Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice

Aarti Jagannath; Norbert Varga; Robert Dallmann; Gianpaolo Rando; Pauline Gosselin; Farid Ebrahimjee; Lewis Taylor; Dragos Mosneagu; Jakub Stefaniak; Steven Walsh; Teele Palumaa; Simona Di Pretoro; Harshmeena Sanghani; Zeinab Wakaf; Grant C Churchill; Antony Galione; Stuart N Peirson; Detlev Boison; Steven A Brown; Russell G Foster; Sridhar R Vasudevan

doi:10.1038/s41467-021-22179-z

Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice

Nat Commun. 2021 Apr 9;12(1):2113. doi: 10.1038/s41467-021-22179-z.

Authors

Aarti Jagannath¹, Norbert Varga², Robert Dallmann³, Gianpaolo Rando⁴, Pauline Gosselin⁴, Farid Ebrahimjee⁵, Lewis Taylor², Dragos Mosneagu⁵, Jakub Stefaniak⁵, Steven Walsh², Teele Palumaa², Simona Di Pretoro², Harshmeena Sanghani⁵, Zeinab Wakaf⁵, Grant C Churchill⁵, Antony Galione⁵, Stuart N Peirson², Detlev Boison⁶, Steven A Brown⁷, Russell G Foster⁸, Sridhar R Vasudevan⁹

Affiliations

¹ Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, Oxford, UK. aarti.jagannath@ndcn.ox.ac.uk.
² Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, Oxford, UK.
³ Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁴ Department of Molecular Biology, University of Geneva, Geneva 4, Switzerland.
⁵ Sleep and Circadian Neuroscience Institute (SCNi), Department of Pharmacology, University of Oxford, Oxford, UK.
⁶ Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
⁷ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
⁸ Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, OMPI-G, Oxford, UK. russell.foster@eye.ox.ac.uk.
⁹ Sleep and Circadian Neuroscience Institute (SCNi), Department of Pharmacology, University of Oxford, Oxford, UK. sridhar.vasudevan@pharm.ox.ac.uk.

Abstract

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A₁/A_2A receptor signalling through the activation of the Ca²⁺ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / metabolism*
Animals
Brain / pathology
Caffeine / pharmacology
Cell Line, Tumor
Chronobiology Disorders / drug therapy
Chronobiology Disorders / etiology
Chronobiology Disorders / pathology
Chronobiology Disorders / physiopathology*
Circadian Clocks / drug effects*
Circadian Clocks / physiology
Circadian Rhythm / drug effects
Circadian Rhythm / physiology
Disease Models, Animal
Humans
Light
Male
Mice
Mice, Transgenic
Period Circadian Proteins / genetics
Period Circadian Proteins / metabolism
Photoperiod
Quinazolines / administration & dosage
Receptor, Adenosine A1 / metabolism
Receptor, Adenosine A2A / metabolism
Signal Transduction / drug effects
Signal Transduction / physiology
Signal Transduction / radiation effects
Sleep / drug effects
Sleep / physiology*
Sleep Deprivation / complications
Triazoles / administration & dosage

Substances

Adora2a protein, mouse
Per1 protein, mouse
Per2 protein, mouse
Period Circadian Proteins
Quinazolines
Receptor, Adenosine A1
Receptor, Adenosine A2A
Triazoles
Caffeine
Adenosine
9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine

Abstract

Publication types

MeSH terms

Substances

Grants and funding