Melatonin Rhythm Research Articles

Melatonin in the treatment of perinatal pathology

The review presents the results of studies that have shown the effectiveness of melatonin use in the treatment of perinatal pathology based on oxidative stress and associated systemic inflammation with excessive production of pro-inflammatory cytokines. It is shown that the lack or absence of the circadian rhythm of epiphyseal maternal melatonin plays a key role in the development of oxidative stress in the single mother-placenta-fetus functional system. The article summarizes the results of experimental studies that reveal the mechanisms of melatonin influence (antioxidant, anti-inflammatory, immunomodulating), which provide the protection of the fetus from damage caused by oxidative stress and inflammation in pregnancy complications. The article presents the results of the use of melatonin in full-term and premature infants in addition to standard therapy of brain damage as a result of hypoxia-ischemia and asphyxia, respiratory distress syndrome, sepsis, and necrotizing enterocolitis. Currently ongoing international studies should determine the dose, duration, safety profile, short-term and long-term effects of melatonin in newborns of various gestational ages for its inclusion in treatment protocols for perinatal pathology.

Assessment of Stress Salivary Markers, Perceived Stress, and Shift Work in a Cohort of Fishermen: A Preliminary Work.

Due to work-related stress, today, work itself represents a daily challenge that must be faced in many occupations. While, in the past, the scientific community has focused on the helping professions, since, an increasing number of professions have since been investigated. Therefore, different approaches exist in order to assess this disorder, representing a scientific field wherein biological and psychological dimensions both need to be evaluated. In this paper, we consider three biological salivary markers: interleukin 1 beta (IL-1β), cortisol, and melatonin. The choice derives from recent contributions to the literature in which the interplay between these markers has been verified. Briefly, such interplay could explain how the central nervous, endocrine, and immune systems communicate with each other, supporting a holistic concept of person. In 30 marine fishermen from the Apulia region of Italy, perceived stress was measured using the Professional Stress Scale (PSS) and sleep disturbances were assessed through the Pittsburgh Sleep Quality Index (PSQI). Salivary markers were collected at 8:00 a.m. and 2:00 p.m. Those subjects reporting sleep disturbance and having altered scores in two PSS subclasses, home–work conflict and self-esteem, presented inverted salivary melatonin and cortisol nictemeral rhythms (with regard to melatonin levels at 8:00 a.m., those workers reporting values higher than the median showed 64.1% versus 48.6% home–work conflict with respect to cortisol levels, subjects having an inverted circadian rhythm showed 69.9% versus 52.5% home–work conflict, and these values resulted 47.7% versus 25.3% when the self-esteem was considered). As regards melatonin, PSQI score is statistically different in the two groups of subjects as identified by median melatonin at 8:00 a.m.; specifically, the subjects who had mean values higher than the median shared higher PSQI scores (10.8 versus 9.8). The same subjects reported more frequent home–work conflict and more sleep disorders. We found a negative correlation between IL-1β at 8:00 a.m. and Cortdiff (the difference between cortisol at 8:00 a.m.–cortisol at 2:00 p.m.), and that high IL-1β at 8:00 a.m. was associated with low Cortdiff. Based on our results we would like to propose this approach in health surveillance, in order to prevent mental and/or physical disorders, however our study is surely preliminary. The interesting perspectives and hypotheses cited in this paper, in which the roles of IL-1β and norepinephrine appear central and important, could remain hypothetical if not supported by more robust observation in order to produce, truly, new knowledge. In the future we will deepen this study with a larger sample, and if these results will be confirmed, this approach could allow preventing, not only mental and physical disorders, but also immuno-mediated diseases, and, perhaps, cancer.

Melatonin, circadian rhythms and glaucoma: current perspective.

Melatonin, circadian rhythms and glaucoma: current perspective.

Measuring Urinary 6-Sulphatoxymelatonin in Humans.

The pineal melatonin rhythm provides a robust reference signal for the timing of the endogenous human circadian system. The rhythm in the major urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT6s), is highly correlated with plasma melatonin and provides a noninvasive method to measure circadian phase, particularly in field-based studies. In this chapter, we describe the protocol for collecting urinary aMT6s and the method used to calculate the acrophase, or peak, time as a circadian phase marker.

Reactivity of stress-implementing system under conditions of light regime change in experiment

Influence of light exposure duration (model 18:6) on hormonal indices of stress-implementing system in laboratory animals blood is studied. Activity of stress systems central link was evaluated based on data on concentration of adrenocorticotrophic hormone, melatonin and β-endorphin in blood serum, observed during enzyme immunoassay. Reaction of peripheric link of the stress-implementing system was evaluated in blood smears based on results of qualitative count of catecholamine granules in erythrocytes. It was established, that variations of hormonal indices of the stress systems for laboratory animals depend on trigger factor activity periods. With increase of the experiment duration to 21-st days the most pronounced reduction of melatonin, β-endorphin and increase of adrenocorticotrophic hormone concentration, as well as sharp increase of catecholamines level are observed in the blood serum. These hormonal changes develop as a result of failure of compensation mechanisms of the stress-implementing systems in connection with melatonin rhythms disturbance, that indicates the gradual development of the general adaptation syndrome. Keywords: endocrine profile, stress-implementing system, general adaptation syndrome, biorhythms, light desynchronosis.

Reduced melatonin levels may facilitate glioblastoma initiation in the subventricular zone.

There is increasing evidence that glioblastoma, a highly aggressive brain tumour, originates from a neural stem cell (NSC) located in the subventricular zone (SVZ) of the lateral cerebral ventricle. Using the most advanced in vivo imaging techniques, Gengatharan and colleagues recently identified a day/night difference in the adult SVZ-NSC division. They reported that the circadian melatonin rhythm and its receptor control the day/night difference in NSC division with high mitotic activity during the day and low activity at night. Expression of melatonin and its receptor diminishes during ageing, which eliminates the regulatory effect of melatonin on NSC mitosis. Moreover, the circadian melatonin rhythm is dampened by light-at-night with the potential of altering the circadian mitotic cycle of NSC in the SVZ. Also, men with a lower melatonin amplitude than women exhibit a 60% higher rate of glioblastoma incidence. Given that ageing contributes significantly to glioblastoma initiation and progression, we suggest that the decline in circadian melatonin synthesis and release as well as its receptors in the SVZ, which also diminish with an ageing act in concert with other factors to facilitate glioblastoma initiation and growth.

Measuring Dim Light Melatonin Onset in Humans.

The pineal melatonin rhythm provides a robust reference signal for the timing of the endogenous human circadian system. Dim light melatonin onset (DLMO) time is considered a gold-standard marker of the central circadian clock when measured from plasma or saliva. In this chapter, we describe the appropriate conditions for collecting plasma and salivary melatonin and the threshold method to calculate the DLMO.

Polycystic Ovary Syndrome, Obesity and Melatonin: An Etiological Perspective

Although the reproductive and metabolic dysfunctions associated with polycystic ovary syndrome are clearly known, the mechanisms between these dysfunctions are still unclear. One of the hypotheses put forward for these mechanisms is related to circadian rhythm. To date, many reproductive and metabolic dysfunctions have been associated with circadian rhythm disorders. Especially in women with polycystic ovary syndrome, the relationship between melatonin rhythm, which lasts until late in the morning and starts early at night, and metabolic dysfunctions has been revealed by recent studies. When the relationship between obesity and melatonin is examined, it is clearly seen that melatonin exhibits its effect on energy expenditure rather than energy intake. This hormone affects energy expenditure through adipogenesis, thermogenesis, mitochondrial functions and adipocytokines release, and shows anti-obesity effect. It is thought that this review will shed light on further studies on the therapeutic use of melatonin in obesity associated with polycystic ovary syndrome and contribute to the development of strategies for the prevention of obesity.

Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?

Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome).

Born without night: the consequence of the no-night environment on reproductive performance in diurnal zebra finches.

We investigated the consequence of no-night environment (constant light, LL) on reproductive performance in zebra finches in the parent (P) and subsequent (F1) generation. As a measure of the overall effects on metabolic reproductive health, we monitored daily activity behaviour, recorded song and cheek patch size in males, and measured body size and hormone levels. As compared with controls under 12 h light:12 h darkness (12h:12 h LD), both P and F1 pairs showed a compromised reproductive success, as evidenced by fewer fledglings and fewer viable offspring with longer fledging durations, and increased offspring mortality with three successive clutches under LL. The overall negative effect of the no-night environment was increased in the F1 generation. As compared with P pairs, F1 pairs had more failed nesting and breeding attempts, took longer to initiate reproduction, incubated fewer eggs, produced fewer viable offspring with longer fledging duration, and showed increased offspring mortality. Consistent with negative reproductive effects, P males showed significant changes in the motif duration and other spectral features of song, and both F1 and F2 males copied poorly the song of their parent under LL. Plasma corticosterone and sex hormone (testosterone in males and oestradiol in females) levels were significantly lower under LL. Daily plasma melatonin rhythm persisted but with a reduced amplitude under LL. These results demonstrate the importance of night in reproduction in a continuously breeding diurnal species, and give insight into the possible impact on physiology of animals whose surrounding environment is consistently losing the darkness of night.

Preliminary Study on Changes of Sleep EEG Power and Plasma Melatonin in Male Patients With Major Depressive Disorder After 8 Weeks Treatment.

Objective: To clarify the effects of escitalopram on sleep EEG power in patients with Major depressive disorder (MDD).Method: Polysomnography (PSG) was detected overnight, and blood samples were collected at 4 h intervals over 24 h from 13 male healthy controls and 13 male MDD patients before and after treatment with escitalopram for 8 weeks. The outcome measures included plasma melatonin levels, sleep architecture, and the sleep EEG power ratio.Results: Compared with healthy controls, MDD patients presented abnormalities in the diurnal rhythm of melatonin secretion, including peak phase delayed 3 h and a decrease in plasma melatonin levels at night and an increase at daytime, accompanied by sleep disturbances, a decrease in low-frequency bands and an increase in high-frequency bands, and the dominant right-side brain activity. Several of these abnormalities (abnormalities in the diurnal rhythm of melatonin secretion, partial sleep architecture parameters) persisted for at least the 8-week testing period.Conclusions: Eight weeks of treatment with escitalopram significantly improved subjective sleep perception and depressive symptoms of patients with MDD, and partially improved objective sleep parameters, while the improvement of circadian rhythm of melatonin was limited.

Impact of Light at Night Is Phase Dependent: A Study on Migratory Redheaded Bunting (Emberiza bruniceps)

Artificial light at night (LAN) alters the physiology and behavior of an organism; however, very little is known about phase-dependent effects of LAN, particularly, in night migratory songbirds. Therefore, in this study, we investigated whether the effects of LAN on daily activity and photoperiodic responses in the Palearctic Indian migratory songbird, redheaded buntings (Emberiza bruniceps), is dependent on the different phases of the night. Male buntings maintained under short photoperiod (8L:16D; L = 100 lux, D < 0.1 lux) in individual activity cages were exposed to LAN (2 lux) for 6 weeks either in 4 h bin given at the different phases of 16 h night (early, mid, or late at ZT 08–12, ZT 14–18, or ZT 20–24, respectively; n = 9 each group) or throughout 16 h night (all night light, n = 6, ZT 08–24, the time of lights ON was considered as Zeitgeber time 0, ZT 0). A group (n = 6) with no LAN served as control. The results showed that LAN at the different phases of night induced differential effects as shown by an intense activity during the night, altered melatonin and temperature rhythms, and showed an increase in body mass and body fattening, food intake, and gonadal size. Midnight light exposure has a greater impact on migration and reproduction linked phenotypes, which is similar to the ones that received light throughout the night. The highlights of this study are that (i) LAN impacts day-night activity behavior, (ii) its continuity with the day alters the perception of day length, (iii) birds showed differential sensitivity to LAN in a phase-dependent manner, (iv) the direction of placing LAN affects the daily responses, e.g., LAN in the early night was “accepted” as extended dusk but the late night was considered as early dawn, and (v) midnight LAN was most effective and induced similar responses as continuous LAN. Overall, LAN induces long day responses in short days and shows differential sensitivity of the different phases of the night toward the light. This information may be valuable in adopting a part-night lighting approach to help reduce the physiological burden, such as early migration and reproduction, of artificial lighting on the nocturnal migrants.

Weekly and seasonal variation in the circadian melatonin rhythm in humans: A response.

We read with interest the commentary by Skeldon and Dijk about our article "Weekly, seasonal and chronotype-dependent variation of dim light melatonin onset." The discussion points raised by Skeldon and Dijk are currently among the most hotly debated in human circadian science. What external factors determine human phase of entrainment? How great is the contribution of natural versus artificial light and sun time versus social time? Our intra-individual data add to the still limited evidence from field studies in this matter. In their commentary, Skeldon and Dijk formulate two either-or hypotheses, postulating that humans entrain either solely to the natural light-dark cycle (sun time referenced by midday) (H1 ) or solely to the light selected by local clock time and social constraints (H2 ). Neither hypothesis accounts for the effect of season on human light exposure. We interpreted our findings along more complex lines, speculating that the 1-h earlier melatonin rise in summer found in our sample is likely the combined result of daylight saving time (DST)-induced behavioral advances and a stronger natural zeitgeber in summer (light exposure determined by social and seasonal factors, Horiginal ). Here, we show how the criticism by Skeldon and Dijk is based on two sentences quoted out of context (misrepresenting our hypothesis as H1 ) and that their hypothesis H2 leaves out important seasonal components in light exposure.

Salivary Melatonin Rhythm and Prostate Cancer: CAPLIFE Study.

We analyzed the association between salivary melatonin rhythm and prostate cancer (PCa). A total of 40 PCa cases and 41 controls from the CAPLIFE study were analyzed to determine the salivary melatonin rhythm through 6 saliva samples. Amplitude (maximum melatonin peak) was categorized as low or high using the cutoff point median of the controls. Acrophase (time of maximum melatonin peak) was classified as early or late using the same criteria. In addition, the following data were collected: characteristics related to sleep habits, and clinical and sociodemographic information. Melatonin rhythms were represented for cases and controls and analyzed according to urinary symptoms, tumor aggressiveness and tumor extension. Variations in melatonin levels were estimated using generalized estimating equations on the ln-transformed values. To estimate the association between amplitude, acrophase and PCa, adjusted odds ratio (aOR) and 95% CI were calculated using logistic regression models. The mean age was 67.0 years (SD 7.3) for cases and 67.5 (SD 5.5) for controls. Melatonin levels were always lower in PCa cases than in controls. On average, melatonin levels in cases were -64.0% (95% CI -73.4, -51.4) than controls. PCa cases had lower amplitude, 26.0 pg/ml (SD 27.8) vs 46.3 pg/ml (SD 28.2; p <0.001). A high amplitude was associated with a decreased risk of PCa, aOR=0.31 (95% CI 0.11, 0.86), while a late acrophase could be increased risk of PCa, aOR=2.36 (95% CI 0.88, 6.27). Patients with PCa always had lower melatonin levels than men without PCa, independent of urinary symptomatology or extension and aggressiveness of the tumor.

Circadian Rhythm and Concentration of Melatonin in Breast Cancer Patients.

Melatonin is a biomarker of the central circadian clock and its chronobiotic actions entraining circadian rhythms to the light-dark cycle are well known. Reduction in melatonin levels and altered circadian rhythms have been associated with a high risk of breast cancer. Melatonin has also been shown to display anti-proliferative effects on breast cancer growth and proliferation. Evaluation of melatonin circadian rhythm alterations in patients bearing breast cancer may have interesting prognostic and therapeutic applications. To review studies evaluating the circadian rhythm of melatonin in breast cancer patients. The effects of surgery and chemotherapy on melatonin secretion were also reviewed. Electronic databases, including PubMed/MEDLINE and Scopus, were searched from their inception to May 2020, using the keywords "Melatonin", "Circadian rhythm" and "Breast cancer". Patients with breast cancer maintain a circadian rhythm of melatonin secretion with relatively high levels during the night and low levels during the day, however, a reduction in nocturnal melatonin peak and decreased amplitude of melatonin circadian rhythms in these patients have also been reported. Melatonin levels can influence estrogen receptor concentrations in hormone-dependent estrogen- positive breast cancer. Chemotherapy alters melatonin levels and breast surgery tends to alter melatonin secretion at first-day post-operation. Melatonin levels correlate with clinical and psychological symptoms of breast cancer, such as sleep quality and depression severity. Circadian rhythm and the concentration of melatonin in the blood are altered in patients with breast cancers, and it can modify not only the sleep-wake cycle and, thus, patients' quality of life but due to melatonin's antioxidant effects, the effect of therapies can be modulated. Due to the heterogonous protocols used to assess melatonin and variable environmental factors during sampling, further studies need to control, such variables in order to tailor clinical trials based on melatonin rhythm adjustment and/or supplementation in breast cancer patients.

Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin.

Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015–2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.

Fetal malnutrition is associated with impairment of endogenous melatonin synthesis in pineal via hypermethylation of promoters of protein kinase C alpha and cAMP response element-binding.

This study investigated whether and how fetal malnutrition would influence endogenous melatonin synthesis, and whether such effect of fetal malnutrition would transmit to the next generation. We enrolled 2466 participants and 1313 of their offspring. The urine 6-hydroxymelatonin sulfate and serum melatonin rhythm were measured. Methylationmicroarray detection and bioinformatics analysis were performed to identify hub methylated sites. Additionally, rat experiment was performed to elucidate mechanisms. The participants with fetal malnutrition had lower 6-hydroxymelatonin sulfate (16.59±10.12μg/24hours vs 24.29±11.99μg/24hours, P<.001) and arear under curve of melatonin rhythm (67.11±8.16pg/mL vs 77.11±8.04pg/mL, P<.001). We identified 961 differentially methylated sites, in which the hub methylated sites were locating on protein kinase C alpha (PRKCA) and cAMP response element-binding protein (CREB1) promoters, mediating the association of fetal malnutrition with impaired melatonin secretion. However, such effects were not observed in the offspring (all P>.05). Impaired histomorphology of pineal, decreased melatonin in serum, pineal, and pinealocyte were also found in the in vivo and in vitro experiments (P<.05 for the differences of the indicators). Hypermethylation of 10 CpG sites on the PRKCA promoter and 8 CpG sites on the CREB1 promoter were identified (all P<.05), which down-regulated PRKCA and CREB1 expressions, leading to decreased expression of AANAT, and then resulting in the impaired melatonin synthesis. Collectively, fetal malnutrition can impair melatonin synthesis through hypermethylation of PRKCA and CREB1 promoters, and such effects cannot be transmitted to the next generation.

Sex-related Changes in Circadian Rhythm of Inflammatory and Oxidative Stress Markers in CKD.

Introduction. Circadian system is deeply involved in renal function. The circadian timing system may be disrupted in chronic kidney disease (CKD) patients. Gender differences in CKD have been reported. This research aimed to investigate the gender differences in the circadian rhythm of inflammatory and oxidant markers of CKD. Methods. Male, intact female, and ovariectomized (OVX) female rats (twenty-four in each group) were randomly assigned to control and CKD groups. The rats were further divided into day (12:00 p.m.) and night (12:00 a.m.) subgroups. Evaluations of each sample were carried out a day after the last day of adenine administration. Results. Final results revealed that the circadian rhythm of plasma melatonin , kidney malondialdehyde (MDA), and transforming growth factor- β (TGF-β) levels in CKD group were the same as the control group. Melatonin and total antioxidant capacity (TAC) levels significantly decreased in the CKD group compared with the control group in day and night subgroups, whereas MDA and TGF-β levels increased. Male group in comparison with the intact female group significantly showed less melatonin and TAC but higher MDA and TGF-β levels which could be due to CKD. Conclusion. Findings of this study represent gender differences in circadian rhythm amplitude of inflammation, melatonin, and oxidative stress in CKD animals, probably in favor of female sex steroids. These findings emphasize on the importance of gender differences in CKD progression; therefore, considerable attention must be paid to gender in the treatment of CKD.Introduction. Circadian system is deeply involved in renal function. The circadian timing system may be disrupted in chronic kidney disease (CKD) patients. Gender differences in CKD have been reported. This research aimed to investigate the gender differences in the circadian rhythm of inflammatory and oxidant markers of CKD. Methods. Male, intact female, and ovariectomized (OVX) female rats (twenty-four in each group) were randomly assigned to control and CKD groups. The rats were further divided into day (12:00 p.m.) and night (12:00 a.m.) subgroups. Evaluations of each sample were carried out a day after the last day of adenine administration. Results. Final results revealed that the circadian rhythm of plasma melatonin , kidney malondialdehyde (MDA), and transforming growth factor- β (TGF-β) levels in CKD group were the same as the control group. Melatonin and total antioxidant capacity (TAC) levels significantly decreased in the CKD group compared with the control group in day and night subgroups, whereas MDA and TGF-β levels increased. Male group in comparison with the intact female group significantly showed less melatonin and TAC but higher MDA and TGF-β levels which could be due to CKD. Conclusion. Findings of this study represent gender differences in circadian rhythm amplitude of inflammation, melatonin, and oxidative stress in CKD animals, probably in favor of female sex steroids. These findings emphasize on the importance of gender differences in CKD progression; therefore, considerable attention must be paid to gender in the treatment of CKD. DOI: 10.52547/ijkd.6242

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

Exploring the effects of large-area dorsal skin irradiation on locomotor activity and plasm melatonin level in C3H/He mice

ABSTRACT As the largest organ exposed to the outside of mammals, skin has direct photosensitivity. Recent studies have even shown that cutaneous irradiation played a role in local circadian systems. However, whether it can further affect the central clock system is controversial. Here, plasm melatonin rhythm of melatonin-proficient C3H/He mice was assessed, and on this basis, a well-designed segmented lighting method was used to investigate the effects of dorsal skin irradiation on locomotor activity and plasm melatonin content in male C3H/He mice. In brief, mice were separately exposed to cutaneous irradiation, intraocular irradiation or darkness for 60 min at specific moments. The results showed that neither blue nor red cutaneous exposure had obvious effect on central rhythm oscillation while intraocular irradiation could significantly change the central clock of mice, and the effect of blue light was more forceful than red light. It suggests that intraocular nonvisual channels still play a dominant role in rhythmic regulation, which has not been challenged by the discovery of local light entrainment in exposed peripheral tissues.