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PubMed2001

Persistence of oviposition rhythm in individuals of Drosophila melanogaster reared in an aperiodic environment for several hundred generations.

The oviposition rhythm of individual flies of Drosophila melanogaster from a population maintained in an aperiodic environment (with light, temperature, humidity, and other factors which could provide time cues, kept constant) for several hundred generations was assayed in constant light (LL), in light/dark (LD 12:12 hr) cycle, and in constant darkness (DD). More than 50% of the flies assayed exhibited rhythmicity in oviposition in all three light regimes. The results indicate that the phenomenon of egg laying is rhythmic in individual D. melanogaster females and is controlled by an endogenous time keeping mechanism. The persistence of the oviposition rhythm in a large proportion of individuals in the population after several hundred generations of rearing in a constant environment strengthens the view that possessing biological clocks may confer some intrinsic fitness advantage even to organisms living in aperiodic environments. J. Exp. Zool. 290:541-549, 2001.

Animals↗
PubMed2006

The aging suprachiasmatic nucleus and cytokines: functional, molecular, and cellular changes in rodents.

The aging process brings about a switch to a low-grade chronic inflammatory condition in the periphery and brain, a condition which may prime brain cells, including those of the hypothalamic suprachiasmatic nucleus (SCN). Little information is available, however, on the responses of the SCN to neuroinflammation and immune-related challenges, and such responses have not been hitherto investigated during aging. We here provide an overview of these issues and summarize data we obtained in the study of the SCN of young and aged mice. In particular, we analyzed: i) the electrophysiological properties of the SCN core (the retino-recipient region) in tissue slices; ii) expression and day/night variation of transcripts encoding the receptors for the cytokines interferon-gamma and tumor necrosis factor-alpha, as well as the expression of transcripts encoding the proteins "suppressors of cytokine signaling" SOCS1 and SOCS3, by means of quantitative real-time polymerase chain reaction; levels of mRNAs were correlated with neuronal activation, revealed by Fos induction, elicited in the SCN by intracerebroventricular injections of a mixture of interferon-gamma and tumor necrosis factor-alpha during the daytime and nighttime; and iii) response of astrocytes and microglia in the SCN to the same paradigm of cytokine administration. Marked changes of all the above-mentioned parameters were found in the aged SCN, indicating that the circadian pacemaker is a target of the aging process. In addition, the findings indicate that neurons and glial cells of the biological clock are sensitive to inflammatory signals, and that the response to such signals is altered during senescence.

Aging↗
PubMed2004

Daily rhythm and regulation of clock gene expression in the rat pineal gland.

Rhythms in pineal melatonin synthesis are controlled by the biological clock located in the suprachiasmatic nuclei. The endogenous clock oscillations rely upon genetic mechanisms involving clock genes coding for transcription factors working in negative and positive feedback loops. Most of these clock genes are expressed rhythmically in other tissues. Because of the peculiar role of the pineal gland in the photoneuroendocrine axis regulating biological rhythms, we studied whether clock genes are expressed in the rat pineal gland and how their expression is regulated.Per1, Per3, Cry2 and Cry1 clock genes are expressed in the pineal gland and their transcription is increased during the night. Analysis of the regulation of these pineal clock genes indicates that they may be categorized into two groups. Expression of Per1 and Cry2 genes shows the following features: (1) the 24 h rhythm persists, although damped, in constant darkness; (2) the nocturnal increase is abolished following light exposure or injection with a beta-adrenergic antagonist; and (3) the expression during daytime is stimulated by an injection with a beta-adrenergic agonist. In contrast, Per3 and Cry1 day and night mRNA levels are not responsive to adrenergic ligands (as previously reported for Per2) and daily expression of Per3 and Cry1 appears strongly damped or abolished in constant darkness. These data show that the expression of Per1 and Cry2 in the rat pineal gland is regulated by the clock-driven changes in norepinephrine, in a similar manner to the melatonin rhythm-generating enzyme arylalkylamine N-acetyltransferase. The expression of Per3 and Cry1 displays a daily rhythm not regulated by norepinephrine, suggesting the involvement of another day/night regulated transmitter(s).

Adrenergic beta-Agonists↗
PubMed1994

Reflections on viruses and cancer.

In recent years human and animal cancers have increasingly been shown to have a viral component in their aetiology. Oncogenic viruses will continue to be discovered although with certain cancers there is also an important environmental component, and with others--congenital cancers and cancers of early childhood--an important genetic component. There is thus the probability that 'cancer' may not be an entity. Rather it may be a syndrome, the phenotypic expression of alteration of cellular metabolism, differentiation and cell death. More information is needed on the mathematics of cell division and destruction, in vivo and in vitro, and the involvement of 'biological clocks', i.e. ageing processes. These data, when available, should help us to understand better the nature of cancer and lead us to more effective methods of prevention and cure.

Anemia↗
PubMed1995

Circadian rhythm generation in the cultured suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) of the hypothalamus is involved in the generation and entrainment of circadian rhythms. The results of a series of experiments in long-term cultured organotypic SCN slices suggest that (1) some but not all SCN neurons display circadian rhythmicity in their extracellular discharges. To the extent they could be studied, these neurons did not usually show synchronized high/low levels of activity; (2) simultaneous daily depolarization of these neurons (K+ pulses) to some extent influenced the distribution of the firing rate of SCN neurons around the time of expected daily pulses; (3) extracellular Ca++ and synaptic input is required for the pacemaker activity of the SCN. We conclude that the mammalian biological clock is a heterogeneous neuronal system in which the circadian pacemaker rhythm is generated and entrained via complex interactions among SCN neurons.

Animals↗
PubMed2006

Melatonin and human rhythms.

Melatonin signals time of day and time of year in mammals by virtue of its pattern of secretion, which defines 'biological night.' It is supremely important for research on the physiology and pathology of the human biological clock. Light suppresses melatonin secretion at night using pathways involved in circadian photoreception. The melatonin rhythm (as evidenced by its profile in plasma, saliva, or its major metabolite, 6-sulphatoxymelatonin [aMT6s] in urine) is the best peripheral index of the timing of the human circadian pacemaker. Light suppression and phase-shifting of the melatonin 24 h profile enables the characterization of human circadian photoreception, and circulating concentrations of the hormone are used to investigate the general properties of the human circadian system in health and disease. Suppression of melatonin by light at night has been invoked as a possible influence on major disease risk as there is increasing evidence for its oncostatic effects. Exogenous melatonin acts as a 'chronobiotic.' Acutely, it increases sleep propensity during 'biological day.' These properties have led to successful treatments for serveal circadian rhythm disorders. Endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. The future holds much promise for melatonin as a research tool and as a therapy for various conditions.

Biological Clocks↗
PubMed2006

The avian pineal gland.

The pineal gland plays a key role in the control of the daily and seasonal rhythms in most vertebrate species. In mammals, rhythmic melatonin (MT) release from the pineal gland is controlled by the suprachiasmatic nucleus via the sympathetic nervous system. In most non-mammalian species, including birds, the pineal gland contains a self-sustained circadian oscillator and several input channels to synchronize the clock, including direct light sensitivity. Avian pineal glands maintain rhythmic activity for days under in vitro conditions. Several physical (light, temperature, and magnetic field) and biochemical (Vasoactive intestinal polypeptide (VIP), norepinephrine, PACAP, etc.) input channels, influencing release of melatonin are also functional in vitro, rendering the explanted avian pineal an excellent model to study the circadian biological clock. Using a perifusion system, we here report that the phase of the circadian melatonin rhythm of the explanted chicken pineal gland can be entrained easily to photoperiods whose length approximates 24 h, even if the light period is extremely short, i.e., 3L:21D. When the length of the photoperiod significantly differs from 24 h, the endogenous MT rhythm becomes distorted and does not follow the light-dark cycle. When explanted chicken pineal fragments were exposed to various drugs targeting specific components of intracellular signal transduction cascades, only those affecting the cAMP-protein kinase-A system modified the MT release temporarily without phase-shifting the rhythm in MT release. The potential role of cGMP remains to be investigated.

Animals↗
PubMed1980

Urinary 3-methoxy-4-hydroxyphenylglycol circadian rhythm. Early timing (phase-advance) in manic-depressives compared with normal subjects.

Twenty-four-hour (circadian) rhythms in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, motor activity, and oral temperature were studied in 14 normal subjects and ten manic-depressive patients. In both groups, a daily rhythm in MHPG excretion was present, with daytime peaks and nighttime lows. This pattern of urinary MHPG excretion may reflect a rhythm in central noradrenergic function. The physiological changes in levels of MHPG excretion associated with the circadian rhythm were at least as great as pathological changes associated with manic-depressive illness. Compared with controls, the timing or phase of circadian rhythms in each variable was one to three hours earlier in the patients, whether depressed or manic. Although the presence of circadian rhythms complicates the task of designing clinical research procedures, their early timing in manic-depressives suggests that disturbances in central biological clocks may be an integral part of the pathophysiology of affective illness and may be related to disturbances of sleep and neuroendocrine function associated with depression.

Adult↗
PubMed2001

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.

Animals↗
PubMed2001

Enhanced NMDA receptor activity in retinal inputs to the rat suprachiasmatic nucleus during the subjective night.

Circadian oscillator mechanisms in the suprachiasmatic nucleus (SCN) can be reset by photic input, which is mediated by glutamatergic afferents originating in the retina. A key question is why light can only induce phase shifts of the biological clock during a restricted period of the circadian cycle, namely the subjective night. One of several possible mechanisms holds that glutamatergic transmission at retinosuprachiasmatic synapses would be altered, in particular the contribution of glutamate receptor subtypes to the postsynaptic response. By studying the contributions of NMDA and non-NMDA glutamate receptors to the retinal input to SCN in whole-cell patch-clamp recordings in acutely prepared slices, we tested the hypothesis that NMDA receptor current evoked by optic nerve activity is potentiated during the subjective night. During the day the NMDA component of the EPSC evoked by optic nerve stimulation was found less frequently and was significantly smaller in magnitude than during the night. In contrast, the non-NMDA component did not show a significant day-night difference. When the magnitude of the NMDA component was normalized to that of the non-NMDA component, the day-night difference was maintained, suggesting a selective potentiation of NMDA receptor conductance. In addition to contributing to electrically evoked EPSCs, the NMDA receptor was found to sustain a small, tonically active inward current during the night phase. No significant tonic contribution by NMDA receptors was detected during the day. These results suggest, first, a dual mode of NMDA receptor function in the SCN and, second, a clock-controlled type of receptor plasticity, which may gate the transfer of photic input to phase-shifting mechanisms operating at the level of molecular autoregulatory feedback loops.

Animals↗
PubMed2005

A functional subdivision of the circadian clock is revealed by differential effects of melatonin administration.

The biological clock of the suprachiasmatic nuclei drives numerous physiological and behavioural circadian rhythms. In this study, we addressed the question as to whether different components of the clock may control separately various circadian functions. Using the rat transpineal microdialysis tool, we analysed the effect of clock perturbation by exogenous melatonin injection on two hormonal clock outputs: pineal melatonin and adrenal corticosterone secretions. As already reported, a single melatonin injection at the light/dark transition induces a marked increase in the endogenous pineal melatonin peak for the two following days. In the same animals, by contrast, the amplitude of the corticosterone rhythm was not altered following melatonin injection. These data show that the melatonin injection does not display an overall effect on the circadian clock, but rather influences a subpopulation of melatonin-sensitive neurons involved, among other functions, in the circadian control of the pineal pathway.

Adrenal Cortex↗
PubMed2002

Perinatal neuroendocrine regulation. Development of the circadian time-keeping system.

During gestation, the perinatal neuroendocrine axis keeps clock time. In primates, the suprachiasmatic nucleus (biological clock in mammals), shows oscillatory function by midgestation. There is evidence in rodents that the mother, during pregnancy, entrains the fetal suprachiasmatic nucleus (SCN) and newborn circadian rhythms. We are investigating the role of maternal melatonin as an entraining signal for the newborn circadian time-keeping system in the Cebus apella (New World non-human primate). Twenty-four hour rhythms of temperature and cortisol are present in the 4 days old C. apella newborn. Preliminary data suggests that inhibition of maternal melatonin by exposing pregnant females to constant light alters these rhythms. We have found binding sites for melatonin and expression of mRNA for Mel 1A receptor in hypothalamus, kidney and testis. These preliminary results suggest that maternal melatonin may play a role in relating the perinatal circadian time-keeping system to environmental signals.

Animals↗
PubMed1988

On the role of protein synthesis in the circadian clock of Neurospora crassa.

Inhibitors of protein synthesis reset the biological clocks of many organisms. This has been interpreted to mean either that the synthesis per se of proteins is a step in the oscillatory feedback loop or merely that certain unstable protein(s) are required at certain times of the cycle to complete the feedback loop. We report here that Neurospora strains bearing the clock mutation frq-7 are relatively insensitive to the resetting action of the protein-synthesis-inhibitor cycloheximide. Protein synthesis itself in this mutant is inhibited by the drug to the same extent as in wild type. Since the clock of frq-7 continues to run relatively unimpeded even in the virtual absence of protein synthesis, it is unlikely that synthesis per se can be a part of the feedback cycle. Rather, we suggest that for normal operation of the Neurospora clock, certain protein(s) with a high turnover rate are required daily and, thus, must be resynthesized each day (at least) during discrete times in the cycle. The frq-7 mutation simultaneously alters several distinct clock characteristics--period length, temperature compensation, and resetting by cycloheximide. A model is presented to unify these observations.

Circadian Rhythm↗
PubMed2006

Hypocretins: the timing of sleep and waking.

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep- and wake-promoting neurons in the hypothalamus to form a bistable switch that controls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.

Behavior↗
PubMed2000

A synthetic oscillatory network of transcriptional regulators.

Networks of interacting biomolecules carry out many essential functions in living cells, but the 'design principles' underlying the functioning of such intracellular networks remain poorly understood, despite intensive efforts including quantitative analysis of relatively simple systems. Here we present a complementary approach to this problem: the design and construction of a synthetic network to implement a particular function. We used three transcriptional repressor systems that are not part of any natural biological clock to build an oscillating network, termed the repressilator, in Escherichia coli. The network periodically induces the synthesis of green fluorescent protein as a readout of its state in individual cells. The resulting oscillations, with typical periods of hours, are slower than the cell-division cycle, so the state of the oscillator has to be transmitted from generation to generation. This artificial clock displays noisy behaviour, possibly because of stochastic fluctuations of its components. Such 'rational network design may lead both to the engineering of new cellular behaviours and to an improved understanding of naturally occurring networks.

Bacterial Proteins↗
PubMed2005

Clocks and the black box: circadian influences on gonadotropin-releasing hormone secretion.

Although the mechanisms underlying hypothalamic surge secretion of gonadotropin-releasing hormone (GnRH) in rodent models have remained enduring mysteries in the field of neuroendocrinology, the identities of two fundamental constituents are clear. Elevated ovarian oestrogen, in conjunction with circadian signals, combine to elicit GnRH surges that are confined to the afternoon of the proestrus phase. The phenomenon of oestrogen positive feedback, although extensively investigated, is not completely understood, and may involve the actions of this steroid directly on GnRH perikarya, as well as on the activity of neuronal afferents. Additionally, whereas many studies have focused upon regulation of GnRH surge secretion by the neuroanatomical biological clock, the suprachiasmatic nucleus, it remains unclear why this daily signal is capable of stimulating surges only in the presence of oestrogen. This review re-examines multiple models of circadian control of reproductive neurosecretion, armed with the recent characterisation of the intracellular transcriptional feedback loops that comprise the circadian clock, and attempts to evaluate previous studies on this topic within the context of these new discoveries. Recent advances reveal the presence of oscillating circadian clocks throughout the central nervous system and periphery, including the anterior pituitary and hypothalamus, raising the possibility that synchrony between multiple cellular clocks may be involved in GnRH surge generation. Current studies are reviewed that demonstrate the necessity of functional clock oscillations in generating GnRH pulsatile secretion in vitro, suggesting that a GnRH-specific intracellular circadian clock may underlie GnRH surges as well. Multiple possible steroidal and neuronal contributions to GnRH surge generation are discussed, in addition to how these signals of disparate origin may be integrated at the cellular level to initiate this crucial reproductive event.

Animals↗
PubMed1999

Oocyte apoptosis: like sand through an hourglass.

Although the study of germ cell death is arguably still in its infancy as a field, several recent breakthroughs have provided the fodder for a story, replete with episodes of apparent mass cellular suicide if not murder, that will undoubtedly serve as a research base for many laboratories over the next several years. Death is known to strike the male and female germlines with roughly equal intensity, but the innate feature of male germ cells being self-renewing while those of the female are not places the death of oocytes in a completely different light. Indeed, the functional life span of the female gonads is defined in most species, including humans, by the size and rate of depletion of the precious endowment of oocytes enclosed within follicles in the ovaries at birth. This continuous loss of oocytes throughout life, referred to by many as the female biological clock, appears to be driven by a genetic program of cell death that is composed of players and pathways conserved from worms to humans. It is on this genetic pathway, and the role of its constituent molecules in regulating female germ cell fate, that this review will focus. Emphasis will be placed on those studies using genetic-null or transgenic models to explore the functional requirement of proteins, such as Bcl-2 family members, Apaf-1, and caspases in vertebrates to CED-9, CED-4, and CED-3 in Caenorhabditis elegans, in oocyte survival and death. Furthermore, hypotheses regarding the potential impact of translating what is now known of the oocyte death pathway into new approaches for the clinical diagnosis and management of female infertility and the menopause will be offered as a means to stimulate further research in this new and exciting field.

Animals↗
PubMed1980

A cytoplasmic clock with the same period as the division cycle in Xenopus eggs.

In most species the cell cycle is arrested in the unfertilized egg. After fertilization the cell cycle is reestablished and a rapid series of cleavages ensues. Preceding the first cleavage in Xenopus the egg undergoes a contraction of its cortex, called the "surface contraction wave," which can be visualized by time-lapse cinematography. This wave of contraction is propagated in a circular manner from the animal pole to the equator. We have found that eggs prevented from cleaving by treatment with antimitotic drugs undergo a sequence of periodic surface contraction waves timed with the cleavage cycle in untreated eggs. In addition, artificially activated eggs, which fail to cleave presumably for lack of a functioning centriole, undergo the same periodic contractions. No nuclear material is required for the periodic waves because a separated egg fragment, produced by constricting a fertilized egg, still undergoes contraction waves with the same period as the cleaving nucleated fragment. These results demonstrate that some expression of the cell cycle persists in the absence of any nuclear material or centrioles, suggesting to us that a biological clock exists in the cytoplasm or cortex of vertebrate eggs, which may be involved in timing the cell cycle.

Animals↗