Human Circadian Rhythms: Developing a Multi-Oscillator Framework

Human function is a result of a carefully orchestrated, hierarchical, multi-oscillator system that interacts with environmental cues.  This oscillator system results in and is comprised of daily (circadian) rhythms in transcription and translation, physiological and behavioural cycles including, core body temperature, melatonin secretion, blood pressure the sleep/wake cycle and cycles of feeding and fasting. It is increasingly recognised that disruption to this oscillator system has serious health consequences.

At this point, there is a working model of how oscillations occur at the individual cellular level where oscillations in protein abundance occur as result of translation/transcription feedback loops to create a circadian clock.  How these individual cellular clocks are coordinated is more controversial, with research suggesting that the suprachiasmatic nuclei (SCN) in the brain act as a master clock but also strong evidence for peripheral pacemakers in major organs such as the lungs, liver, pancreas and spleen that help explain systematic phase differences between processes in different organs. It is known that a circadian clock is a key component to understanding sleep/wake regulation and that at least two circadian oscillators are involved in generating the sleep-wake cycle but the precise mechanism by which oscillations at the cellular level cause behavioural changes at the whole body level is unclear.   Furthermore, it is known that environmental factors such as light and temperature, endogenous factors such as age and health and sociological factors such as sleep/wake timing, exercise, nutrition, alcohol and drugs all play a role in determining overt circadian rhythms.  For example, recent research has demonstrated that not only can changes in the circadian clock result in changes in the sleep/wake cycle, but that changing the sleep/wake cycle can substantially disrupt the clock.   In rats, it has been shown that the phase of peripheral clocks in the liver is more strongly affected by the timing of nutrition than by cues from the SCN. Finally, physiological consequences of behaviour, such as changes in body temperature associated with the sleep-wake cycle, or changes in hormones such as cortisol, associated with fasting or stress, can affect core molecular elements of the circadian clock.

If we are to develop a deep understanding of real world behaviour of the circadian system then it is time to consolidate existing knowledge and recognise that the architecture of the full hierarchical, coupled system needs to be considered.  In other words, how do oscillations in different cells result in coordinated oscillations at the level of an organ?  How are oscillations in different organs coupled to lead to rhythms at the whole body level?  How do rhythms at the whole body level in turn affect oscillations at smaller scales? How do environmental, endogenous and sociological factors act to influence overt circadian rhythmicity?

The aim of this workshop is to bring experimentalists and modellers together from different communities, all interested in modelling human circadian rhythms but from different perspectives. There will be an emphasis on considering integrative approaches in which oscillators are viewed within the context of the whole organism and the complexity of the environment with which it interacts.