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Circadian Timekeeping in the Suprachiasmatic Nucleus: Genes, Neurotransmitters, Neurons, and Astrocytes

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Neuroendocrine Clocks and Calendars

Part of the book series: Masterclass in Neuroendocrinology ((MANEURO,volume 10))

Abstract

The nocturnal secretion of melatonin by the pineal gland drives photoperiodic seasonal rhythms in mammals. In turn, the pineal is controlled by daily cues generated intrinsically by the circadian (circa- approximately, −diem a day) clock of the hypothalamic suprachiasmatic nucleus (SCN). Photic cues from the retina both synchronize the SCN and also acutely suppress melatonin synthesis. As a result, the duration of the nocturnal secretion of melatonin encodes the length of the night and hence season. This chapter will consider recent developments in understanding how the SCN generates an internal representation of solar time and thereby functions as a clock and calendar. The first level of timekeeping pivots around intracellular transcriptional and translational feedback loops (TTFLs) that constitute cell-autonomous circadian timers. These mechanisms are common to many, if not all, mammalian tissues, but three properties beyond its TTFLs make the SCN the principal pacemaker. First, it is the sole component of the mammalian circadian system to receive retinal input and is therefore directly entrained to the cycle of day and night. The TTFLs of SCN cells are therefore a high-fidelity, internal proxy of solar time. Second, its neural connections to the hypothalamus and beyond enable the SCN to direct rhythmic endocrine (including melatonin) and autonomic and behavioral rhythms that in turn coordinate the innumerable cellular and tissue-based clocks distributed across the body. Third, the timekeeping power that enables the SCN to sustain this internal coordination is derived from the circuit-level integration of the ~20,000 neurons into a robust and resilient circuit-level pacemaker. Activity across the cellular TTFLs is tightly synchronized but not simultaneous, as cells peak in activity in different phases. Importantly, this network-level pattern of activity is plastic, the long days of summer increasing the phase dispersal between cells. This response of the SCN to daylength causes a reciprocal widening or narrowing of the dependent melatonin profile. The daily clock thereby generates an internal representation of season. The intercellular mechanisms that underpin network integration are twofold. First, neuropeptidergic cues released from various populations of SCN neurons act in a slow paracrine manner, over circadian time and SCN circuit space, to synchronize and amplify the individual intracellular TTFLs. Second, it has recently become clear that astrocytes play an important role in network function, as they are able to initiate SCN neuronal oscillations and behavioral circadian rhythms and impose their own cell-autonomous period. Analysis of the network-level interactions between neurons and astrocytes will therefore advance understanding of how both circadian and seasonal information is encoded and distributed by the SCN.

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Acknowledgements

MH was supported by the Medical Research Council, U.K. MC_U105170643. MB was supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

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  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Michael H. Hastings

  2. Department of Brain Sciences, UK Dementia Research Institute at Imperial College London, London, UK

    Marco Brancaccio

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Correspondence to Michael H. Hastings .

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  1. School of Life Sciences, University of Nottingham, Nottingham, UK

    Francis J. P. Ebling

  2. School of Life Sciences, University of Bristol, Bristol, UK

    Hugh D. Piggins

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Hastings, M.H., Brancaccio, M. (2020). Circadian Timekeeping in the Suprachiasmatic Nucleus: Genes, Neurotransmitters, Neurons, and Astrocytes. In: Ebling, F.J.P., Piggins, H.D. (eds) Neuroendocrine Clocks and Calendars. Masterclass in Neuroendocrinology, vol 10. Springer, Cham. https://doi.org/10.1007/978-3-030-55643-3_11

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