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Bureš lecture series "Circadian Clocks The genes, cells and circuits that time our lives"

Prof. Michael Hastings, MRC Laboratory of Molecular Biology, Cambridge, Great Britain

The alternation of our world between day and night presents us with a regular and predictable series of environmental challenges and opportunities.  To adapt to this, evolution has furnished us with daily rhythms of physiology and behaviour, the most obvious being the sleep and wakefulness cycle (SWC) that sustains energetic daytime engagement with the world and night-time withdrawal to allow rest, growth and repair.  Underlying and supporting the SWC, almost every aspect of our metabolism, brain function, endocrine and autonomic states proceed through a regular daily programme.  In essence, our body is a 24-hour machine and what it is pre-programmed to do in the day is very different from its capabilities at night.  An important observation is that even though our daily rhythms are ordinarily synchronised to the light/dark cycle, they are not caused by it.  Rather, when humans and experimental animals are isolated in a time-free environment of constant light, temperature etc., the SWC and its attendant rhythms continue to run with a period of approximately one day (hence, circa-dian).  This autonomy demonstrates that these rhythms are driven by an internal timing system, a biological clock.  In fact, we now know that our bodies contain innumerable cellular circadian clocks, the local actions of which give rise to daily rhythms of tissue function.  Embedded in an oscillatory network across the body, these local clocks are in turn synchronised by a central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus.  The SCN, in turn, is synchronised to the light/ dark cycle, so that internal circadian time maps on to external solar time and thereby ensures our temporal adaptation to the world.  Circadian time therefore pervades every level of biological organisation, from molecules to society.  By introducing the dimension of time to our analyses, alongside an improved understanding of its cellular mechanisms, we shall gain new insights into the basis of a healthy physiology.  Such knowledge also offers important opportunities to mitigate the consequences of circadian disruption, so prevalent in modern societies, that arise from shiftwork, ageing and neurodegenerative disease.  This presentation will therefore consider the molecular, cellular and physiological basis of the circadian clock of mammals, with a focus on the SCN as our primary pacemaker.  What is it that makes the 20,000 cells of the SCN such a powerful clock, that it is able to influence every aspect of our lives?



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