The analogue and digital clock: Role and mechanisms of analogue signalling in the brain's master circadian clock and its outputs.

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Circadian (~24h) rhythms pervade many aspects of our physiology and behaviour. For example, our body shows daily variation or rhythms in metabolism, cognition, cardiovascular output, hormonal production, arousal, and the sleep-wake cycle. Disruption of these rhythms as a result of our modern 24h society lifestyles (e.g. chronic jet-lag or shift-work) can have wide implications for some serious illnesses, such as mental health, metabolic syndrome, cardiovascular disease, sleep disorders, and cancer. In mammals, including humans, circadian rhythms are orchestrated by a master circadian clock within the brain, called the suprachiasmatic nucleus (SCN), through the rhythmic and synchronised activity of the so-called core clock genes/proteins (the molecular clock). It was long believed that in order to coordinate circadian rhythms in our body, SCN neurons discharge a type of electrical signal called action potentials (APs: an all or nothing digital code), whose frequency increases during the day and falls at night. However, we now know that there are at least two types of SCN neurons, those that contain the molecular clock (clock neurons), and those that do not (non-clock neurons). We also know that the digital peak of firing activity during the day is, in fact, mostly the activity of non-clock neurons. Remarkably, throughout most of the day, clock neurons become so excited (hyperexcited) that they stop generating APs, and instead, they start signalling with a continuous wave, the "analogue" code. Since this analogue code is the electrical output of clock neurons, we argue here that it must be critical for the overall functioning of the SCN and circadian timekeeping. Sadly, as yet, unlike its digital counterpart, the role of analogue signalling in SCN function remains unknown. In this proposed work, we will use state-of-the-art tools previously unavailable in neuroscience research, to investigate the importance of analogue signalling in the SCN, by examining the crucial link between the clock and non-clock neurons. We will also examine the signal that is emitted by clock neurons when they start communicating in the analogue code, and investigate how this cooperates with the non-clock digital signal to broadcast circadian timing to the brain and body. This work will bridge a critical neurophysiological knowledge-gap in our understanding of the functional relationship between the molecular clock and SCN neuronal activity. The results will provide a step change in our knowledge of how circadian rhythms are generated and communicated in the SCN, and signalled to its brain targets. This will arm us with the necessary knowledge of how to fix a "broken clock" following disruptions, as during jet-lag, shift work, disease and ageing.