Gut Microbiota Mediate the Neuroprotective Effect of Oolong Tea Polyphenols in Cognitive Impairment Induced by Circadian Rhythm Disorder.

Oolong tea polyphenols (OTP) have attracted wide attention due to their ability to reduce inflammatory response, regulate gut microbiota, and improve cognitive function. However, exactly how the gut microbiota modulates nervous system activity is still an open question. We previously expounded that supplementing with OTP alleviated neuroinflammation in circadian rhythm disorder (CRD) mice. Here, we showed that OTP can relieve microglia activation by reducing harmful microbial metabolites lipopolysaccharide (LPS) that alleviate CRD-induced cognitive decline. Mechanistically, OTP suppressed the inflammation response by regulating the gut microbiota composition, including upregulating the relative abundance of Muribaculaceae and Clostridia_UCG-014 and downregulating Desulfovibrio, promoting the production of short-chain fatty acids (SCFAs). Moreover, the use of OTP alleviated intestinal barrier damage and decreased the LPS transport to the serum. These results further inhibited the activation of microglia, thus alleviating cognitive impairment by inhibiting neuroinflammation, neuron damage, and neurotoxicity metabolite glutamate elevation. Meanwhile, OTP upregulated the expression of synaptic plasticity-related protein postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN) by elevating the brain-derived neurotrophic factor (BDNF) level. Taken together, our findings suggest that the OTP has the potential to prevent CRD-induced cognition decline by modulating gut microbiota and microbial metabolites.

Polymethoxyflavones in Citrus Regulate Lipopolysaccharide-Induced Oscillating Decay of Circadian Rhythm Genes by Inhibiting Nlrp3 Expression.

The aim of this study is to compare the regulatory abilities of citrus flavonoids on the oscillating expression of circadian genes. Seven varieties of citrus fruits and twenty-five citrus flavonoids were selected and evaluated. Per2 luciferase bioluminescence report system and serum shock were used to induce circadian gene expression in mouse microglia BV-2 cells. In vivo experiments were carried out using C57BL6/J mice to evaluate the regulation of flavonoids on the oscillatory expression of liver biorhythm genes. Lipopolysaccharide was used to interfere the gene oscillating expression. QRT-PCR was performed to detect the expression of circadian rhythm-related genes, including Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Rev-erbα, Rev-erbß, Rorα, Dbp, and Npas2. The results show that the polymethoxyflavones (PMFs) exerted stronger circadian gene regulatory capability, while the flavonoids containing glycosides showed no biological activity. Also, all tested flavonoids decreased LPS-induced nitric oxide release, but only polymethoxyflavones inhibited circadian rhythm disorder. PMFs inhibited Nlrp3 inflammasome-related genes and proteins, including Nlrp3, IL-1ß, ASC, and Caspase1, while other flavonoids only affected IL-1ß and Caspase1 expression. This mechanism was preliminarily verified using the Nlrp3 inhibitor INF39.

Reversible modulation of circadian time with chronophotopharmacology.

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology.

Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice.

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases.

The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants' metabolism and their defense against pathogens but mostly the animals and humans' metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics' technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.

Omics Analyses of Gut Microbiota in a Circadian Rhythm Disorder Mouse Model Fed with Oolong Tea Polyphenols.

Microbiome has been revealed as a key element involved in maintaining the circadian rhythms. Oolong tea polyphenols (OTP) has been shown to have potential prebiotic activity. Therefore, this study focused on the regulation mechanisms of OTP on host circadian rhythms. After 8 weeks of OTP administration, a large expansion in the relative abundance of Bacteroidetes with a decrease in Firmicutes was observed, which reflected the positive modulatory effect of OTP on gut flora. In addition, Kyoto Encyclopedia of Genes and Genomes pathways of ATP-binding cassette transporters, two-component system, and the biosynthesis of amino acids enriched the most differentially expressed genes after OTP treatment. Of the differentially expressed proteins identified, most were related to metabolism, genetic information processing, and environmental information processing. It underscores the ability of OTP to regulate circadian rhythm by enhancing beneficial intestinal microbiota and affecting metabolic pathways, contributing to the improvement of host microecology.

Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes.

Acrylamide, mainly formed in Maillard browning reaction during food processing, causes defects in liver circadian clock and mitochondrial function by inducing oxidative stress. Resveratrol is a polyphenol that has powerful antioxidant and anti-inflammatory activity. However, the preventive effects of resveratrol on acrylamide-triggered oxidative damage and circadian rhythm disorders are unclear at the current stage. The present research revealed that resveratrol pretreatment prevented acrylamide-induced cell death, mitochondrial dysfunction, and inflammatory responses in HepG2 liver cells. Acrylamide significantly triggered disorders of circadian genes transcription and protein expressions including Bmal1 and Cry 1 in primary hepatocytes, which were prevented by resveratrol pretreatment. Moreover, we found that the beneficial effects of resveratrol on stimulating Nrf2/NQO-1 pathway and mitochondrial respiration complex expressions in acrylamide-treated cells were Bmal1-dependent. Similarly, the inhibitory effects of resveratrol on inflammation signaling NF-κB were Cry1-dependent. In conclusion, these results demonstrated resveratrol could be a promising compound in suppressing acrylamide-induced hepatotoxicity and balancing the circadian clock.

Aging renders desynchronization between clock and immune genes in male Wistar rat kidney: chronobiotic role of curcumin.

Suprachiasmatic nucleus (SCN) contains the central clock that orchestrate circadian rhythms in physiology and behavior in mammals. Tightly interlocked transcriptional and translational feedback loops (TTFLs) comprising of various clock genes such as Clock, Bmal1, Periods, Cryptochromes etc. in the SCN, send the timing signals to peripheral clocks that governs local metabolism with similar TTFLs. Peripheral clocks in kidney regulates several circadian rhythms like blood pressure, immunity etc. However, aging leads to circadian and inflammatory disorders in kidney. Though there are increasing evidences on age associated perturbations, studies elucidating the rhythmic expression of clock and immune genes across aging in kidney are obscure. We therefore studied changes in daily rhythms of clock and immune genes in kidney. In this study we measured mRNA expression of clock genes rBmal1, rPer1, rPer2, rCry1, rCry2, rRev-erbα, rRorα, and inflammatory genes rNfκb1, rTnfα, rIl6, rTlr4 and rTlr9 in 3, 12 and 24 months male Wistar rat kidney using qRT-PCR. From our study, we did not observe significant changes in clock genes expression except rRorα, but immune genes showed significant phase alterations as well as increase in mean 24 h levels. Pearson correlation analysis of data showed desynchronization between immune and clock genes expression. We further studied the effect of administration of curcumin which has anti-aging, anti-inflammatory, anti-oxidant etc. properties, and evaluated its chronobiotic properties. We here report differential effects of curcumin administration on daily rhythms of clock and immune genes expression.

Melatonin receptors as therapeutic targets in the suprachiasmatic nucleus.

INTRODUCTION: Disorders of rhythmicity can cause a variety of pathologies and are known to impair processes involved in metabolism, as well as in cardiovascular disease and cancer. Developing strategies to treat or prevent such diseases is a new challenge for medicine. Rhythms depend on a complex multi-oscillatory circadian network which, in mammals, is hierarchically organized with the suprachiasmatic nuclei (SCN) as master clock. The SCN, thus form an ideal structure for target discovery in circadian pathologies. AREAS COVERED: The development of strategies to treat or prevent disorders of rhythmicity is a new challenge for medicine. Several pharmacological approaches have been suggested, but until now, it has been mostly melatonin (MTL) or MTL-agonists which have demonstrated usefulness in modulating clock activities in vivo. A great number of structurally different MTL receptor ligands have been developed, some of which are already approved and marketed as drugs. The MTL receptor involved in phase-shifting circadian rhythms (chronobiotic effect) is the MT1 subtype. EXPERT OPINION: As the two receptor subtypes for MTL may have divergent functions, the development of highly selective MT1 and MT2 agonists (and antagonists) is key for the discovery of novel therapeutic agents in specifically defined circadian pathologies. The identification of cells expressing the different MTL receptor subtypes should also permit a better understanding of MLT physiology/pharmacology.

Molecular Targets for Small-Molecule Modulators of Circadian Clocks.

BACKGROUND: Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. METHODS: Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. RESULTS: Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. CONCLUSION: Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases.

[CHRONOBIOLOGICAL ASPECTS OF THE USE OF PROLIT SUPER SEPTO IN PATIENTS WITH INFECTIOUS AND INFLAMMATORY DISEASES OF THE URINARY SYSTEM].

This paper presents results of a study involving 120 patients with infectious and inflammatory diseases of the urinary system, divided into four groups. Groups 1 and 3 included patients with acute serous non-obstructive pyelonephritis, groups 2 and 4--patients with exacerbation of chronic recurrent bacterial cystitis. Patients in groups 3 and 4 received a 10 day course of antibiotic therapy combined with Prolit super septo while patients in groups 1 and 2--only the standard antibiotic therapy. The authors studied changes in the clinical presentation, chronorhythms and psycho-emotional condition of the patients. At baseline, all patients showed signs of severe desynchronosis and psycho-emotional disorders. Combination therapy with Prolit super septo more effectively suppressed inflammation, improved clinical symptoms, corrected patient psycho-emotional status and restored normal chronorhythms regardless of the inflammation location.

Chronic constant light-induced hippocampal late-phase long-term potentiation impairment in vitro is attenuated by antagonist of D1/D5 receptors.

Previous study reported that chronic constant light exposure caused hippocampus-dependent long-term memory deficit. However, the underlying cellular mechanism of this impairment is still unclear. Multiple lines of evidence indicated that long-term potentiation (LTP) is a cellular model for memory formation. Here we found that, by recording of field excitatory postsynaptic potential (fEPSP) in vitro, chronic constant light (CCL, 3 weeks) exposure impaired the late long-term potentiation (L-LTP), but not early long-term potentiation (E-LTP) and basal transmission in Schaffer collateral (SC)-CA1 synapses of hippocampal slices from rats. Because L-LTP depends on D1/D5 receptors, we examined whether interference of D1/D5 receptors can modulate L-LTP of CCL rats. Bath application of D1/D5 receptors antagonist SCH23390 (1µM) blocked L-LTP in control rats and attenuated the impaired L-LTP in CCL rats. In contrast, pre-incubation of D1/D5 receptors agonist SKF38393 (25µM) occluded further L-LTP in control rats while exacerbated the L-LTP impairment in CCL rats. These results suggested that CCL-induced L-LTP impairment can be modulated by D1/D5 receptors. Our findings may contribute to the further understanding of synaptic plasticity mechanism underlying hippocampal long-term memory impairment induced by circadian rhythm disruption.

[The use of melatonin in the treatment of chronic fatigue syndrome and circadian rhythm disorders in Parkinson's disease].

Chronic fatigue syndrome (CFS), a specific asthenic condition, is identified in a half of patients with Parkinson's disease (PD). An aim of the study was to evaluate an effect of melatonin (melaxen) on the severity of CFS, affective disorders, quality of life and sleep disorders in 30 patients with early and late stages of PD. After treatment, there was a decrease by 21% (p<0,05) on the Parkinson fatigue scale. At the same time, the improvement of sleep, assessed by the PDSS, decrease in the state anxiety on the Spilberger's scale and improvement of quality of life on the PDQ-39 (p<0,05) were found. No significant differences in motor, cognitive autonomic disorders and depression level were noted compared to baseline. Therefore, melatonin, together with optimized antiparkinsonian treatment, can treat CFS, improve sleep and quality of life of PD patients.

Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

An open-label efficacy trial of escitalopram for night eating syndrome.

OBJECTIVE: Night eating syndrome (NES) has become increasingly recognized as a disorder in need of effective treatments. Selective serotonin reuptake inhibitors have shown efficacy in previous trials, so we sought to expand our understanding of the efficacy of escitalopram in the current trial. METHOD: Thirty-one adults with NES participated in a 12-week open-label trial of escitalopram. Outcome measures included the Night Eating Symptom Scale (NESS), percent of daily intake after the evening meal (% intake) and number of nocturnal ingestions/week (NI), weight, total awakenings/week, mood, and quality of life. Mixed-effects models were used to assess change over time. RESULTS: Significant reductions were observed from week 0 to week 12 for the NESS (30.2 to 15.2), % intake (46% to 17%), NI (5.8 to 1.2), weight (90.2 to 88.6 kg), awakenings (8.1 to 2.7), and BDI-II (12.1 to 7.7). Outcomes did not differ significantly by gender, age, race, or psychiatric co-morbidity status. Eighteen of 31 completed 12 weeks of treatment. DISCUSSION: This open-label trial of escitalopram showed significant reductions in symptoms associated with NES. Randomized controlled trials are warranted to test these findings. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01401595.

Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats.

Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions.

[Dysfunctions of biological clocks and their treatments]. / Dysfonctionnements de l'horloge biologique et leurs traitements.

Biological rhythms are periodic phenomena entrained to environmental changes by exogenous factors called synchronizers or entraining agents namely the light-dark cycle, the rest-activity cycle and the seasons, among others. In humans the major synchronizers are the light-dark and rest activity cycles. The endogenous component of a biological rhythm is dependent upon a number of clock genes. The main biological clock (oscillator or pacemaker) is the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The photoperiod (light-dark cycle) perceived by the retina acts on the SCN genes. Peripheral clocks have also been described in a number of tissues e.g. retina, adrenals. In a number of occurrences the synchronizers are badly perceived (transmeridian flights, shiftwork, nightwork...) or are not at all perceived (blindness). This situation is named rhythm desynchronization, it is external when the desynchronization is strictly related to the environment or internal when it is related to a dysfunction of the clock like in e.g. aging, Alzheimer disease, seasonal affective disorders (SAD) or hormone-dependent cancers which results in fatigue, sleep and mood disorders... A number of drugs called resynchronizing agents or chronobiotics which act on the biological clock are able to resynchronize the clock and to improve the patients' condition. Bright light is used in the treatment of SAD, melatonin, the pineal hormone, is also of interest when administered at precise timings in the 24hours scale. Other drugs like B12 vitamin or psychotropic drugs have also been proposed as chronobiotics.

Decreased agonist, but not antagonist, binding to the naturally occurring Thr92Lys variant of the h5-HT7(a) receptor.

In the present study on transfected human embryonic kidney (HEK)293 cells, we aimed at establishing whether expression of the naturally occurring Thr92Lys variation of the Gs-coupled h5-HT7(a) receptor leads to changes of ligand binding properties, of agonist-evoked cAMP formation and/or of antagonist-mediated blockade of the latter. Binding of [3H]5-carboxamidotryptamine ([3H]5-CT) to membranes and stimulated [3H]cAMP accumulation in whole cells were determined. Saturation binding experiments in membranes of transiently transfected cells expressing either the wild-type or the variant receptor revealed a single binding site in both cases and no difference in Bmax between both receptor isoforms. In competition binding experiments in membranes of stably transfected cells, the Thr92Lys variant exhibited a 2.8-11 times lower binding affinity of the ligands 5-hydroxytryptamine (5-HT), 5-CT, 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4yl)-1H-indole (RU24969), (+/-)-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and sumatriptan compared to the wild-type receptor. However, the variant did not differ from the wild-type with respect to the binding properties of the antagonists (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)-pyrrolodine-1-sulfonyl)phenol hydrochloride (SB-269970), risperidone, mesulergine and clozapine. In agreement with the decreased binding affinity of 5-HT, 5-CT, RU24969 and 8-OH-DPAT for the variant receptor, these agonists were less potent in stimulating [3H]cAMP accumulation in cells stably expressing the Thr92Lys h5-HT7(a) receptor. Sumatriptan did not stimulate cAMP accumulation in spite of its affinity for both receptor isoforms pointing to a putative weak antagonistic property of this drug at the h5-HT7 receptor. SB-269970 and clozapine were equipotent at both the variant and the wild-type receptor in producing a rightward shift of the 5-HT concentration-response curve for its stimulant effect on [3H]cAMP accumulation. In view of, e.g., the purported involvement of the 5-HT7 receptor in the regulation of circadian rhythm, it may be concluded that the decrease in affinity of 5-HT and other 5-HT receptor agonists at the (Thr92Lys) h5-HT7 receptor may be associated with changes of sleep physiology and of actions of new 5-HT7 receptor agonists designed to treat circadian dysregulation.

Importance and relevance of melatonin to human biological rhythms.

The pineal hormone melatonin is a remarkable molecule, with a conserved time-keeping function across species. It is extensively used as a self-administered remedy for sleep disturbance in countries where it is freely available, and to some extent when it is available on prescription, as in the UK. In some circumstances, notably free-running sleep disorder of the blind, it is the treatment of choice. It is also the marker rhythm of choice for the determination of circadian phase and period. This review outlines the current state of knowledge within a physiological perspective with emphasis on human biological rhythms.