Network Dynamics Mediate Circadian Clock Plasticity

A circadian clock governs most aspects of mammalian behavior. Although its properties are in part genetically determined, altered light-dark environment can change circadian period length through a mechanism requiring de novo DNA methylation. We show here that this mechanism is mediated not via cell-autonomous clock properties, but rather through altered networking within the suprachiasmatic nuclei (SCN), the circadian “master clock,” which is DNA methylated in region-specific manner. DNA methylation is necessary to temporally reorganize circadian phasing among SCN neurons, which in turn changes the period length of the network as a whole. Interruption of neural communication by inhibiting neuronal firing or by physical cutting suppresses both SCN reorganization and period changes. Mathematical modeling suggests, and experiments confirm, that this SCN reorganization depends upon GABAergic signaling. Our results therefore show that basic circadian clock properties are governed by dynamic interactions among SCN neurons, with neuroadaptations in network function driven by the environment

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

Environmental control of biological rhythms: effects on development, fertility and metabolism

Internal temporal organisation properly synchronised to the environment is crucial for health maintenance. This organisation is provided at the cellular level by the molecular clock, a macromolecular transcription-based oscillator formed by the clock and the clock-controlled genes that is present in both central and peripheral tissues. In mammals, melanopsin in light-sensitive retinal ganglion cells plays a considerable role in the synchronisation of the circadian timing system to the daily light/dark cycle. Melatonin, a hormone synthesised in the pineal gland exclusively at night and an output of the central clock, has a fundamental role in regulating/timing several physiological functions, including glucose homeostasis, insulin secretion and energy metabolism. As such, metabolism is severely impaired after a reduction in melatonin production. Furthermore, light pollution during the night and shift work schedules can abrogate melatonin synthesis and impair homeostasis. Chronodisruption during pregnancy has deleterious effects on the health of progeny, including metabolic, cardiovascular and cognitive dysfunction. Developmental programming by steroids or steroid-mimetic compounds also produces internal circadian disorganisation that may be a significant factor in the aetiology of fertility disorders such as polycystic ovary syndrome. Thus, both early and late in life, pernicious alterations of the endogenous temporal order by environmental factors can disrupt the homeostatic function of the circadian timing system, leading to pathophysiology and/or disease.This work was supported by grants 1110220 from FONDECYT and ACT1116 from CONICYT, Chile (to HGR); Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Tecnológico e Científico (CNPq; Brazil, to AMC, FGA and JCN); Pro-Reitoria de Pesquisa Universidade Federal de Minas Gerais, Brazil (to MOP); fellowship 21120472 from CONICYT (Chile) to (NM) and an NIEHS sponsored Pilot Grant from the Department of Environmental Medicine at the University of Rochester School of Medicine to MTS

Circadian Rhythms in Urinary Functions: Possible Roles of Circadian Clocks?

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In this review, we briefly introduce circadian clocks and their organization in mammals. We then summarize known daily or circadian variations in urinary function. Importantly, recent findings by others as well as results obtained by us suggest an active role of circadian clock genes in various urinary functions. Finally, we discuss possible research avenues for the circadian control of urinary function

Effects of circadian disruption on physiology and pathology: from bench to clinic (and back)

Nested within the hypothalamus, the suprachiasmatic nuclei (SCN) represent a central biological clock that regulates daily and circadian (i.e., close to 24 h) rhythms in mammals. Besides the SCN, a number of peripheral oscillators throughout the body control local rhythms and are usually kept in pace by the central clock. In order to represent an adaptive value, circadian rhythms must be entrained by environmental signals or zeitgebers, the main one being the daily light?dark (LD) cycle. The SCN adopt a stable phase relationship with the LD cycle that, when challenged, results in abrupt or chronic changes in overt rhythms and, in turn, in physiological, behavioral, and metabolic variables. Changes in entrainment, both acute and chronic, may have severe consequences in human performance and pathological outcome. Indeed, animal models of desynchronization have become a useful tool to understand such changes and to evaluate potential treatments in human subjects. Here we review a number of alterations in circadian entrainment, including jet lag, social jet lag (i.e., desynchronization between body rhythms and normal time schedules), shift work, and exposure to nocturnal light, both in human subjects and in laboratory animals. Finally, we focus on the health consequences related to circadian/entrainment disorders and propose a number of approaches for the management of circadian desynchronization.Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Circadian rhythms and fertility

Circadian rhythms impact on a wide range of physiological systems and this impact extends to fertility, such that disruptions to timing systems can impact upon reproductive capacity. This is highlighted most obviously in mutant mouse models whereby deletion or mutation of single genes results not only in disrupted circadian rhythmicity, but also compromised male and female reproductive function. In this review, we discuss the presence of circadian clocks in female and male reproductive tissues and the role these clocks play in the generation of oestrus cycles, ovulation, sperm generation, implantation and the maintenance of pregnancy. Given the increased incidence of shiftwork and international travel which disrupt circadian rhythmicity, and the increasing prevalence of reproductive technologies whereby early embryo development occurs without external time cues, it is important for us to consider the role of circadian rhythms in fertility.David J. Kennaway, Michael J. Boden and Tamara J. Varco

Clocks underneath: the role of peripheral clocks in the timing of female reproductive physiology

The central circadian pacemaker in the suprachiasmatic nucleus (SCN) is a critical component of the neuroendocrine circuit controlling gonadotropin secretion from the pituitary gland. The SCN conveys photic information to hypothalamic targets including the gonadotropin releasing hormone (GnRH) neurons. Many of these target cells are also cell autonomous clocks. It has been suggested that, rather then being singularly driven by the SCN, the timing of gonadotropin secretion depends on the activity of multiple hypothalamic oscillators. While this view provides a novel twist to an old story, it does little to diminish the central role of rhythmic hypothalamic output in this system. It is now clear that the pituitary, ovary, uterus and oviduct have functional molecular clocks. Evidence supports the notion that the clocks in these tissues contribute to the timing of events in reproductive physiology. The goal of this review is to highlight the current evidence for molecular clock function in the peripheral components of the female hypothalamo-pituitary-gonadal (HPG) axis as it relates to the timing of gonadotropin secretion, ovulation and parturition