The supraoptic nucleus as a key brain hub in the circadian and light control of the sleep-wake cycle.

Intrinsic circadian rhythms and associated daily rhythms in light exposure pervade essentially all aspects of physiology and behaviour. Nowhere is this more apparent than in our daily sleep and wake cycles, a known critical determinant of health, wellbeing, and productivity. It is alarming, therefore, that there is a widespread prevalence of circadian and sleep disturbances across the population, driven in no small part by our modern lifestyles (reduced daylight exposure and greatly increased exposure to light at night, shift work, jetlag, etc.) and associated with increased risks of chronic disease (e.g. diabetes, cardiovascular disease and various forms of cancer) and reduced quality of life. Despite many decades of research, understanding of the brain mechanisms involved in the daily regulation of our sleep-wake cycles remains incomplete. Building on recent developments in the field and our exciting new preliminary data, this proposal will directly address these issues to provide new insight into the mechanism by which light and the circadian system regulate daily sleep-wake cycles, with the potential to open new avenues reducing circadian/sleep disturbances in humans and animals and, therefore, of direct relevance to BBSRC strategic priorities of 'Healthy ageing across the life course' and 'Animal Health'.

Until recently it seemed all the key sleep-promoting brain regions had been identified. Remarkably, however, recent advances in intersectional genetic approaches have identified a brain region that had previously only been viewed as an accessory structure associated with sleep-related physiological changes (e.g., osmoregulation), as a critical regulator of the sleep-wake cycle - the supraoptic nucleus (SON). Indeed, direct activations of a specific population of SON neurons strongly promote slow-wave sleep, whereas conditional ablation or suppression caused diminished sleep.

Cells of the SON express the molecular circadian clock machinery and we show these cells sustain intrinsic rhythms in electrical activity and receive strong and direct circadian signals from the mammalian master circadian clock, the suprachiasmatic nucleus (SCN). Given that the SON also receives direct retinal input and is well-connected to other known sleep-wake centres of the brain, we propose the SON is a previously overlooked key brain hub for the daily/circadian control of the sleep-wake cycle.

Here, we draw on the complementary skills and expertise of the project team to comprehensively test this overarching hypothesis, by combining innovative approaches for brain circuit manipulation and mapping, in and ex vivo, sophisticated machine-learning and data assimilation mathematics, with comprehensive physiological and behavioural measurements, both in mice and our powerful new day-active rodent model (Rhabdomys). Using these approaches, we will: 1) Comprehensively map the intrinsic ionic mechanisms driving daily excitability rhythms in the SON sleep regulatory neurons; 2) Define how circadian and light information via SCN and retinal inputs in processed and integrated across the SON network; 3) Confirm the roles of SCN and retinal inputs to SON in regulating the sleep-wake cycles in behaving mice and 4) Identify mechanisms responsible for the inverted relationship between sleep and the environmental light-dark cycle in day vs. night-active mammals.

Collectively, we expect this work to drive a step-change in our understanding of the brain mechanisms responsible for daily and circadian control of the sleep-wake cycle and much-needed insights into how these mechanisms differ between nocturnal and diurnal mammals (such as ourselves), with the potential to inform future practical applications intended to promote human or animal health.