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Wiley, Journal of Neuroendocrinology, 1(26), p. 2-10, 2014

DOI: 10.1111/jne.12125

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Circadian Pacemaking in Cells and Circuits of the Suprachiasmatic Nucleus

Journal article published in 2014 by Michael H. Hastings, Marco Brancaccio ORCID, Elizabeth S. Maywood
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co-ordinates the daily rhythms of sleep and wakefulness, physiology and behaviour that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet-lag but more insidiously with rotational shift-work, can have severely deleterious effects for mental function and long-term health. This review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time-keeper. It first focuses on the intra-cellular transcriptional/post-translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neuron. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca(2+) ]i ) which are both outputs from, and inputs to, the TTFL, and the critical role of VIP signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 hours) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G-protein-coupled signalling in individual SCN neurons, and how manipulation of Gq/[Ca(2+) ]i -signalling in VIP neurons can re-programme the circuit-level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively few gene products, operating in a clearly defined neuronal circuit, with both cell-autonomous and emergent, circuit-level properties. This article is protected by copyright. All rights reserved.