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Generation of circadian rhythms in the suprachiasmatic nucleus

Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus is remarkable. Despite numbering only about 10,000 neurons on each side of the third ventricle, the SCN is our principal circadian clock, directing the daily cycles of behaviour and physiology that set the tempo of our lives. When this nucleus is isolated in organotypic culture, its autonomous timing mechanism can persist indefinitely, with precision and robustness. The discovery of the cell-autonomous transcriptional and post-translational feedback loops that drive circadian activity in the SCN provided a powerful exemplar of the genetic specification of complex mammalian behaviours. However, the analysis of circadian time-keeping is moving beyond single cells. Technical and conceptual advances, including intersectional genetics, multidimensional imaging and network theory, are beginning to uncover the circuit-level mechanisms and emergent properties that make the SCN a uniquely precise and robust clock. However, much remains unknown about the SCN, not least the intrinsic properties of SCN neurons, its circuit topology and the neuronal computations that these circuits support. Moreover, the convention that the SCN is a neuronal clock has been overturned by the discovery that astrocytes are an integral part of the timepiece. As a test bed for examining the relationships between genes, cells and circuits in sculpting complex behaviours, the SCN continues to offer powerful lessons and opportunities for contemporary neuroscience.

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Fig. 1: Circadian organization in mammals.
Fig. 2: Circadian coupling between molecular feedback loops and neural signalling.
Fig. 3: Circuit-level time-keeping in the SCN: spatiotemporal heterogeneity, cell clusters and seasonal coding.
Fig. 4: Probing for pacemakers: how altering cell-autonomous clocks can affect behavioural and circuit-level SCN rhythms.
Fig. 5: A model of circadian astrocyte–neuronal interactions in the SCN.

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Acknowledgements

The authors are grateful to A. Patton, N. Smyllie and W. Schafer (MRC Laboratory of Molceular Biology (LMB)) and C. Partch (University of California, Santa Cruz) for very helpful discussions on the text and to P. Margiotta (MRC LMB) for graphic support. The work of the authors is supported by MRC funding to M.H.H. (MC_U105170643).

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The authors all researched data for the article, provided a substantial contribution to discussion of its content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Michael H. Hastings.

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Supplementary information

41583_2018_26_MOESM1_ESM.mov

Supplementary information (video): Representative combined time-lapse recording of PER2:; Luciferase-reported TTFL bioluminescence rhythm (cyan) and GCaMP-reported [Ca2+]i rhythms (green) in SCN organotypic slice. Note the phase difference between the two reporters and the phase dispersion between cells leading to regular progressive waves across the SCN circuit. Reproduced with permission from REF. 56, Elsevier.

Supplementary Box 1: Structural insights into the molecular clockwork explain circadian behaviour

Glossary

Emergent properties

Properties expressed at a circuit level that do not occur in isolated cells (for example, synchrony of cellular circadian gene expression, ensemble period and phase divergence).

Amplitude

The range from peak level to trough level of a circadian rhythm (for example, the range for gene expression or intensity of behavioural activity).

Ensemble period

The circadian period of oscillation shared by all SCN cells in the intact, synchronized circuit.

Synchrony

The temporal order of individual oscillators expressing a common period and stable phase relationships.

Phase dispersion

The range of phases present in a population of oscillators (for example, between rhythmic cells in an intact SCN circuit).

Circadian time

(CT). Internal temporal scale of a tissue or an individual expressing a free-running circadian cycle, with predicted dawn denoted as CT0 and the period of the entire cycle divided into 24 circadian hours.

Entrainment

A process whereby a rhythmic physical or biological cue sets the period and the phase of a circadian oscillation.

Small-world network

A naturally occurring network topology in which most nodes are directly connected to only a few neighbours (which facilitates local information processing as modules) with a few richly connected nodes (hubs) that facilitate integration between nodes and modules.

Hubs

Nodes in a network with higher-than-average connections.

Nodes

Individual elements in a network.

Cell-autonomous clock

The mechanism within most mammalian cells that enables them to express, independent of external cues, circadian cycles of gene expression and cellular metabolism.

Cre

Cre-recombinase enzyme that catalyses the site-specific recombination of DNA between loxP sites in a target gene.

Rich club

A restricted group of interconnected hubs in a network.

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Hastings, M.H., Maywood, E.S. & Brancaccio, M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 19, 453–469 (2018). https://doi.org/10.1038/s41583-018-0026-z

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