In mammals, the exact role of melatonin (Mel) in the circadian timing system remains to be determined. However, exogenously administered Mel, as reported in the present mini-review, has been shown to affect the circadian clock. The sites and mechanisms of action involved in this "chronobiotic" effect of Mel have begun to be characterized. The suprachiasmatic nuclei (SCN) appear to be an important site for the entrainment effect of Mel and the presence of Mel receptors appears to be a prerequisite. However, the pharmacological dose of Mel needed to entrain circadian rhythms means that very probably other sites and mechanisms also play a role.

Melatonin, an important marker of the endogenous rhythmicity in mammals, also plays a role in the body defence against pathogens and injuries. In vitro experiments have shown that either pro- or anti-inflammatory agents, acting directly in the organ, are able to change noradrenaline-induced pineal indoleamine production. Whereas corticosterone potentiates melatonin production, incubation of the gland with tumour necrosis factor-alpha decreases pineal hormonal production. In the present study, we show that nocturnal melatonin production measured by intra-pineal microdialysis is enhanced in pineals perfused with corticosterone at concentrations similar to those measured in inflamed animals. In vitro experiments suggest that this enhancement may be due to an increase in the activity of the two enzymes that convert serotonin to N-acetylserotonin (NAS) and NAS to melatonin. The present results support the hypothesis that the pineal gland is a sensor of inflammation mediators and that it plays a central role in the control of the inflammatory response.

In wild mammals, offspring development must anticipate forthcoming metabolic demands and opportunities. Within species, different developmental strategies may be used, dependent on when in the year conception takes place. This phenotypic flexibility is initiated before birth and is linked to the pattern of day length (photoperiod) exposure experienced by the mother during pregnancy. This programming depends on transplacental communication via the pineal hormone melatonin. Here, we show that, in the Siberian hamster (Phodopus sungorus), the programming effect of melatonin is mediated by the pars tuberalis (PT) of the fetal pituitary gland, before the fetal circadian system and autonomous melatonin production is established. Maternal melatonin acts on the fetal PT to control expression of thyroid hormone deiodinases in ependymal cells (tanycytes) of the fetal hypothalamus, and hence neuroendocrine output. This mechanism sets the trajectory of reproductive and metabolic development in pups and has a persistent effect on their subsequent sensitivity to the photoperiod. This programming effect depends on tanycyte sensitivity to thyroid stimulating hormone (TSH), which is dramatically and persistently increased by short photoperiod exposure in utero. Our results define the role of the fetal PT in developmental programming of brain function by maternal melatonin and establish TSH signal transduction as a key substrate for the encoding of internal calendar time from birth to puberty.photoperiodism | developmental programming | hypothalamus | pars tuberalis | thyroid

In mammals, the complex interaction of neural, hormonal, and behavioral outputs from the suprachiasmatic nucleus (SCN) drives circadian expression of events, either directly or through coordination of the timing of peripheral oscillators. Melatonin, one of the endocrine output signals of the clock, provides the organism with circadian information and can be considered as an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and to maintain their mutual phase-relationship at the different levels of the circadian network. Moreover, exogenous melatonin, through an action on the circadian clock, affects all levels of the circadian network. The molecular mechanisms underlying this chronobiotic effect have also been investigated in rats. REV-ERB alpha seems to be the initial molecular target.

Allali KE, Achaâban MR, Bothorel B, Piro M, Bouâouda H, Allouchi ME, Ouassat M, Malan A, Pévet P. Entrainment of the circadian clock by daily ambient temperature cycles in the camel (Camelus dromedarius). Am J Physiol Regul Integr Comp Physiol 304: R1044 -R1052, 2013. First published March 13, 2013 doi:10.1152/ajpregu.00466.2012.-In mammals the light-dark (LD) cycle is known to be the major cue to synchronize the circadian clock. In arid and desert areas, the camel (Camelus dromedarius) is exposed to extreme environmental conditions. Since wide oscillations of ambient temperature (Ta) are a major factor in this environment, we wondered whether cyclic Ta fluctuations might contribute to synchronization of circadian rhythms. The rhythm of body temperature (Tb) was selected as output of the circadian clock. After having verified that Tb is synchronized by the LD and free runs in continuous darkness (DD), we submitted the animals to daily cycles of Ta in LL and in DD. In both cases, the Tb rhythm was entrained to the cycle of Ta. On a 12-h phase shift of the Ta cycle, the mean phase shift of the Tb cycle ranged from a few hours in LD (1 h by cosinor, 4 h from curve peaks) to 7-8 h in LL and 12 h in DD. These results may reflect either true synchronization of the central clock by Ta daily cycles or possibly a passive effect of Ta on Tb. To resolve the ambiguity, melatonin rhythmicity was used as another output of the clock. In DD melatonin rhythms were also entrained by the T a cycle, proving that the daily T a cycle is able to entrain the circadian clock of the camel similar to photoperiod. By contrast, in the presence of a LD cycle the rhythm of melatonin was modified by the T a cycle in only 2 (or 3) of 7 camels: in these specific conditions a systematic effect of T a on the clock could not be evidenced. In conclusion, depending on the experimental conditions (DD vs. LD), the daily T a cycle can either act as a zeitgeber or not.camel; circadian clock; body temperature; daily ambient temperature; melatonin; nonphotic entrainment RHYTHMICITY in physiological processes is a fundamental property of all living organisms (32). A number of biological functions display daily and seasonal variations in a way to anticipate and adapt to the upcoming cycling changes in environment (light, temperature, food availability, etc.). In mammals, the circadian clock, located in the suprachiasmatic nuclei of the hypothalamus (SCN), is central for these adaptive processes. This clock is a strong autonomous oscillator cycling with a period close to 24 h under constant conditions (23) and entrained by environmental cues to an exact period of 24 h. Thus SCN play a pivotal role to control numerous circadian biological rhythms such as those of body temperature (T b ), melatonin, or behavioral features. In all mammals studied, the light-dark cycle is the most powerful synchronizer (zeitgeber) of the master clock (for a review see Ref. 15). T b rhythm represents a robust output of the clock, widely used in clinical research to determine pro...

Relatively little is known about the function of the biological clock and its efferent pathways in diurnal species, despite the fact that its major transmitters and neuronal connections are also conserved in humans. The mammalian biological clock is located in the hypothalamic suprachiasmatic nuclei (SCN). Several lines of evidence suggest that the activity cycle of the SCN itself is similar in nocturnal and diurnal mammals. Previously, we showed that, in the rat, vasopressin (VP) derived from the SCN has a strong inhibitory effect on the release of adrenal corticosterone and is an important component in the generation of a daily rhythm in plasma corticosterone concentrations. In the present study we investigated the role of VP in the control of the daily corticosterone rhythm in a diurnal rodent, i.e. Arvicanthis ansorgei. Contrary to our previous (rat) results, VP administered to the hypothalamic paraventricular nucleus in A. ansorgei had a stimulatory effect on the release of corticosterone. Moreover, both the morning and evening rise in corticosterone were blocked by the administration of a VP receptor antagonist. These results show that with regard to the circadian control of the corticosterone rhythm in diurnal and nocturnal rodents, temporal information is carried along the same pathway from the SCN to its target areas, but the response of the target area may be quite different. We propose that the reversed response to VP is due to a change in the phenotype of the target neurons that are contacted by the SCN efferents, i.e. glutamatergic instead of gamma-aminobutyric acid (GABA)ergic.

The effect of exogenous melatonin on pineal melatonin synthesis was studied in the rat in vivo. Daily melatonin profiles were measured by transpineal microdialysis over 4 consecutive days in rats maintained on a 12-h light : 12-h dark schedule (LD 12 : 12). Curve-fitting was used to determine the amplitude of the peak of melatonin production, and the times of its onset (IT50) and offset (DT50). A subcutaneous injection of melatonin (1 mg/kg) at the onset of darkness (ZT12) induced an advance of IT50 on the second day after the treatment, in 50% of the animals kept in LD. When the animals were switched to constant darkness, the treatment caused no detectable advance of IT50, while 70% of individuals showed a significant delay in DT50 2 days after the injection. Locally infusing the drug by reverse microdialysis into the suprachiasmatic nuclei (SCN) failed to enhance the shift in melatonin onset. Following subcutaneous melatonin injection, a significant increase ( approximately 100%) in melatonin peak amplitude was observed. This increase persisted over 2 days and occurred only when the melatonin was applied at ZT12, but not at ZT6, 17 or 22. The effect was also observed when the drug was infused directly into the SCN, but not into the pineal. Thus, the SCN are the target site for the effect of exogenous melatonin on the amplitude of the endogenous melatonin rhythm, with a similar window of sensitivity as its phase-shifting effect on the pacemaker.

In vivo trans-pineal microdialysis was performed in male Wistar rats maintained under a 12 hr light:12 hr dark (LD 12:12) cycle. Collected dialysates were assayed by radioimmunoassay for melatonin concentrations. A non-linear regression was fitted through the obtained datapoints to determine the time points at which a 50% increase (IT50) and decrease (DT50) of the nocturnal melatonin peak were reached. In a first experiment, the nocturnal melatonin profiles of four animals were determined throughout 5 consecutive days. In a second experiment, we analysed the melatonin profiles during the night in rats originating from three different breeding colonies (Dépré Harlan, and Iffa-Cŕedo). A low intraindividual variability was found on the phase markers IT50 and DT50, as on peak duration of melatonin rhythms estimated over 5 subsequent days in the same animal. In contrast, animals showed a large interindividual variability in their profile phase markers and the values were dependent on the origin of the breeding colony. Each rat colony was characterized by early or late IT50 and DT50 as long or short peak length. It is concluded from experiment 1 that the melatonin rhythm is a very stable circadian marker. Nevertheless, great caution must be taken in the choice of animal groups while studying circadian rhythms due to the large interindividual variability observed in experiment 2. Therefore, as the technique allows the use of the animal as its own control, the present study demonstrated that the use of the microdialysis technique is of interest in studies on the circadian system.