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

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.

SUBMITTER: Jagannath A

PROVIDER: S-EPMC8035342 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Jagannath Aarti A Varga Norbert N Dallmann Robert R Rando Gianpaolo G Gosselin Pauline P Ebrahimjee Farid F Taylor Lewis L Mosneagu Dragos D Stefaniak Jakub J Walsh Steven S Palumaa Teele T Di Pretoro Simona S Sanghani Harshmeena H Wakaf Zeinab Z Churchill Grant C GC Galione Antony A Peirson Stuart N SN Boison Detlev D Brown Steven A SA Foster Russell G RG Vasudevan Sridhar R SR

Nature communications 20210409 1

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 slee ...[more]

PMID: 33837202

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Project description:BackgroundDuring adolescence, sleep and circadian timing shift later, contributing to restricted sleep duration and irregular sleep-wake patterns. The association of these developmental changes in sleep and circadian timing with cognitive functioning, and consequently academic outcomes, has not been examined prospectively. The role of ambient light exposure in these developmental changes is also not well understood. Here, we describe the protocol for the Circadian Light in Adolescence, Sleep and School (CLASS) Study that will use a longitudinal design to examine the associations of sleep-wake timing, circadian timing and light exposure with academic performance and sleepiness during a critical stage of development. We also describe protocol adaptations to enable remote data collection when required during the COVID-19 pandemic.MethodsApproximately 220 healthy adolescents aged 12-13 years (school Year 7) will be recruited from the general community in Melbourne, Australia. Participants will be monitored at five 6 monthly time points over 2 years. Sleep and light exposure will be assessed for 2 weeks during the school term, every 6 months, along with self-report questionnaires of daytime sleepiness. Circadian phase will be measured via dim light melatonin onset once each year. Academic performance will be measured via national standardised testing (National Assessment Program-Literacy and Numeracy) and the Wechsler Individual Achievement Test-Australian and New Zealand Standardised Third Edition in school Years 7 and 9. Secondary outcomes, including symptoms of depression, anxiety and sleep disorders, will be measured via questionnaires.DiscussionThe CLASS Study will enable a comprehensive longitudinal assessment of changes in sleep-wake timing, circadian phase, light exposure and academic performance across a key developmental stage in adolescence. Findings may inform policies and intervention strategies for secondary school-aged adolescents.Ethics and disseminationEthical approval was obtained by the Monash University Human Research Ethics Committee and the Victorian Department of Education. Dissemination plans include scientific publications, scientific conferences, via stakeholders including schools and media.Study datesRecruitment occurred between October 2019 and September 2021, data collection from 2019 to 2023.

Project description:Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4) is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG) in melanopsin-deficient (Opn4(-/-)) mice under various light-dark (LD) schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7-10 Hz) and gamma (40-70 Hz) activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4(-/-) mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-hratio1-h schedule revealed that the failure to respond to light in Opn4(-/-) mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN) and in sleep-active ventrolateral preoptic (VLPO) neurons was importantly reduced in Opn4(-/-) mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4(-/-) mice slept 1 h less during the 12-h light period of a LD 12ratio12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4(-/-) mice for most of the (subjective) dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4(-/-) mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior.

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

Publications

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

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