bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flies and Fish: Birds of a Feather
Authors: Katherine Tamai T. , Vardhanabhuti V. , Arthur S. , Foulkes N. S. , Whitmore D. 
Published: May 2003

AbstractThe identification of specific clock‐containing structures has been a major endeavour of the circadian field for many years. This has lead to the identification of many key components of the circadian system, including the suprachiasmatic nucleus in mammals, and the eyes and pineal glands in lower vertebrates. However, the idea that these structures represent the only clocks in animals has been challenged by the discovery of peripheral pacemakers in most organs and tissues, and even a number of cell lines. In Drosophila, and vertebrates such as the zebrafish, these peripheral clocks appear to be highly autonomous, being set directly by the environmental light/dark cycle. However, a hierarchy of clocks may still exist in mammals. In this review, we examine some of the current views regarding peripheral clocks, their organization and how they are entrained.
Importance and Relevance of Melatonin to Human Biological Rhythms
Authors: Arendt J. 
Published: May 2003

AbstractThe pineal hormone melatonin is a remarkable molecule, with a conserved time‐keeping function across species. It is extensively used as a self‐administered remedy for sleep disturbance in countries where it is freely available, and to some extent when it is available on prescription, as in the UK. In some circumstances, notably free‐running sleep disorder of the blind, it is the treatment of choice. It is also the marker rhythm of choice for the determination of circadian phase and period. This review outlines the current state of knowledge within a physiological perspective with emphasis on human biological rhythms.
Sensitization: A Mechanism for Melatonin Action in the Pars Tuberalis
Authors: Barrett P. , Schuster C. , Mercer J. , Morgan P. J. 
Published: May 2003

AbstractSensitization of adenylate cyclase is a recently discovered phenomenon. Melatonin can induce a sensitized response of adenylate cyclase in ovine pars tuberalis cells where the receptor for melatonin is endogenously expressed. Although the mechanism is not fully understood, sensitization of adenylate cyclase may be an important part of the mechanism by which melatonin encodes daylength in the pars tuberalis of sheep and other animals. We used this as a hypothesis to search for a natural ligand that would activate adenylate cyclase in ovine pars tuberalis cells. The approach revealed pituitary adenylate cyclase activating polypeptide to be an indirect activator of adenylate cyclase in the ovine pars tuberalis. We discuss this in relation to the mechanism and importance of sensitization to the function to the pars tuberalis.
Role of Melatonin in the Regulation of Human Circadian Rhythms and Sleep
Authors: Cajochen C. , Kräuchi K. , Wirz‐Justice A. 
Published: May 2003

AbstractThe circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.
Clock Genes and the Long‐Term Regulation of Prolactin Secretion: Evidence for a Photoperiod/Circannual Timer in the Pars Tuberalis
Authors: Lincoln G. A. , Andersson H. , Hazlerigg D. 
Published: May 2003

AbstractProlactin secretion is regulated by photoperiod through changes in the 24‐h melatonin profile and displays circannual rhythmicity under constant photoperiod. These two processes appear to occur principally within the pituitary gland, controlled by the pars tuberalis. This is evident because: (i) hypothalamic‐pituitary disconnected (HPD) sheep show marked changes in prolactin secretion in response to switches in photoperiod and manipulations of melatonin, similar to brain‐intact controls; (ii) HPD sheep also show photoperiod‐specific, long‐term cycles in prolactin secretion under constant long or short days, with the timing maintained even when prolactin secretion is blocked for 2–3 months; and (iii) pars tuberalis cells, but not lactotrophs, express high concentrations of melatonin (MT1) receptor, and exhibit a duration‐sensitive, cAMP‐dependant, inhibitory response to physiological concentrations of melatonin. This suggests the existence of an intrinsic, reversible photoperiod‐circannual timer in pars tuberalis cells. A full complement of clock genes (Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the ovine pars tuberalis, and undergo 24‐h cyclical expression as observed in a cell autonomous, circadian clock. Activation of Per genes occurs in the early day (melatonin off‐set), while activation of Cry genes occurs in the early night (melatonin on‐set). This temporal association is evident under both long and short days, thus the Per–Cry interval varies directly with photoperiod. Because, PER : CRY, protein : protein interactions affect stability, nuclear entry and gene transcription based on rodent data, the change in phasing of Per/Cry expression provides a potential mechanism for decoding the long day/short day melatonin signal. A speculative, but testable, extension of this hypothesis is that intrinsically regulated changes in the phase of Per/Cry rhythms, regulates both photorefractoriness and the generation of circannual rhythms in prolactin secretion.
The Circadian Clock: A Manager of Biochemical Processes Within the Organism
Authors: Holzberg D. , Albrecht U. 
Published: May 2003

AbstractThe periodic succession of night and day has influenced life on earth for millions of years. Many organisms have ‘internalized’ this periodic change in the form of the circadian clock. Its main function is to organize the time course of biochemical, physiological and behavioural processes thereby optimizing an organism's performance in anticipating changing environmental conditions. Therefore, it is important to understand the underlying mechanisms that connect the core pacemaker, which is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, with peripheral organs. Several laboratories set out to identify genes that are under the influence of the circadian clock. It appears that the circadian clock coordinates transcription of key metabolic pathways thereby orchestrating the time course of physiological and behavioural processes. We review these investigations and put our experiments, the comparison of gene expression in SCN tissue of Per2 mutant and wild‐type mice, in the context of these findings.
Genetic, Temporal and Developmental Differences Between Melatonin Rhythm Generating Systems in the Teleost Fish Pineal Organ and Retina
Authors: Falcón J. , Gothilf Y. , Coon S. L. , Boeuf G. , Klein D. C. 
Published: May 2003

AbstractComplete melatonin rhythm generating systems, including photodetector, circadian clock and melatonin synthesis machinery, are located within individual photoreceptor cells in two sites in Teleost fish: the pineal organ and retina. In both, light regulates daily variations in melatonin secretion by controlling the activity of arylalkylamine N‐acetyltransferase (AANAT). However, in each species examined to date, marked differences exist between the two organs which may involve the genes encoding the photopigments, genes encoding AANAT, the times of day at which AANAT activity and melatonin production peak and the developmental schedule. We review the fish pineal and retinal melatonin rhythm generating systems and consider the evolutional pressures and other factors which led to these differences.
Molecular Control of Xenopus Retinal Circadian Rhythms
Authors: Green C. B. 
Published: May 2003

AbstractVertebrate retinas contain endogenous circadian clocks that control many aspects of retinal physiology. Our work has focused on studying the molecular mechanism of this clock and the way in which it controls the many cellular rhythms within the retina. These studies focus on the retina of Xenopus laevis, a well‐established model system extensively used for the study of both retinal physiology and circadian function. We have cloned Xenopus homologues of the genes thought to be critical for vertebrate clock function, including Clock, Bmal1, cryptochromes and period, as well as other rhythmic genes such as nocturnin. We have used these genes to manipulate the clock within different subsets of retinal photoreceptors via cell‐specific promoters, in order to study the location of the clock within the retina. These in vivo experiments have shown that photoreceptor cells contain clocks that are necessary for the rhythmic production of melatonin. We have also used biochemical approaches to further investigate the molecular events that drive specific rhythmic outputs, such as circadian regulation of nocturnin gene transcription and control of post‐transcriptional events within these clock‐containing cells.
14‐3‐3 Proteins in Pineal Photoneuroendocrine Transduction: How Many Roles?
Authors: Klein D. C. , Ganguly S. , Coon S. L. , Shi Q. , Gaildrat P. , Morin F. , Weller J. L. , Obsil T. , Hickman A. , Dyda F. 
Published: May 2003

AbstractRecent studies suggest that a common theme links the diverse elements of pineal photoneuroendocrine transduction –regulation via binding to 14‐3‐3 proteins. The elements include photoreception, neurotransmission, signal transduction and the synthesis of melatonin from tryptophan. We review general aspects of 14‐3‐3 proteins and their biological function as binding partners, and also focus on their roles in pineal photoneuroendocrine transduction.
Melatonin: A Clock‐Output, A Clock‐Input
Authors: Stehle J. H. , Von Gall C. , Korf H.‐W. 
Published: May 2003

AbstractIn mammals, the circadian system is comprised of three major components: the lateral eyes, the hypothalamic suprachiasmatic nucleus (SCN) and the pineal gland. The SCN harbours the endogenous oscillator that is entrained every day to the ambient lighting conditions via retinal input. Among the many circadian rhythms in the body that are driven by SCN output, the synthesis of melatonin in the pineal gland functions as a hormonal message encoding for the duration of darkness. Dissemination of this circadian information relies on the activation of melatonin receptors, which are most prominently expressed in the SCN, and the hypophyseal pars tuberalis (PT), but also in many other tissues. A deficiency in melatonin, or a lack in melatonin receptors should therefore have effects on circadian biology. However, our investigations of mice that are melatonin‐proficient with mice that do not make melatonin, or alternatively cannot interpret the melatonin message, revealed that melatonin has only minor effects on signal transduction processes within the SCN and sets, at most, the gain for clock error signals mediated via the retino‐hypothalamic tract. Melatonin deficiency has no effect on the rhythm generation, or on the maintenance of the oscillation. By contrast, melatonin is essential for rhythmic signalling in the PT. Here, melatonin acts in concert with adenosine to elicit rhythms in clock gene expression. By sensitizing adenylyl cyclase, melatonin opens a temporally‐restricted gate and thus lowers the threshold for adenosine to induce cAMP‐sensitive genes. This interaction, which determines a temporally precise regulation of gene expression, and by endocrine–endocrine interactions possibly also pituitary output, may reflect a general mechanism by which the master clock in the brain synchronizes clock cells in peripheral tissues that require unique phasing of output signals.
Encoding Time of Day and Time of Year by the Avian Circadian System
Authors: Brandstätter R. 
Published: May 2003

AbstractThe most important zeitgeber for seasonal rhythmicity of physiology and behaviour in birds is the annual cycle of photoperiod. Regulatory mechanisms are less well understood in birds than in mammals since photic information can be perceived by photoreceptors in the retina and the pineal gland, as well as in the brain, and photoperiodic time measurement might be performed with reference to at least three autonomous circadian systems, the retina, the pineal gland and a hypothalamic oscillator. In many bird species, the pineal melatonin rhythm plays a central role in circadian organization. Durations of elevated melatonin in the blood reflect night length when animals are kept under natural photoperiodic conditions, as well as under different light/dark schedules in the laboratory. In the house sparrow, time of year is encoded in a particular melatonin signal, being short in duration and high in amplitude in long photoperiods and being long in duration and low in amplitude in short photoperiods, independent of whether the light zeitgeber is natural or artificial or varies in strength. Specific features of the melatonin signal are retained in vivo as well as in vitro when birds or isolated pineal glands are transferred to constant conditions. To regulate daily and seasonal changes of behaviour and physiology, melatonin may act at various target sites, including a complex hypothalamic oscillator that, unlike that in mammals, is not confined to a single cell group in the house sparrow. There is increasing evidence that interactions between two or more components of the songbird circadian pacemaking system are essential to encode and store biologically meaningful information about time, and thus provide the basis for photoperiodic time measurements and after effects in birds.
The Photoreceptive Capacity of the Developing Pineal Gland and Eye of the Golden Hamster (Mesocricetus auratus)
Authors: Foster R. G. , Provencio I. , Bovee‐Geurts P. H. M. , DeGrip W. J. 
Published: May 2003

AbstractAnatomical and physiological studies have suggested that the pineal gland of neonatal mammals has a photoreceptive capacity. Using the golden hamster (Mesocricetus auratus) as our model, we applied biochemical approaches to look for a functional photopigment within the pineal during early development. Immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA) were used to localize and quantify opsin, and high‐performance liquid chromatography (HPLC) to identify photopigment chromophore (11‐cis and all‐trans retinaldehyde) in the developing eye and pineal. For HPLC analysis, retinaldehydes were converted to their corresponding retinoid oximes. Eluted retinoids were identified by comparison with standard vitamin A1 retinoid oxime isomers on the basis of relative elution sequence and characteristic absorbance spectra. Both immunocytochemistry and ELISA suggested an increase in the opsin content of the pineal during the first week of life. In the eye, 11‐cis retinaldehyde was first detected between days 3 and 5 after birth. In three separate extractions, and using a considerable excess of pineal tissue, we failed to identify chromophore within the pineal during the first week of postnatal development. The appearance of 11‐cis retinaldehyde within the eye between postnatal days 3–5 is consistent with the hypothesis that retinol isomerase activity is coordinated with outer segment development. The failure to identify chromophore within the neonatal pineal suggests that this gland lacks a functional opsin‐based photopigment. These data contradict physiological evidence suggesting that the neonatal pineal of mammals contains photoreceptors.
An Essential Role for Peptidergic Signalling in the Control of Circadian Rhythms in the Suprachiasmatic Nuclei
Authors: Harmar A. J. 
Published: May 2003

AbstractTwo structurally related neuropeptides, pituitary adenylate cyclase‐activating polypeptide (PACAP), colocalized with glutamate in neurones of the retinohypothalamic tract, and vasoactive intestinal peptide (VIP), present in light‐responsive cells of the suprachiasmatic nuclei (SCN), appear to play distinct and important roles in the control of mammalian circadian rhythms. Mice deficient in the PACAP‐selective PAC1 receptor exhibit altered responsiveness of the SCN clock to light‐induced phase‐shifts, but display robust circadian patterns of wheel‐running behaviour. By contrast, our studies of mice lacking the VPAC2 receptor, which responds to both PACAP and VIP, indicate that this receptor plays a critical role in rhythm generation in the SCN. The predominant factor determining wheel‐running activity in VPAC2 receptor null (Vipr2–/–) mice is ‘masking’ by light. Mutant animals re‐entrain immediately to advances or delays in the light/dark cycle and do not exhibit robust circadian rhythms of behaviour when in constant darkness. The mice do not exhibit circadian expression of core clock genes (mPer1, mPer2, mCry1), or of the clock‐controlled gene arginine vasopressin (AVP), in the SCN. We propose that VIP signalling between SCN neurones provides a paracrine reinforcing signal that is essential for sustained rhythm generation. The presence of VIP signalling in the SCN may explain why SCN neurones are capable of generating long‐lasting self‐sustained oscillations, whereas rhythmic clock gene expression in other tissues is dependent on periodic reinforcement by neural or hormonal signals.
Optimization of Light and Melatonin to Phase‐Shift Human Circadian Rhythms
Authors: Skene D. J. 
Published: May 2003

AbstractBoth light and melatonin, appropriately timed, have been shown to phase‐shift human circadian rhythms. In addition, both light and melatonin have acute physiological and behavioural effects. Depending on the dose, melatonin can reduce core body temperature and induce sleepiness. Conversely, light at night increases body temperature and enhances alertness and performance. The acute and phase‐shifting effects of light and melatonin have justified their investigation and use in the treatment of circadian rhythm sleep disorders. Melatonin is the treatment of choice for blind people with non‐24 h sleep/wake disorder. Current research is directed towards optimizing these therapies with respect to time of administration, dose and formulation of melatonin, intensity, duration and spectral composition of light. Our studies in totally blind people with non‐24 h sleep/wake disorder have shown that, in addition to improving sleep, daily administration of melatonin can entrain their free‐running circadian rhythms. The ability of melatonin to entrain free‐running rhythms depends, in part, on the time of melatonin administration relative to the subject's circadian phase. Subjects who were entrained by melatonin began their treatment in the phase advance portion (CT 6–18) of the published melatonin phase‐response curves (PRCs), whereas those who failed to entrain began their melatonin treatment in the delay portion of the PRC. Whether the effect of light on the human circadian axis can be optimized by altering its spectral composition has been investigated. Recently, it was demonstrated that light‐induced melatonin suppression in humans is sensitive to short wavelength light (420–480 nm; λmax approximately 460 nm), a response very different to the classical scotopic and photopic visual systems. Whether other nonvisual light responses (e.g. circadian phase resetting) show a similar spectral sensitivity is currently being studied.
Leptin and Seasonal Mammals
Authors: Rousseau K. , Atcha Z. , Loudon A. S. I. 
Published: May 2003

AbstractSeasonal mammals commonly exhibit robust annual cycles of adiposity, food intake and energy metabolism. These cycles are driven by changes in the external daylength signal, which generates a diurnal melatonin profile and acts on neuroendocrine pathways. The white adipose tissue hormone leptin reflects overall adiposity in seasonal mammals, and consequently undergoes significant seasonal fluctuations in secretion. The seasonally breeding Siberian (Djungarian) hamster is a convenient laboratory model to study the effect of a seasonal time‐keeping clock on energy metabolism, appetite regulation and the control of adiposity. We have shown that administration of exogenous leptin at physiological doses induces significant loss of adipose tissue for short‐day housed winter‐like hamsters in which endogenous adipose tissue and leptin concentrations are already low. By contrast, long‐day housed hamsters with high adipose tissue reserves are refractory to the effects of leptin. This phenomenon of seasonal leptin resistance appears to be a general feature of other seasonally breeding mammals, and may reflect the operation of an annual timer controlling leptin uptake and/or action on central nervous system signal transduction pathways. The mobilization of fat by leptin in short‐day housed hamsters is not associated with changes in expression in either anorexic or anabolic peptides expressed in leptin‐receptor rich structures in the arcuate region of the hypothalamus, and suggests that leptin may target other structures. These data contrast with studies, which show that homeostatic mechanisms in response to feed‐restriction induce changes in hypothalamic peptides in a similar manner to nonphotoperiodic species. Thus, the long‐term seasonal regulation of body weight set point and leptin feedback may operate through separate pathways to those responsible for acute responses to food restriction.
Therapeutic Perspectives for Melatonin Agonists and Antagonists
Authors: Delagrange P. , Atkinson J. , Boutin J. A. , Casteilla L. , Lesieur D. , Misslin R. , Pellissier S. , Pénicaud L. , Renard P. 
Published: May 2003

AbstractMelatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic‐like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion‐induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.