[Insomnia and the biological clock]. / Insomnie et horloge biologique.

INSOMNIA AND THE BIOLOGICAL CLOCK. Multiple physiological and biological rhythms known as «circadian¼ are generated by the biological clock that controls them within the suprachiasmatic nuclei of the hypothalamus. However, the most emblematic circadian rhythm is that of sleep and awakening. It is therefore crucial to check how the clock may be involved in chronic insomnia. What is the influence of the clock on the time and quality of sleep? What are the typical clock disorders that explain insomnia in adolescents, shift and night workers, the elderly and the blind individuals? What are the tools to recommend in general and specialized medicine in the evaluation of the clock in insomnia? What influence finally of the light on the clock and the light therapy to recommend? So many questions and elements of understanding often-poorly known of chronic insomnia.

INSOMNIE ET HORLOGE BIOLOGIQUE. De multiples rythmes physiologiques et biologiques dits « circadiens ¼ sont influencés par l'horloge biologique qui les contrôle au sein des noyaux suprachiasmatiques de l'hypothalamus. Mais le rythme circadien le plus emblématique est celui du sommeil et de l'éveil. Il est donc indispensable de vérifier comment l'horloge biologique peut être impliquée dans une insomnie chronique : quelle est son influence sur les horaires et la qualité du sommeil ? Quels sont les troubles caractéristiques de l'horloge biologique expliquant l'insomnie des adolescents, des travailleurs postés et de nuit, des personnes âgées et des non-voyants ? Quels outils conseiller en médecine générale et spécialisée pour évaluer l'horloge biologique face à une insomnie ? Quelle influence, enfin, de la lumière sur l'horloge biologique et quels conseils donner vis-à-vis de la lumière ? Autant de questions et d'éléments de compréhension sur l'insomnie chronique éclaircis.

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs.

Mammalians' circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). SCN control biological rhythms such as the sleep-wake rhythm and homeostatic functions of steroid hormones and their receptors. Alterations in these biological rhythms are implicated in the outcomes of pathogenic conditions such as depression, diabetes, and cancer. Chronotherapy is about optimizing treatment to combat risks and intensity of the disease symptoms that vary depending on the time of day. Thus, conditions/diseases such as allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease, prone to manifest severe symptoms depending on the time of day, would be benefited from chronotherapy. Monitoring rhythm, overcoming rhythm disruption, and manipulating the rhythms from the viewpoints of underlying molecular clocks are essential to enhanced chronopharmacotherapy. New drugs focused on molecular clocks are being developed to improve therapeutics. In this review, we provide a critical summary of literature reports concerning (a) the rationale/mechanisms for time-dependent dosing differences in therapeutic outcomes and safety of antitumor drugs, (b) the molecular pathways underlying biological rhythms, and (c) the possibility of pharmacotherapy based on the intra- and inter-individual variabilities from the viewpoints of the clock genes.

Endogenous carbon monoxide (CO) as a modulating factor of molecular biological clock in the hypothalamic structures involved in light transmission in pig and wild boar hybrid during long and short day season.

Mature males of a wild boar-pig crossbreed, during the long and short day season, were used for the study which demonstrates that the chemical light carrier CO regulates the expression of biological clock genes in the hypothalamus via humoral pathways. Autologous blood with experimentally elevated concentrations of endogenous CO (using lamps with white light-emitting diodes) was infused into the ophthalmic venous sinus via the right dorsal nasal vein. Molecular biology methods: qPCR and Western Blot were used to determine the expression of genes and biological clock proteins. The results showed that elevated endogenous CO levels, through blood irradiation, induces changes in genes expression involved in the functioning of the main biological clock located in suprachiasmatic nuclei. Changes in the expression of the transcription factors Bmal1, Clock and Npas2 have a similar pattern in both structures, where a very large decrease in gene expression was shown after exposure to elevated endogenous CO levels. The changes in the gene expression of PER 1-2, CRY 1-2, and REV-ERB α-ß and ROR ß are not the same for both POA and DH hypothalamic structures, indicating that both structures respond differently to the humoral signal received. The results indicate that CO is a chemical light molecule whose production in an organism depends on the amount of light. An adequate amount of light is an essential factor for the proper functioning of the main biological clock.

Nuclear Receptors and Clock Components in Cardiovascular Diseases.

Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and smoking, the alteration of circadian rhythms, in shift workers for instance, has recently been recognized as an additional risk factor. Accordingly, targeting a pro-atherogenic pathway at the right time window, namely chronotherapy, has proven its efficiency in reducing plaque progression without affecting healthy tissues in mice, thus providing the rationale of such an approach to treat CVD and to reduce drug side effects. Nuclear receptors are transcriptional factors involved in the control of many physiological processes. Among them, Rev-erbs and RORs control metabolic homeostasis, inflammatory processes and the biological clock. In this review, we discuss the opportunity to dampen atherosclerosis progression by targeting such ligand-activated core clock components in a (chrono-)therapeutic approach in order to treat CVD.

Endogenous Oscillations Time-Constrain Linguistic Segmentation: Cycling the Garden Path.

Speech is transient. To comprehend entire sentences, segments consisting of multiple words need to be memorized for at least a while. However, it has been noted previously that we struggle to memorize segments longer than approximately 2.7 s. We hypothesized that electrophysiological processing cycles within the delta band (<4 Hz) underlie this time constraint. Participants' EEG was recorded while they listened to temporarily ambiguous sentences. By manipulating the speech rate, we aimed at biasing participants' interpretation: At a slow rate, segmentation after 2.7 s would trigger a correct interpretation. In contrast, at a fast rate, segmentation after 2.7 s would trigger a wrong interpretation and thus an error later in the sentence. In line with the suggested time constraint, the phase of the delta-band oscillation at the critical point in the sentence mirrored segmentation on the level of single trials, as indicated by the amplitude of the P600 event-related brain potential (ERP) later in the sentence. The correlation between upstream delta-band phase and downstream P600 amplitude implies that segmentation took place when an underlying neural oscillator had reached a specific angle within its cycle, determining comprehension. We conclude that delta-band oscillations set an endogenous time constraint on segmentation.

Cell wall remodeling and vesicle trafficking mediate the root clock in Arabidopsis.

In Arabidopsis thaliana, lateral roots initiate in a process preceded by periodic gene expression known as the root clock. We identified the vesicle-trafficking regulator GNOM and its suppressor, ADENOSINE PHOSPHATE RIBOSYLATION FACTOR GTPase ACTIVATION PROTEIN DOMAIN3, as root clock regulators. GNOM is required for the proper distribution of pectin, a mediator of intercellular adhesion, whereas the pectin esterification state is essential for a functional root clock. In sites of lateral root primordia emergence, both esterified and de-esterified pectin variants are differentially distributed. Using a reverse-genetics approach, we show that genes controlling pectin esterification regulate the root clock and lateral root initiation. These results indicate that the balance between esterified and de-esterified pectin states is essential for proper root clock function and the subsequent initiation of lateral root primordia.

[Light - darkness and bipolar disorder]. / Lumière ­ obscurité et trouble bipolaire.

Circadian rhythmicity generated by the biological clock structures the functioning of human beings over a period of almost 24 hours. This clock is entrained daily by internal and external cues among which light is the most powerful. Several disturbances, whether clinical or biological, observed in bipolar disorders are suggestive of a disruption of the circadian rhythm. Thus, treatments that modulate the biological clock have been developed. So far, the results of light therapy are not unanimous and invite us to better specify the treatment modalities. Dark therapy is a promising intervention that is still not much studied nowadays and therefore opens up great prospects for research in the future.

Le rythme circadien généré par l'horloge biologique structure le fonctionnement de l'être humain sur une période de presque 24 heures. Cette horloge est quotidiennement «â€…mise à l'heure ¼ par des synchronisateurs internes et externes parmi lesquels la lumière est la plus puissante. Plusieurs perturbations tant cliniques que biologiques observées chez les personnes souffrant d'un trouble bipolaire sont évocatrices d'un dérèglement du rythme circadien. Ainsi, des traitements permettant de moduler l'horloge biologique ont été développés. Actuellement, les résultats de la luminothérapie ne sont pas unanimes et cela nous invite à mieux préciser les modalités du traitement. La thérapie par l'obscurité est une intervention prometteuse, peu étudiée et ouvre donc de belles perspectives de recherche.

Circadian Variation in Human Milk Composition, a Systematic Review.

BACKGROUND: Breastfeeding is considered the most optimal mode of feeding for neonates and mothers. Human milk changes over the course of lactation in order to perfectly suit the infant's nutritional and immunological needs. Its composition also varies throughout the day. Circadian fluctuations in some bioactive components are suggested to transfer chronobiological information from mother to child to assist the development of the biological clock. This review aims to give a complete overview of studies examining human milk components found to exhibit circadian variation in their concentration. METHODS: We included studies assessing the concentration of a specific human milk component more than once in 24 h. Study characteristics, including gestational age, lactational stage, sampling strategy, analytical method, and outcome were extracted. Methodological quality was graded using a modified Newcastle-Ottawa Scale (NOS). RESULTS: A total of 83 reports assessing the circadian variation in the concentration of 71 human milk components were included. Heterogeneity among studies was high. The methodological quality varied widely. Significant circadian variation is found in tryptophan, fats, triacylglycerol, cholesterol, iron, melatonin, cortisol, and cortisone. This may play a role in the child's growth and development in terms of the biological clock.

A Simulation Study on the Pacing and Driving of the Biological Pacemaker.

The research on the biological pacemaker has been very active in recent years. And turning nonautomatic ventricular cells into pacemaking cells is believed to hold the key to making a biological pacemaker. In the study, the inward-rectifier K+ current (I K1) is depressed to induce the automaticity of the ventricular myocyte, and then, the effects of the other membrane ion currents on the automaticity are analyzed. It is discovered that the L-type calcium current (I CaL) plays a major part in the rapid depolarization of the action potential (AP). A small enough I CaL would lead to the failure of the automaticity of the ventricular myocyte. Meanwhile, the background sodium current (I bNa), the background calcium current (I bCa), and the Na+/Ca2+ exchanger current (I NaCa) contribute significantly to the slow depolarization, indicating that these currents are the main supplementary power of the pacing induced by depressing I K1, while in the 2D simulation, we find that the weak electrical coupling plays a more important role in the driving of a biological pacemaker.

Clarifying the role of sleep in depression: A narrative review.

It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented.

Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase.

A flavone luteolin has various health-promoting activities. Several studies reported that high dose of luteolin activates the Nrf2/ARE pathway in the liver. However, the effect of the low dose of luteolin that can be taken from a dietary meal on the Nrf2 activation remain unclear. It is expected that the flavonoid metabolism possesses a circadian rhythm, since nutritional metabolism processes daily cycle. In this study we investigated whether an administration affects the Nrf2 activation. ICR mice were orally administered 0.01-10 mg/kg body weight of luteolin once a day for 7 days at two time-points: at the start of active phase (ZT12) or at that of inactive phase (ZT0). Luteolin increased the nuclear translocation of Nrf2, resulting in the increases in its target gene products HO-1 and NQO1 at ZT12 but not at ZT0. The expression level of Nrf2 was lower at ZT12 than at ZT0 in the liver. We also found that the level of luteolin aglycon in the plasma is higher at ZT12 than at ZT0. These results suggest that the low dose of luteolin can activate Nrf2 pathway and the aglycon form of luteolin may mainly contribute to activate the Nrf2 pathway at ZT12 in the liver.

[The Italian contribution to studies on the biological rhythms implicated in psychiatric disorders]. / Il contributo italiano agli studi sui ritmi biologici implicati nei disturbi psichiatrici.

This editorial summarizes the main studies, carried out in the last 10 years, by various Italian research groups, on the alterations of circadian rhythms in psychiatric disorders. The results of these researches, as well as those obtained in various international contexts, encourage to teach in the medical schools for psychiatry, about the new chronoterapeutic interventions and the implementation of combined therapies for increasingly personalized psychiatric therapies.

Estimating Representative Group Intrinsic Circadian Period from Illuminance-Response Curve Data.

The human circadian pacemaker entrains to the 24-h day, but interindividual differences in properties of the pacemaker, such as intrinsic period, affect chronotype and mediate responses to challenges to the circadian system, such as shift work and jet lag, and the efficacy of therapeutic interventions such as light therapy. Robust characterization of circadian properties requires desynchronization of the circadian system from the rest-activity cycle, and these forced desynchrony protocols are very time and resource intensive. However, circadian protocols designed to derive the relationship between light intensity and phase shift, which is inherently affected by intrinsic period, may be applied more broadly. To exploit this relationship, we applied a mathematical model of the human circadian pacemaker with a Markov-Chain Monte Carlo parameter estimation algorithm to estimate the representative group intrinsic period for a group of participants using their collective illuminance-response curve data. We first validated this methodology using simulated illuminance-response curve data in which the intrinsic period was known. Over a physiological range of intrinsic periods, this method accurately estimated the representative intrinsic period of the group. We also applied the method to previously published experimental data describing the illuminance-response curve for a group of healthy adult participants. We estimated the study participants' representative group intrinsic period to be 24.26 and 24.27 h using uniform and normal priors, respectively, consistent with estimates of the average intrinsic period of healthy adults determined using forced desynchrony protocols. Our results establish an approach to estimate a population's representative intrinsic period from illuminance-response curve data, thereby facilitating the characterization of intrinsic period across a broader range of participant populations than could be studied using forced desynchrony protocols. Future applications of this approach may improve the understanding of demographic differences in the intrinsic circadian period.

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.

Circadian regulation of membrane physiology in neural oscillators throughout the brain.

Twenty-four-hour rhythmicity in physiology and behavior are driven by changes in neurophysiological activity that vary across the light-dark and rest-activity cycle. Although this neural code is most prominent in neurons of the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, there are many other regions in the brain where region-specific function and behavioral rhythmicity may be encoded by changes in electrical properties of those neurons. In this review, we explore the existing evidence for molecular clocks and/or neurophysiological rhythms (i.e., 24 hr) in brain regions outside the SCN. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators. For example, the cerebellum expresses rhythmicity in over 2,000 gene transcripts, and yet we know very little about how circadian regulation drives 24-hr changes in the neural coding responsible for motor coordination. Finally, we conclude with a discussion of how our understanding of circadian regulation of electrical properties may yield insight into disease mechanisms which may lead to novel chronotherapeutic strategies in the future.

Dynamics of sleep oscillations is coupled to brain temperature on multiple scales.

KEY POINTS: Sleep spindle frequency positively, duration negatively correlates with brain temperature. Local heating of the thalamus produces similar effects in the heated area. Thalamic network model corroborates temperature dependence of sleep spindle frequency. Brain temperature shows spontaneous microfluctuations during both anesthesia and natural sleep. Larger fluctuations are associated with epochs of REM sleep. Smaller fluctuations correspond to the alteration of spindling and delta epochs of infra-slow oscillation. ABSTRACT: Every form of neural activity depends on temperature, yet its relationship to brain rhythms is poorly understood. In this work we examined how sleep spindles are influenced by changing brain temperatures and how brain temperature is influenced by sleep oscillations. We employed a novel thermoelectrode designed for measuring temperature while recording neural activity. We found that spindle frequency is positively correlated and duration negatively correlated with brain temperature. Local heating of the thalamus replicated the temperature dependence of spindle parameters in the heated area only, suggesting biophysical rather than global modulatory mechanisms, a finding also supported by a thalamic network model. Finally, we show that switches between oscillatory states also influence brain temperature on a shorter and smaller scale. Epochs of paradoxical sleep as well as the infra-slow oscillation were associated with brain temperature fluctuations below 0.2°C. Our results highlight that brain temperature is massively intertwined with sleep oscillations on various time scales.

[Evaluation of Naturally Occurring Compounds Regulating Brown/Beige Adipocyte Differentiation].

Brown adipose tissue is a critical regulator of metabolic health, and contributes to thermogenesis by uncoupling oxidative phosphorylation through the action of mitochondrial uncoupling protein 1 (Ucp1). Recent studies have shown that cold exposure and the stimulation of ß3-adrenergic receptors induce the development of brown cell-like "beige" adipocytes in white adipose tissue. Brown and/or beige adipocyte-mediated thermogenesis suppresses high-fat diet-associated obesity. Therefore, the development of brown/beige adipocytes may prevent obesity and metabolic diseases. In the present study, we elucidated whether naturally occurring compounds contribute to regulating the cellular differentiation of brown/beige adipocytes. We screened for the up-regulated expression of Ucp1 during beige adipogenesis using extracts of crude herbal drugs frequently used in Kampo prescriptions (therapeutic drugs in Japanese traditional medicine). This screening revealed that the extract prepared from Citri Unshiu Pericarpium [the peel of Citrus unshiu (Swingle) Marcov.] increased the expression of Ucp1 in beige adipocytes. We also focused on the function of clock genes in regulating brown/beige adipogenesis. Therefore, another aim of the present study was to evaluate naturally occurring compounds that regulate brain and muscle Arnt-like 1 (Bmal1) gene expression. In this review, we focus on naturally occurring compounds that affect regulatory processes in brown/beige adipogenesis, and discuss better preventive strategies for the management of obesity and other metabolic disorders.

Extreme sleep pattern in Lewy body dementia: a hypothalamic matter?

Excessive sleep during the night and for >2 hours during the day is part of the fluctuating wakefulness criterion of dementia with Lewy bodies (DLB). The phenomenon 'sleep days' is not uncommon in nursing homes. Here, we describe a woman who, for months, slept for 3 days and nights in a row and thereafter was awake for 3 days and nights. Electroencephalogram (EEG) showed slow background activity and increased delta activity. No epileptiform activity was detected. Polysomnography showed a severely disturbed, markedly fragmented sleep pattern. On her death, neuropathology revealed degeneration and loss of neurons along with α-synuclein-containing Lewy body inclusions and neurites in the substantia nigra, locus coeruleus, hypothalamus, and neocortex, thus fulfilling the criteria of DLB, cortical type. We propose that the hypothalamic degeneration contributed significantly to the clinical profile in this case. We suggest that patients with sleep days should be investigated for other DLB signs.

Biomolecular Composition and Revenue Explained by Interactions between Extrinsic Factors and Endogenous Rhythms of Saccharina latissima.

This review provides a systematic overview of the spatial and temporal variations in the content of biomolecular constituents of Saccharina latissima on the basis of 34 currently-available scientific studies containing primary measurements. We demonstrate the potential revenue of seaweed production and biorefinery systems by compiling a product portfolio of high-value extract products. An investigation into the endogenous rhythms and extrinsic factors that impact the biomolecular composition of S. latissima is presented, and key performance factors for optimizing seaweed production are identified. Besides the provisioning ecosystem service, we highlight the contribution of green-engineered seaweed production systems to the mitigation of the ongoing and historical anthropogenic disturbances of the climate balance and nutrient flows. We conclude that there are risks of mismanagement, and we stress the importance and necessity of creating an adaptive ecosystem-based management framework within a triple-helix partnership for balancing the utilization of ecosystem services and long-term resilience of aquatic environment.

Biological clocks, some clock-related diseases, and medicinal plants.

Progress in chronobiology thus far has been built on botanical field investigation records, experiments on the development of biological clocks, open questions, established rules, and molecular mechanisms. In this review, three clock-related diseases, namely cancer, Alzheimer's disease (AD), and depression, are discussed. Evidence-based mechanisms of action of active compounds, namely epigallocatechin-3-gallate (EGCG), curcumin, and melatonin, from three medicinal plants, Camellia sinensis K., Curcuma longa L., and Hypericum perforatum L., respectively, as potential therapies against cancer, AD, and depression, respectively, have been explained. Feedback loops of basic inputs and application outputs of various studies will lead to the development of chronobiology for applications in time-keeping, disease prevention, and control, and future agricultural practices.