The internal time-giver role of melatonin. A key for our health

doi:10.1016/j.neurol.2014.05.008

Revue Neurologique

Volume 170, Issue 11, November 2014, Pages 646-652

https://doi.org/10.1016/j.neurol.2014.05.008 Get rights and content

Abstract

Daily rhythms in physiological and behavioural processes are controlled by a network of circadian clocks. In mammals, at the top of the network is a master clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The nocturnal synthesis and release of melatonin by the pineal gland are tightly controlled by the SCN clock. Several roles of melatonin in the circadian system have been identified. As a major hormonal output, melatonin distributes temporal cues generated by the SCN to the multitude of tissues expressing melatonin receptors. In some target tissues, these melatonin signals can drive daily rhythmicity that would otherwise be lacking. In other target structures, melatonin signals are used for the synchronization (i.e., adjustment of the timing of existing oscillations) of peripheral oscillators. Due to the expression of melatonin receptors in the SCN, endogenous melatonin is also able to feedback onto the master clock. Of note, pharmacological treatment with exogenous melatonin can synchronize the SCN clock. From a clinical point of view, provided that the subject is not exposed to light at night, the daily profile of circulating melatonin provides a reliable estimate of the timing of the human SCN. During the past decade, a number of melatonin agonists have been developed. These drugs may target the SCN for improving circadian timing or act indirectly at some downstream level of the circadian network to restore proper internal synchronization.

Résumé

Les rythmes circadiens dépendent d’un réseau complexe d’horloges centrales et périphériques, de synchronisateurs environnementaux, d’afférences et efférences nerveuses et endocrines, bref d’un système circadien multi-oscillant complexe. Chez les mammifères, le chef, d’orchestre de ce réseau est l’horloge présente dans les noyaux suprachiasmatiques de l’hypothamus (SCN). Les SCN génèrent des rythmes circadiens d’environ 24 h mais sont entraînables à 24 h précise (remis à l’heure) par divers synchroniseurs. Le synchroniseur le plus puissant est le cycle jour/nuit. Chez les mammifères, à partir des SCN, les informations circadiennes sont transportées par voies nerveuses en particulier à la pinéale. Dans cette glande, le message nerveux est traduit en un message hormonal : la sécrétion rythmique de mélatonine. La mélatonine distribue donc un signal circadien hormonal dans tout l’organisme via la circulation générale. Comme il y a des récepteurs pour la mélatonine dans les SCN, il est possible, à partir de mélatonine exogène, d’agir sur les SCN. Au cours de la dernière décennie, un certain nombre d’agonistes ont été développés et mis sur le marché. Ces médicaments ciblent les SCN ou agissent indirectement à d’autres niveaux du réseau circadien pour rétablir une bonne synchronisation interne de nos fonctions.

Section snippets

The circadian system: a complex network of circadian clocks/oscillators

Daily rhythms in physiological and behavioural processes are a common feature in living organisms. They do not correspond to a passive consequence of cyclic fluctuations in the environment, but rely on a complex network comprising circadian clocks, synchronizing inputs, various outputs as well as multiple central and peripheral oscillators [6], [7], [8]. This circadian network permits optimal and anticipatory temporal organization of biological functions in relation to periodic changes of the

Sites and mechanisms of action mediating the chronobiotic effects of melatonin

Due to the lipophilic nature of MEL able to enter any tissue and cellular compartments, actions elicited via interactions with specific intracellular proteins or with putative nuclear receptors have been proposed [49]. As for other hormones, MEL exerts its effect primarily through G protein-coupled receptors [50]. Cloning studies have revealed at least three MEL receptor subtypes, two of which are found in mammals, MT1 and MT2, localized in the central nervous system and in peripheral tissues.

Conclusions and perspectives

As discussed in this article, the correct timing of different functions in an organism relative to the timing of the different organ functions (e.g., daily food intake should be precisely coordinated with the daily functioning of the glucose-insulin axis, or appropriate timing of sleep-wake cycle with the light/dark cycle), depends on a complex circadian network. Acting on this network to promote proper internal synchronization of functions is one of the strategies to treat, prevent or delay

Disclosure of interest

The author declares that he has no conflicts of interest concerning this article.

Acknowledgements

The author is grateful to Dr David Hicks for editorial corrections. Our studies were supported by a general grant from the CNRS.

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Update in neurosciencesThe internal time-giver role of melatonin. A key for our healthLa mélatonine, un donneur de temps interne : une clé pour la santé chez l’Homme

Abstract

Résumé

Section snippets

The circadian system: a complex network of circadian clocks/oscillators

Sites and mechanisms of action mediating the chronobiotic effects of melatonin

Conclusions and perspectives

Disclosure of interest

Acknowledgements

Neurosci Biobehav Rev

Prog Mol Biol Transl Sci

Prog Mol Biol Transl Sci

J Biol Chem

Brain Res

Eur J Pharmacol

Sleep Med Rev

Behav Brain Res

Sleep Med

Neuron

Neuroscience

Neuroscience

Neurosci Lett

Circadian clocks and metabolism

Handb Exp Pharmacol

Night work and risk of breast cancer night work and risk of breast cancer

Epidemiology

High-fat feeding alters the clock synchronization to light

J Physiol

Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocytes

Obes Rev

Central and peripheral circadian clocks in mammals

Annu Rev Neurosci

Brain clocks: from the suprachiasmatic nuclei to a cerebral network

Neuroscientist

The mammalian circadian timing system: organization and coordination of central and peripheral clocks

Ann Rev Physiol

Interactions between photic and nophotic stimuli to synchronize the mammalian circadian clock

Front Biosci

Molecular components of the Mammalian circadian clock

Handb Exp Pharmacol

The cerebellum harbors a circadian oscillator involved in food anticipation

J Neurosci

Period2 luciferase real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues

Proc Natl Acad Sci USA

Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting

Cell Tissue Res

The melatonin

Dialogues Clin Neurosci

Generation of the melatonin endocrine message in mamals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides and other pineal transmitters

Pharmacol Rev

Melaton characteristics concerns prospects

J Biol Rhythms

Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing

Eur J Neurosci

Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway

J Comp Neurol

Suprachiasmatic control of melatonin synthesis in rats: inhibitory and stimulatory mechanisms

Eur J Neurosci

Update in neurosciences
The internal time-giver role of melatonin. A key for our healthLa mélatonine, un donneur de temps interne : une clé pour la santé chez l’Homme