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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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).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
- 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).
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.
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.
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.
Nodes in a network with higher-than-average connections.
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-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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