The mechanism of sleep control through a sleep-active sleep-promoting neuron

Projektinformationen

SLEEPCONTROL

ID Finanzhilfevereinbarung: 637860

DOI

10.3030/637860

Projekt abgeschlossen

EK-Unterschriftsdatum 23 Februar 2015

Startdatum 1 September 2015

Enddatum 28 Februar 2022

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

TECHNISCHE UNIVERSITAET DRESDEN
Germany

Periodic Reporting for period 5 - SLEEPCONTROL (The mechanism of sleep control through a sleep-active sleep-promoting neuron)

Berichtszeitraum: 2020-11-01 bis 2022-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Sleep is vital for animal and human life and many individuals are suffering from sleeping problems in modern societies. However, little is known about how sleep is controlled. The overall goal of this project is to understand sleep control in a model organism, Caenorhabditis elegans. Like other animals and humans, C. elegans shows sleep behavior. Sleep is controlled in both mammals and C. elegans by sleep active neurons. C. elegans uses one single sleep active neuron called RIS, which, like its mammalian counterparts, is GABAergic and peptidergic. Little is known about the control of sleep-active neurons at the molecular level in any system. C. elegans is a molecularly accessible system and solving the regulation of sleep by RIS should be feasible.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The project focussed on mechanisms that control the RIS sleep neuron. The genetic dissection of upstream signaling pathways revealed that pathways that are known to control aging control the activation of RIS, Wu et al. . Core activators of RIS were shown by us to be FoxO and AMP activated Kinase. This work is important as it provided a molecular link between pathways that counteract aging and sleep. Sleep neuron activation hence is a part of the anti-aging action of longevity genes. Transcriptomic analyis of RIS-expressed genes revealed the next upstream pathway that controls RIS: EGFR signaling. We demonstrated that this pathway becomes active upon exogenous stressors such as a heat shock. This insult leads to the release of EGF, which activates EGFR in both RIS direclty as well as in the ALA neuron, which we could demostrate presents an upstream activator neuron for RIS. This work is important as it shows how stress causes tiredness and sleep by activation of an EGFR - responsive circuit, Konietzka et al. Yet another molcular signaling system that we discovered were antimicrobial peptides. We also solved a neuronal circuit that activates RIS . By perforiming translational work in mice we could demonstrate that RIS expressed genes have homologs in mammals that fullfil also sleep functions. Specifically we could show that both TFAP2a and TFAP2b control sleep in mammals, this is important as it validates the C. elegans system, Hu et al.. In the final reporting period we could show that upon wounding epidermal peptides are released and act as neuroendocrine signals to the nervous sytem to activate the sleep neuron RIS, RIS activation in turn promotes the survival and healing of the wound. Hence we could for the first time show that a signaling system exists that couples the sos signal caused by the wound to protective sleep, Sinner et al. .

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

This project has been tremendously successful. We have identifed multiple molecular pathways for RIS control, including aging pathways (Foxo, AMPK), EGFR signaling, and antimicrobial peptides. Furthermore we identified the neuronal circuits and mechanisms underlying sleep induction and RIS activation. The pathways and genes that we have disovered are all highly conserved and should also play similar roles in mammalian sleep. To validate the relevance of our system we have translated our findings to mammals and could indeed demonstrate a conserved role for AP2 transcription factors. Hence the pathways found here are important for understanding human sleep and its disorders.

Presynaptic neurons control the activity of the sleep-active RIS neuron.