A time to every purpose: SCN cell-specific control of daily physiological timing

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Almost every bodily function is influenced by a dominant biological clock within the brain, the suprachiasmatic nucleus (SCN). The timing information provided by the SCN serves to optimise our internal physiology in anticipation of expected demands across the 24h day. Since the timing of peak demand varies between different behavioural or physiological processes (e.g. sleep, cardiovascular and gastrointestinal), particular aspects of physiology need to be individually timed to ensure health and well-being. The impact of temporary disruptions to this internal coordination will be familiar to anyone who has experienced jet-lag. Unfortunately, it is now clear that longer-term disruptions to our internal timing mechanism are associated with a number of serious health consequences including increased risk of cancer and metabolic disease. Accordingly, here we seek to understand the biological mechanisms by which the SCN clock coordinates activity across the rest of brain and body, and how this is disturbed during shifts in the environment. In particular, we will determine whether the ability of the SCN clock to differentially control so many different aspects of physiology stems from the presence of multiple subsets of 'clock cells', each with unique properties. In support of this view, it is well known that clock cells produce a variety of different neurochemical messengers and/or send signals to different regions of the brain. Our own recent work indicates that the functional properties of clock cells are also diverse, with different groups of clock cells becoming electrically active at different times of day. Similarly, it is well established that the major signal required for synchronising the SCN clock to the external world is supplied by the retina, and we and others have now identified various groups of clock cells that exhibit distinct responses to changes in lighting conditions. Until now a major impediment to answering this fundamental question as to how the SCN orchestrates physiology has been an inability to directly connect the functional properties of particular subgroups of clock cells to specific aspects of physiology. Recent advances in viral and genetic targeting now make this goal achievable. We will employ these cutting-edge approaches to allow us to selectively identify and monitor the activity of groups of clock cells communicating to specific brain regions and/or producing particular chemical messengers. We will thus be able to determine the nature of the timing signals supplied to key regulatory centres across the brain and how these are influenced by short or longer term changes in the light environment. We will then use similar approaches to specifically manipulate the activities of the these cell groups during comprehensive physiological and behavioural monitoring, allowing us to unequivocally link the activity of particular groups of SCN cells to specific body functions (such as metabolic rate, feeding behaviour, heart rate, etc).This project will produce a crucial advance in our understanding of how our internal clock influences the rest of the body. Moreover, by determining how the activities of various groups of SCN cells are influenced by changes in light environment, this work will also provide new insight into the mechanistic basis of the physiological disruptions that occur as a result of shift work or crossing time zones. Finally, we expect this work to uncover new ways of using light to selectively adjust the activities of specific SCN cell groups with particular physiological roles. Such strategies that could be of substantial practical benefit to the wide sections of society whose internal clocks are misaligned with their societally imposed schedules.