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An introduction to circadian molecular clockworks

Michael Hastings
MRC Laboratory of Molecular Biology, University of Cambridge , UK

Circadian rhythms, the most evident of which is the cycle of sleep and wakefulness, are a basic feature of behaviour and metabolism. Indeed it is difficult to imagine a more fundamental and profound alteration of neural state than sleep and wake, and yet it occurs with remarkable regularity and precision. The central pacemaker driving sleep and other daily cycles resides within the suprachiasmatic nuclei (SCN) of the hypothalamus. Individual SCN neurons act as circadian clocks, driven by an intra-cellular molecular oscillator based upon transcriptional/ post-translational negative feedback loops in which expression of the “clock” genes Period and Cryptochrome is periodically inhibited by their own protein products. The SCN clock is synchronised to solar time by direct glutamatergic retinal innervation. The molecular oscillations at the heart of the clock can be monitored in real-time by bioluminescence and fluorescence imaging of reporter genes driven by elements of the Period promoter. Neuropeptidergic signalling between SCN neurons is necessary not only to synchronise them but also to maintain the high amplitude of circadian gene expression. This cellular clockwork of the SCN is recapitulated in peripheral tissues and numerous brain regions, such that isolated organotypic slice cultures of (inter alia) kidney, lung, hippocampus and cerebellum also show spontaneous circadian gene expression. This identification of autonomous circadian clocks within various brain regions raises interesting questions about their organisation and function. In vivo these local clocks will be synchronised by the SCN such that local time is matched to solar time and the brain as a whole follows a single coherent temporal programme. The output factors of the SCN that mediate this synchronisation include neuropeptidergic signals to diencephalic structures regulating arousal. By analogy with studies of peripheral clocks, it is likely that the local brain clocks co-ordinate temporal programmes of gene expression that encompass 10- 20% of the local transcriptome/ proteome. Our working hypothesis is that these daily cycles of gene expression up- and down-regulate pathways involved in attention, synaptic plasticity and memory consolidation. Hence, local neural circuits are pre-adapted biochemically to the alternating demands of sleep and wakefulness, thereby enhancing their function. Furthermore, disorders of the local circadian programme may contribute to cognitive and affective disturbances associated with shift work and neurological and psychiatric diseases.