2020 Amsterdam (virtual conference), Netherlands Bohacek Johannes;
FENS Annual Meeting 2020 Poster Molecular roadmap of the healthy stress response in the mouse hippocampus. 11.07.2020 Glasgow, Ireland Bohacek Johannes;
FENS Annual Meeting 2020 Poster A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents 11.07.2020 Glasgow (virtual event, Covid), Ireland Privitera Mattia; Bohacek Johannes;
Alzheimer's Association International Conference Talk given at a conference The locus coeruleus: nexus of behavioral and cognitive problems in dementia. 26.06.2020 Amsterdam (virtual meeting), Netherlands Bohacek Johannes;
Magdeburg Locus Coeruleus Meeting Talk given at a conference The locus coeruleus under stress 13.12.2019 Magdeburg, Germany Bohacek Johannes;
Pharmacology Seminar Individual talk Chasing Acute Stress from Locus Coeruleus to Hippocampus 20.11.2019 Zurich, Switzerland Bohacek Johannes;
Italian Institute of Technology Neuroscience Seminar Individual talk Connectomic and Transcriptomic Assessment of Locus Coerulues Activation 05.11.2019 Genova, Italy Bohacek Johannes;
Department of Animal Welfare Seminar Individual talk The acute stress response: a network perspective 03.10.2019 Bern, Switzerland Bohacek Johannes;
European Brain and Behavior Society Annual Meeting Talk given at a conference Stress and the locus coeruleus: From circuits to networks 24.09.2019 Prag, Czech Republic Bohacek Johannes;
Danders Institute for Brain Research Seminar Individual talk Acute Stress: From locus coeruleus to hippocampus, from connectome to transcriptome 03.09.2019 Nijmegen, Netherlands Bohacek Johannes;
Neuromodulator Conference NM2 in Geneva Poster Digging deeper into the molecular effects of acute stress on mouse hippocampus. 24.05.2019 Geneva, Switzerland Privitera Mattia; Bohacek Johannes;
Neuromodulator Conference NM2 in Geneva Poster Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation 24.05.2019 Geneva, Switzerland Privitera Mattia; Bohacek Johannes;
Institute for Neuroinformatics Colloquium Individual talk Stress & Noradrenaline: New tools for old questions. 10.05.2019 Zurich, Switzerland Bohacek Johannes;
Neurolunch Individual talk Tools for Stress 29.03.2019 Zurich, Switzerland Bohacek Johannes;
Munich Winter Conference on Stress Poster Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation 17.03.2019 Garmisch-Partenkirchen, Germany Bohacek Johannes;
Annual Meeting of the Swiss Stress Network Talk given at a conference The molecules of acute stress 27.02.2019 Basel, Switzerland Bohacek Johannes;
Swiss Society for Neuroscience Meeting Poster The dynamic transcriptomic and proteomic responses to acute stress in the mouse hippocampus and its sub-regions 01.02.2019 Geneva, Switzerland Bohacek Johannes;
Colloquium of the Max Planck Institute for Biological Cybernetics Individual talk Dissecting the acute stress response: from molecules to circuits and networks. 01.02.2019 Tübingen, Germany Bohacek Johannes;
Forschungskolloquium: AE Genetic Psychology Individual talk Circuits and networks under the control of the locus coeruleus. 07.01.2019 Bochum, Germany Bohacek Johannes;
FENS Annual Meeting 2018 Poster Distinct transcriptomic, proteomic and epigenetic stress-responses in dorsal and ventral hippocampus 07.07.2018 Berlin, Germany Bohacek Johannes;
Stress Neurobiology Workshop Poster Distinct transcriptomic, proteomic and epigenetic stress-responses in dorsal and ventral hippocampus 08.06.2018 Banff, Canada Bohacek Johannes;
Swiss Stress Network: Stress in Health and Disease Individual talk Molecular dissection of the acute stress response. 14.03.2018 Lausanne, Switzerland Bohacek Johannes;
Swiss Society for Neuroscience Annual Meeting Poster Distinct transcriptomic, proteomic and epigenetic stress-responses in dorsal and ventral hippocampus 09.02.2018 Zurich, Switzerland Bohacek Johannes;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Big Behavior Brainpod: Podcast for the journal Neuropsychopharmacology International 2020
Talks/events/exhibitions Stress during the Covid-19 pandemic (Youth Forum Switzerland 2020) German-speaking Switzerland 2020
New media (web, blogs, podcasts, news feeds etc.) Transparency Thursday European Animal Research Association International 2020
Talks/events/exhibitions Your body under stress (Youth Forum Switzerland 2020) International 2020
Talks/events/exhibitions Unser Gehirn unter Stress: Überleben und Erkranken (Brain Awareness Week, Basel) German-speaking Switzerland 2019

Associated projects

Number Title Start Funding scheme
204372 A molecular roadmap to the acute stress response in health and disease 01.01.2022 Project funding (Div. I-III)

Abstract

Severely stressful experiences can trigger anxiety and mood disorders, which affect hundreds of millions of people worldwide, creating grave personal suffering and a large societal and financial burden. The first-line medications for treating anxiety disorders act on serotonin and norepinephrine, neurotransmitter systems strongly activated by stressful events. However, these drugs are often inefficient, have unwanted side effects, and their mechanism of action remains unclear. Importantly, the ability of stress to induce anxiety, and the molecular mechanisms underlying the effects of clinically effective anxiolytic drugs, are highly conserved between mammals and are very similar in mice and in humans. In this proposal, we capitalize on these similarities and use the powerful molecular and genetic tools available in mice to provide a better understanding of the molecular link between the anxiogenic effects of stress, and the causal involvement of noradrenergic and serotonergic systems mediating these effects. We bring together behavioral testing and RNA-sequencing to establish detailed maps of the molecular changes underlying stress-induced anxiety, and combine this approach with optogenetic and chemogenetic targeting of noradrenergic and serotonergic circuitries to directly modulate the impact of stress on anxiety. These data will be highly relevant for basic research, identify molecular pathways for treatment of anxiety, and possibly other stress-related mental disorders.
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