Light sets the brain's daily clock by regional quickening and slowing of the molecular clockworks at dawn and dusk.

How daily clocks in the brain are set by light to local environmental time and encode the seasons is not fully understood. The suprachiasmatic nucleus (SCN) is a central circadian clock in mammals that orchestrates physiology and behavior in tune with daily and seasonal light cycles. Here, we have found that optogenetically simulated light input to explanted mouse SCN changes the waveform of the molecular clockworks from sinusoids in free-running conditions to highly asymmetrical shapes with accelerated synthetic (rising) phases and extended degradative (falling) phases marking clock advances and delays at simulated dawn and dusk. Daily waveform changes arise under ex vivo entrainment to simulated winter and summer photoperiods, and to non-24 hr periods. Ex vivo SCN imaging further suggests that acute waveform shifts are greatest in the ventrolateral SCN, while period effects are greatest in the dorsomedial SCN. Thus, circadian entrainment is encoded by SCN clock gene waveform changes that arise from spatiotemporally distinct intrinsic responses within the SCN neural network.

The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep.

Light regulates daily sleep rhythms by a neural circuit that connects intrinsically photosensitive retinal ganglion cells (ipRGCs) to the circadian pacemaker, the suprachiasmatic nucleus. Light, however, also acutely affects sleep in a circadian-independent manner. The neural circuits involving the acute effect of light on sleep remain unknown. Here we uncovered a neural circuit that drives this acute light response, independent of the suprachiasmatic nucleus, but still through ipRGCs. We show that ipRGCs substantially innervate the preoptic area (POA) to mediate the acute light effect on sleep in mice. Consistently, activation of either the POA projecting ipRGCs or the light-responsive POA neurons increased non-rapid eye movement (NREM) sleep without influencing REM sleep. In addition, inhibition of the light-responsive POA neurons blocked the acute light effects on NREM sleep. The predominant light-responsive POA neurons that receive ipRGC input belong to the corticotropin-releasing hormone subpopulation. Remarkably, the light-responsive POA neurons are inhibitory and project to well-known wakefulness-promoting brain regions, such as the tuberomammillary nucleus and the lateral hypothalamus. Therefore, activation of the ipRGC-POA circuit inhibits arousal brain regions to drive light-induced NREM sleep. Our findings reveal a functional retina-brain circuit that is both necessary and sufficient for the acute effect of light on sleep.

NPAS4 regulates the transcriptional response of the suprachiasmatic nucleus to light and circadian behavior.

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals and is entrained by environmental light. However, the molecular basis of the response of the SCN to light is not fully understood. We used RNA/chromatin immunoprecipitation/single-nucleus sequencing with circadian behavioral assays to identify mouse SCN cell types and explore their responses to light. We identified three peptidergic cell types that responded to light in the SCN: arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), and cholecystokinin (CCK). In each cell type, light-responsive subgroups were enriched for expression of neuronal Per-Arnt-Sim (PAS) domain protein 4 (NPAS4) target genes. Further, mice lacking Npas4 had a longer circadian period under constant conditions, a damped phase response curve to light, and reduced light-induced gene expression in the SCN. Our data indicate that NPAS4 is necessary for normal transcriptional responses to light in the SCN and critical for photic phase-shifting of circadian behavior.

Light-induced changes in the suprachiasmatic nucleus transcriptome regulated by the ERK/MAPK pathway.

The mammalian master circadian pacemaker within the suprachiasmatic nucleus (SCN) maintains tight entrainment to the 24 hr light/dark cycle via a sophisticated clock-gated rhythm in the responsiveness of the oscillator to light. A central event in this light entrainment process appears to be the rapid induction of gene expression via the ERK/MAPK pathway. Here, we used RNA array-based profiling in combination with pharmacological disruption methods to examine the contribution of ERK/MAPK signaling to light-evoked gene expression. Transient photic stimulation during the circadian night, but not during the circadian day, triggered marked changes in gene expression, with early-night light predominately leading to increased gene expression and late-night light predominately leading to gene downregulation. Functional analysis revealed that light-regulated genes are involved in a diversity of physiological processes, including DNA transcription, RNA translation, mRNA processing, synaptic plasticity and circadian timing. The disruption of MAPK signaling led to a marked reduction in light-evoked gene regulation during the early night (32/52 genes) and late night (190/191 genes); further, MAPK signaling was found to gate gene expression across the circadian cycle. Together, these experiments reveal potentially important insights into the transcriptional-based mechanisms by which the ERK/MAPK pathway regulates circadian clock timing and light-evoked clock entrainment.

A genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms.

The regulatory mechanisms of circadian rhythms have been studied primarily at the level of the transcription-translation feedback loops of protein-coding genes. Regulatory modules involving noncoding RNAs are less thoroughly understood. In particular, emerging evidence has revealed the important role of microRNAs (miRNAs) in maintaining the robustness of the circadian system. To identify miRNAs that have the potential to modulate circadian rhythms, we conducted a genome-wide miRNA screen using U2OS luciferase reporter cells. Among 989 miRNAs in the library, 120 changed the period length in a dose-dependent manner. We further validated the circadian regulatory function of an miRNA cluster, miR-183/96/182, both in vitro and in vivo. We found that all three members of this miRNA cluster can modulate circadian rhythms. Particularly, miR-96 directly targeted a core circadian clock gene, PER2. The knockout of the miR-183/96/182 cluster in mice showed tissue-specific effects on circadian parameters and altered circadian rhythms at the behavioral level. This study identified a large number of miRNAs, including the miR-183/96/182 cluster, as circadian modulators. We provide a resource for further understanding the role of miRNAs in the circadian network and highlight the importance of miRNAs as a genome-wide layer of circadian clock regulation.

Rapid Jetlag Resetting of Behavioral, Physiological, and Molecular Rhythms in Proestrous Female Mice.

A gradual adaptation to a shifted light-dark (LD) cycle is a key element of the circadian clock system and believed to be controlled by the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Endocrine factors have a strong influence on the regulation of the circadian clock network and alter acute photic responses of the SCN clock. In females, endocrine function depends on the stage of the ovarian cycle. So far, however, little is known about the effect of the estrous cycle on behavioral and molecular responses to shifts in the LD rhythm. Based on this, we investigated whether estrous state affects the kinetics of phase shift during jetlag in behavior, physiology, and molecular clock rhythms in the SCN and in peripheral tissues. Female mice exposed to an advanced LD phase at proestrous or metestrous showed different phase-shift kinetics, with proestrous females displaying accelerated adaptation in behavior and physiology. Constant darkness release experiments suggest that these fast phase shifts do not reflect resetting of the SCN pacemaker. Explant experiments on SCN, adrenal gland, and uterus confirmed this finding with proestrous females showing significantly faster clock phase shifts in peripheral tissues compared with the SCN. Together, these findings provide strong evidence for an accelerated adaptation of proestrous compared with metestrous females to new LD conditions that is accompanied by rapid behavioral, physiological, and molecular rhythm resetting. Not only do these findings open up a new avenue to understand the effect of estrous cycle on the clock network under changing environmental conditions but also imply a greater susceptibility in proestrous females.

Light Has Diverse Spatiotemporal Molecular Changes in the Mouse Suprachiasmatic Nucleus.

To be physiologically relevant, the period of the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), has to match the solar day in a process known as circadian photoentrainment. However, little is known about the spatiotemporal molecular changes that occur in the SCN in response to light. In this study, we sought to systematically characterize the circadian and light effects on activity-dependent markers of transcriptional (cFos), translational (pS6), and epigenetic (pH3) activities in the mouse SCN. To investigate circadian versus light influences on these molecular responses, we harvested brains from adult wild-type mice in darkness at different circadian times (CT) or from mice exposed to a 15-min light pulse at the middle of the subjective day (CT6, no phase shifts), early subjective night (CT14, large phase delays), or late subjective night (CT22, small phase advances). We found that cFos and pS6 exhibited rhythmic circadian expression in the SCN with distinct spatial rhythms, whereas pH3 expression was undetectable at all circadian phases. cFos rhythms were largely limited to the SCN shell, whereas pS6 rhythms encompassed the entire SCN. pH3, pS6, and cFos showed gating in response to light; however, we were surprised to find that the expression levels of these markers were not higher at phases when larger phase shifts are observed behaviorally (CT14 versus CT22). We then used animals lacking melanopsin (melanopsin knockout [MKO]), which show deficits in phase delays, to further investigate whether changes in these molecular markers correspond to behavioral phase shifts. Surprisingly, only pS6 showed deficits in MKOs at CT14. Therefore, our previous understanding of the molecular pathways that lead to circadian photoentrainment needs to be revised.

Monochromatic Blue Light Activates Suprachiasmatic Nucleus Neuronal Activity and Promotes Arousal in Mice Under Sevoflurane Anesthesia.

Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.

TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses.

The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.

Inhibitor of DNA binding 2 (Id2) Regulates Photic Entrainment Responses in Mice: Differential Responses of the Id2-/- Mouse Circadian System Are Dependent on Circadian Phase and on Duration and Intensity of Light.

ID2 is a rhythmically expressed helix-loop-helix transcriptional repressor, and its deletion results in abnormal properties of photoentrainment. By examining parametric and nonparametric models of entrainment, we have started to explore the mechanism underlying this circadian phenotype. Id2-/- mice were exposed to differing photoperiods, and the phase angle of entrainment under short days was delayed 2 h as compared with controls. When exposed to long durations of continuous light, enhanced entrainment responses were observed after a delay of the clock but not with phase advances. However, the magnitude of phase shifts was not different in Id2-/- mice tested in constant darkness using a discrete pulse of saturating light. No differences were observed in the speed of clock resetting when challenged by a series of discrete pulses interspaced by varying time intervals. A photic phase-response curve was constructed, although no genotypic differences were observed. Although phase shifts produced by discrete saturating light pulses at CT16 were similar, treatment with a subsaturating pulse revealed a ~2-fold increase in the magnitude of the Id2-/- shift. A corresponding elevation of light-induced per1 expression was observed in the Id2-/- suprachiasmatic nucleus (SCN). To test whether the phenotype is based on a sensitivity change at the level of the retina, pupil constriction responses were measured. No differences were observed in responses or in retinal histology, suggesting that the phenotype occurs downstream of the retina and retinal hypothalamic tract. To test whether the phenotype is due to a reduced amplitude of state variables of the clock, the expression of clock genes per1 and per2 was assessed in vivo and in SCN tissue explants. Amplitude, phase, and period length were normal in Id2-/- mice. These findings suggest that ID2 contributes to a photoregulatory mechanism at the level of the SCN central pacemaker through control of the photic induction of negative elements of the clock.

Double recording system of Period1 gene expression rhythm in the olfactory bulb and liver in freely moving mouse.

Clock genes express circadian rhythms in most organs. These rhythms are organized throughout the whole body, regulated by the suprachiasmatic nucleus (SCN) in the brain. Disturbance of these clock gene expression rhythms is a risk factor for diseases such as obesity and cancer. To understand the mechanism of regulating clock gene expression rhythms in vivo, multiple real time recording systems are required. In the present study, we developed a double recording system of Period1 expression rhythm in peripheral tissue (liver) and the brain. In peripheral tissue, quantification of gene expression in a steadily moving target was achieved by using a photomultiplier tube (PMT) attached to a tissue contact optical sensor (TCS). Using this technique, we were able to analyze circadian rhythms of clock gene expression over a prolonged period in the liver and olfactory bub (OB) of the brain. The present double recording system has no effect on behavioral activity or rhythm. Our novel system thus successfully quantifies clock gene expression in deep areas of the body in freely moving mice for a period sufficient to analyze circadian dynamics. In addition, our double recording system can be widely applied to many areas of biomedical research, as well as applications beyond medicine.

Retinal innervation tunes circuits that drive nonphotic entrainment to food.

Daily changes in light and food availability are major time cues that influence circadian timing1. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output1-3. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs)4. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGLNPY neurons), guiding the assembly of a functional IGLNPY-SCN circuit. Moreover, silencing IGLNPY neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGLNPY terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGLNPY-SCN circuit to allow entrainment to time-restricted feeding.

The Excitatory Effects of GABA within the Suprachiasmatic Nucleus: Regulation of Na-K-2Cl Cotransporters (NKCCs) by Environmental Lighting Conditions.

The suprachiasmatic nucleus (SCN) contains a pacemaker that generates circadian rhythms and entrains them with the 24-h light-dark cycle (LD). The SCN is composed of 16,000 to 20,000 heterogeneous neurons in bilaterally paired nuclei. γ-amino butyric acid (GABA) is the primary neurochemical signal within the SCN and plays a key role in regulating circadian function. While GABA is the primary inhibitory neurotransmitter in the brain, there is now evidence that GABA can also exert excitatory effects in the adult brain. Cation chloride cotransporters determine the effects of GABA on chloride equilibrium, thereby determining whether GABA produces hyperpolarizing or depolarizing actions following activation of GABAA receptors. The activity of Na-K-2Cl cotransporter1 (NKCC1), the most prevalent chloride influx cotransporter isoform in the brain, plays a critical role in determining whether GABA has depolarizing effects. In the present study, we tested the hypothesis that NKCC1 protein expression in the SCN is regulated by environmental lighting and displays daily and circadian changes in the intact circadian system of the Syrian hamster. In hamsters housed in constant light (LL), the overall NKCC1 immunoreactivity (NKCC1-ir) in the SCN was significantly greater than in hamsters housed in LD or constant darkness (DD), although NKCC1 protein levels in the SCN were not different between hamsters housed in LD and DD. In hamsters housed in LD cycles, no differences in NKCC1-ir within the SCN were observed over the 24-h cycle. NKCC1 protein in the SCN was found to vary significantly over the circadian cycle in hamsters housed in free-running conditions. Overall, NKCC1 protein was greater in the ventral SCN than in the dorsal SCN, although no significant differences were observed across lighting conditions or time of day in either subregion. These data support the hypothesis that NKCC1 protein expression can be regulated by environmental lighting and circadian mechanisms within the SCN.

Two-Community Noisy Kuramoto Model Suggests Mechanism for Splitting in the Suprachiasmatic Nucleus.

Recent mathematical results for the noisy Kuramoto model on a 2-community network may explain some phenomena observed in the functioning of the suprachiasmatic nucleus (SCN). Specifically, these findings might explain the types of transitions to a state of the SCN in which 2 components are dissociated in phase, for example, in phase splitting. In contrast to previous studies, which required additional time-delayed coupling or large variation in the coupling strengths and other variations in the 2-community model to exhibit the phase-split state, this model requires only the 2-community structure of the SCN to be present. Our model shows that a change in the communication strengths within and between the communities due to external conditions, which changes the excitation-inhibition (E/I) balance of the SCN, may result in the SCN entering an unstable state. With this altered E/I balance, the SCN would try to find a new stable state, which might in some circumstances be the split state. This shows that the 2-community noisy Kuramoto model can help understand the mechanisms of the SCN and explain differences in behavior based on actual E/I balance.

Perturbing Circadian Oscillations in an In Vitro Suprachiasmatic Nucleus With Magnetic Stimulation.

Many neurological disorders are associated with abnormal oscillatory dynamics. The suprachiasmatic nucleus (SCN) is responsible for the timing and synchronization of physiological processes. We performed experiments on PERIOD2::LUCIFERASE transgenic "knock-in" mice. In these mice, a gene that is expressed in a circadian pattern is fused to an inserted gene that codes for luciferase, which is a bioluminescent enzyme. A one-time 3 min magnetic stimulation (MS) was applied to excised slices of the SCN. The MS consisted of a 50-mT field that was turned on and off 4,500 times. The rise time and fall time of the field were 75 µs. A photon count that extended over the full 5 days that the slice remained viable, subsequently revealed how the MS affected the circadian cycle. The MS was applied at points in the circadian cycle that correspond to either maximal or minimal bioluminescence. It was found that both the amplitude and period of the endogenous circadian oscillation are affected by MS and that the effects strongly depend on where in the circadian cycle the stimulation was applied. Our MS dose is in the same range as clinically applied doses, and our findings imply that transcranial MS may be instrumental in remedying disorders that originate in circadian rhythm abnormalities. Bioelectromagnetics. 2020;41:63-72 © 2019 Wiley Periodicals, Inc.

Evidence for Internal Desynchrony Caused by Circadian Clock Resetting.

Circadian disruption has been linked to markers for poor health outcomes in humans and animal models. What is it about circadian disruption that is problematic? One hypothesis is that phase resetting of the circadian system, which occurs in response to changes in environmental timing cues, leads to internal desynchrony within the organism. Internal desynchrony is understood as acute changes in phase relationships between biological rhythms from different cell groups, tissues, or organs within the body. Do we have strong evidence for internal desynchrony associated with or caused by circadian clock resetting? Here we review the literature, highlighting several key studies from measures of gene expression in laboratory rodents. We conclude that current evidence offers strong support for the premise that some protocols for light-induced resetting are associated with internal desynchrony. It is important to continue research to test whether internal desynchrony is necessary and/or sufficient for negative health impact of circadian disruption.

The effect of the cannabinoid receptor agonist and antagonist on the light-induced changes in the suprachiasmatic nucleus of rats.

The CB1 cannabinoid receptors have been found in the rodent suprachiasmatic nucleus, and their activation suppresses the light-induced phase shift in locomotor rhythmicity of mice and hamsters. Here, we show that the CB1 receptor agonist CP55940 significantly attenuates the light-induced phase delay in rats as well. Furthermore, it blocks the light induction of c-Fos and light-induced downregulation of pERK1/2 in the SCN, and the CB1 antagonist AM251 prevents the photic induction of pERK1/2 and reduces pGSK3ß after photic stimulation. Our data suggest that the modulation of the cannabinoid receptor activity may affect the photic entrainment via the setting of the SCN sensitivity to light.

Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling.

The suprachiasmatic nucleus (SCN) co-ordinates circadian behaviour and physiology in mammals. Its cell-autonomous circadian oscillations pivot around a well characterised transcriptional/translational feedback loop (TTFL), whilst the SCN circuit as a whole is synchronised to solar time by its retinorecipient cells that express and release vasoactive intestinal peptide (VIP). The cell-autonomous and circuit-level mechanisms whereby VIP synchronises the SCN are poorly understood. We show that SCN slices in organotypic culture demonstrate rapid and sustained circuit-level circadian responses to VIP that are mediated at a cell-autonomous level. This is accompanied by changes across a broad transcriptional network and by significant VIP-directed plasticity in the internal phasing of the cell-autonomous TTFL. Signalling via ERK1/2 and tuning by its negative regulator DUSP4 are critical elements of the VIP-directed circadian re-programming. In summary, we provide detailed mechanistic insight into VIP signal transduction in the SCN at the level of genes, cells and neural circuit.

A-to-I RNA editing enzyme ADAR2 regulates light-induced circadian phase-shift.

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and it orchestrates peripheral clocks in the whole body to organize physiological and behavioral rhythms. Light-induced phase-shift of the SCN clock enables synchronization of the circadian clock system with 24-h environmental light/dark cycle. We previously found that adenosine deaminase acting on RNA 2 (Adar2), an A-to-I RNA editing enzyme catalyzing rhythmic A-to-I RNA editing, governs a wide range of mRNA rhythms in the mouse liver and regulates the circadian behavior. In brain, ADAR2-mediated A-to-I RNA editing was reported to occur in various transcripts encoding ion channels and neurotransmitter receptors, which could influence neuronal function of the SCN. Here we show that ADAR2 plays a crucial role for light-induced phase-shift of the circadian clock. Intriguingly, exposure of Adar2-knockout mice to a light pulse at late night caused an aberrant phase-advance of the locomotor rhythms. By monitoring the bioluminescence rhythms of the mutant SCN slices, we found that a phase-advance induced by treatment with pituitary adenylyl cyclase-activating polypeptide (PACAP) was markedly attenuated. The present study suggests that A-to-I RNA editing in the SCN regulates a proper phase response to light in the mouse circadian system.

The Effect of Light Exposure at Night (LAN) on Carcinogenesis via Decreased Nocturnal Melatonin Synthesis.

In mammals, a master clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus, a region that receives input from the retina that is transmitted by the retinohypothalamic tract. The SCN controls the nocturnal synthesis of melatonin by the pineal gland that can influence the activity of the clock's genes and be involved in the inhibition of cancer development. On the other hand, in the literature, some papers highlight that artificial light exposure at night (LAN)-induced circadian disruptions promote cancer. In the present review, we summarize the potential mechanisms by which LAN-evoked disruption of the nocturnal increase in melatonin synthesis counteracts its preventive action on human cancer development and progression. In detail, we discuss: (i) the Warburg effect related to tumor metabolism modification; (ii) genomic instability associated with L1 activity; and (iii) regulation of immunity, including regulatory T cell (Treg) regulation and activity. A better understanding of these processes could significantly contribute to new treatment and prevention strategies against hormone-related cancer types.