Review Paper
Melatonin: Both master clock output and internal time-giver in the circadian clocks network

https://doi.org/10.1016/j.jphysparis.2011.07.001Get rights and content

Abstract

Daily rhythms in physiological and behavioral processes are controlled by a network of circadian clocks, reset by inputs and delivering circadian signals to the brain and peripheral organs. In mammals, at the top of the network is a master clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, mainly reset by ambient light. The nocturnal synthesis and release of melatonin by the pineal gland are tightly controlled by the SCN clock and inhibited by light exposure. 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 tissue targets expressing melatonin receptors. In some target structures, like the Pars tuberalis of the adenohypophysis, 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, such as the fetal adrenal gland. Due to the expression of melatonin receptors in the SCN, endogenous melatonin is also able to feedback onto the master clock, although its physiological significance needs further characterization. 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 for treating circadian, psychiatric and sleep disorders. 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.

Highlights

► New vista on the circadian clocks network in mammals. ► Melatonin: both a master clock output and an internal time-giver. ► Nervous and endocrine pathways involved in the distribution of circadian signals. ► Role of endogenous melatonin in the circadian system of mammals. ► Chronobiotic effects of exogenous melatonin.

Introduction

In humans, disorders of rhythmicity are characteristic of, and may underlie, a variety of troubles. For example, sleep and circadian rhythms are often disrupted in neurological disorders. Increasing evidence indicates that alterations in the sleep/wake cycle is associated with (or may be responsible for) many types of neurological or psychiatric disorders. Epidemiological studies demonstrate that altered re-synchronization to local time (jet-lag or shift-work rotation) has deleterious consequences and is often associated with general malaise (especially insomnia), decrements in work productivity and increases in accidents. This field of research is rapidly expanding, and disturbances of circadian functions are also known to impair processes resulting in metabolic disorders (obesity, diabetes, hypercholesteremia), as well as cardiovascular disease and cancer (Karlsson et al., 2003, Schernhammer et al., 2006, Sookoian et al., 2007, Dochi et al., 2009). The importance of circadian (also seasonal) rhythmicity for human health and welfare is becoming increasingly recognized. Developing counteractive strategies to treat, prevent or delay such disturbances is a new challenge for science and medicine. This task requires a more complete knowledge of the circadian timing system. Nowadays, it is known that a complex multi-oscillatory circadian network governs optimal and anticipatory temporal organization of functions. During the past decade, the prospects of manipulating the melatonin system to treat patients have been enhanced. In this review, we will present the circadian system and further detail the role of melatonin in regulating clock-controlled circadian rhythms.

Section snippets

The mammalian circadian system: a network of circadian clocks

Daily rhythms in physiological and behavioral processes are a common feature in living organisms. These rhythms are not just a passive consequence of cyclic fluctuations in the environment, but relies on a complex network comprising circadian clocks, synchronizing inputs, various outputs as well as multiple central and peripheral oscillators (Takahashi, 2004, Mendoza and Challet, 2009, Dibner et al., 2010). This circadian network permits optimal and anticipatory temporal organization of

Nervous and endocrine pathways involved in the distribution of circadian signals

Today, physiological and anatomical evidence shows that the SCN conveys its circadian signals by using different humoral and hormonal cues, neural connections, and rhythmic behavioral cues (Buijs and Kalsbeek, 2001, Buijs et al., 2003, Kalsbeek et al., 2006b)

The restoration within a week of the circadian rhythm of locomotor activity and drinking behavior in SCN-lesioned animals, after having received encapsulated SCN grafts (Silver et al., 1996) proved that the SCN distributes part of its

SCN control of the rhythmic synthesis of pineal melatonin

The chemical nature of this hormone isolated in 1958 from bovine pineal was identified as N-acetyl-5-methoxytryptamine (Lerner et al., 1960). Briefly, Mel is synthesized from the amino-acid tryptophan which is first converted into 5-hydroxytryptophan by tryptophan-hydroxylase before being decarboxylated into serotonin. From serotonin two major enzymatic steps are then involved. The first step is N-acetylation by the arylalkylamine-N-acetyltransferase (AA-NAT) to yield N-acetylserotonin. The

Conclusions and perspectives

We now know that disorders of rhythmicity are characteristic of a variety of pathologies (e.g., psychiatry disorders, metabolic alterations). It is also known that disturbed circadian rhythmicity, whether due to living conditions (e.g., shift-work, jet-lag) or natural circumstances (e.g., aging) can promote the development of specific pathologies (sleep disorders and metabolic perturbations such as obesity, diabetes, hypercholesteremia, cardiovascular diseases and cancer). A snowball effect is

Acknowledgments

The authors are grateful to David Hicks for correction of the language; Our studies were supported by grants from the Centre National de la Recherche Scientifique (P.P. and E.C.) and Agence Nationale pour la Recherche/jeunes chercheurs (E.C).

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