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PubMed2001

Molecular mechanisms of the biological clock in cultured fibroblasts.

In mammals, the central circadian pacemaker resides in the hypothalamic suprachiasmatic nucleus (SCN), but circadian oscillators also exist in peripheral tissues. Here, using wild-type and cryptochrome (mCry)-deficient cell lines derived from mCry mutant mice, we show that the peripheral oscillator in cultured fibroblasts is identical to the oscillator in the SCN in (i) temporal expression profiles of all known clock genes, (ii) the phase of the various mRNA rhythms (i.e., antiphase oscillation of Bmal1 and mPer genes), (iii) the delay between maximum mRNA levels and appearance of nuclear mPER1 and mPER2 protein, (iv) the inability to produce oscillations in the absence of functional mCry genes, and (v) the control of period length by mCRY proteins.

ARNTL Transcription Factors↗
PubMed1976

Nucleus suprachiasmaticus: the biological clock in the hamster?

Destruction of the suprachiasmatic nuclei in the golden hamster by bilateral radiofrequency lesions abolishes three well-documented circadian rhythms--locomotor activity, estrous cyclicity, and photoperiodic photosensitivity. Entrainment of these rhythms by light cycles fails in lesioned hamsters; females become persistently estrous; in both sexes locomotor activity becomes sporadic, confined primarily to the light instead of darkness, and is totally arrhythmic when lesioned animals are exposed to continuous darkness; the photoperiodic gonadal response (gonadal regression induced by short day lengths) is abolished; lesioned animals remain reproductively mature irrespective of photoperiodic treatment.

Animals↗
PubMed1999

[The biological clock in mammals: structure and function].

The mammalian circadian timing system has three principal components: entrainment pathways, pacemakers and efferent pathways that couple the pacemaker to effector systems which exhibit temporal organization for physiological processes and behaviour. Light is the primary circadian Zeitgeber and the suprachiasmatic nuclei (SCN) functions as the major pacemaker in the mammalian circadian timing system. A number of investigators have focused attention on the intergeniculate leaflet (IGL) and the geniculohypothalamic tract (GHT) that mediate the effects of nonphotic stimuli on SCN activity and how these pathways interact with photic information being transmitted to the SCN.

Animals↗
PubMed1978

The pineal gland: a biological clock in vitro.

Circadian rhythmicity was studied by following the course of N-acetyl-transferase activity in the pineal glands of chickens in vitro. The results indicate (i) a daily change during day 1 of organ culture in constant dark that was dependent on the time the chickens were killed, (ii) equivocal persistence of the daily change in constant dark during 6 to 7 days of organ culture, (iii) an effect of light, (iv) inhibition by adrenergic agents and cycloheximide, and (v) stimulation by dibutyryl adenosine 3',5'-monophosphate and related compounds.

Acetyltransferases↗
PubMed2000

Biological clocks and the digestive system.

Circadian rhythms play a major role in regulating the digestive systems of many organisms. Cell proliferation, migration, differentiation, and even structure vary as a function of time of day in many different digestive organs (i.e., stomach, gut, liver, and pancreas) and cell types, resulting in regionally specific temporal variations in protein and gene expression. Feeding and light set the hands of the digestive clock(s). However, the clockwork has a genetic basis. During the last 10 years, new developments have emerged in our understanding of how cells keep time. Surprisingly, clock genes in mammals are expressed not only in specialized time keepers in the brain, but also in peripheral organs, suggesting that the ability to keep time may also belong to cells within the digestive system. This article reviews several classic examples of circadian variation in the digestive system, with an emphasis on rhythms in cell proliferation, function, and structure. It also briefly summarizes several new ideas about how cells in the brain and possibly the digestive system keep time.

Animals↗
PubMed2005

The biological clock of an hematophagous insect: locomotor activity rhythms, circadian expression and downregulation after a blood meal.

Despite the importance of circadian rhythms in vector-borne disease transmission, very little is known about its molecular control in hematophagous insect vectors. In Drosophila melanogaster, a negative feedback loop of gene expression has been shown to contribute to the clock mechanism. Here, we describe some features of the circadian clock of the sandfly Lutzomyia longipalpis, a vector of visceral leishmaniasis. Compared to D. melanogaster, sandfly period and timeless, two negative elements of the feedback loop, show similar peaks of mRNA abundance. On the other hand, the expression of Clock (a positive transcription factor) differs between the two species, raising the possibility that the different phases of Clock expression could be associated with the observed differences in circadian activity rhythms. In addition, we show a reduction in locomotor activity after a blood meal, which is correlated with downregulation of period and timeless expression levels. Our results suggest that the circadian pacemaker and its control over the activity rhythms in this hematophagous insect are modulated by blood intake.

Animals↗
PubMed1981

The biological clock in Gonyaulax controls luciferase activity by regulating turnover.

Luciferase activity in cell-free extracts of the bioluminescent marine dinoflagellate Gonyaulax polyedra undergoes a cyclic daily change such that activities of extracts made in the middle of the night phase may be 10 times greater than in extracts of day phase cells. These cyclic changes continue under constant conditions, in a manner indicative of control by an endogenous circadian cellular mechanism. This paper describes the purification and properties of the higher molecular weight unproteolyzed luciferase from both day and night phase cells. Comparisons of the two preparations with respect to several physicochemical, enzymatic, and immunological criteria were made in order to establish the basis for the activity difference; no differences between day and night species were found. A given amount of antiluciferase inactivated the same amount of luciferase activity in both day and night extracts; their specific activities are therefore the same. These data strongly suggest that the luciferase is the same polypeptide in day and night extracts, and that such extracts contain different amounts of the enzyme. We therefore postulate that the circadian rhythm of luciferase activity is a result of biological clock-controlled synthesis and/or degradation of the luciferase polypeptide.

Amino Acids↗
PubMed2005

Alcohol consumption and the body's biological clock.

This review summarizes new findings on the bidirectional interactions between alcohol and the clock genes, underlying the generation of circadian rhythmicity. At the behavioral level, both adult and perinatal ethanol treatments after the free-running period and light response of the circadian clock in rodents; genetic ethanol preference in alcohol-preferring rat lines is also associated with alterations in circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, circadian functions of beta-endorphin-containing neurons that participate in the control of alcohol reinforcement become disturbed after chronic alcohol intake. In turn, per2 gene activity regulates alcohol intake through its effects on the glutamatergic system through glutamate reuptake mechanisms and thereby may affect a variety of physiological processes that are governed by our internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic alcohol intake. Thus, chronic alcohol intake alters the expression of per genes, and as a consequence, a variety of neurochemical and neuroendocrine functions become disturbed. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control, and, as a final consequence, addictive behavior might be triggered or sustained by this cascade.

Alcohol Drinking↗
PubMed1989

The biological clock of Neurospora in a microgravity environment.

The circadian rhythm of conidiation in Neurospora crassa is thought to be an endogenously derived circadian oscillation; however, several investigators have suggested that circadian rhythms may, instead, be driven by some geophysical time cue(s). An experiment was conducted on space shuttle flight STS-9 in order to test this hypothesis; during the first 7-8 cycles in space, there were several minor alterations observed in the conidiation rhythm, including an increase in the period of the oscillation, an increase in the variability of the growth rate and a diminished rhythm amplitude, which eventually damped out in 25% of the flight tubes. On day seven of flight, the tubes were exposed to light while their growth fronts were marked. Some aspect of the marking process reinstated a robust rhythm in all the tubes which continued throughout the remainder of the flight. These results from the last 86 hours of flight demonstrated that the rhythm can persist in space. Since the aberrant rhythmicity occurred prior to the marking procedure, but not after, it was hypothesized that the damping on STS-9 may have resulted from the hypergravity pulse of launch. To test this hypothesis, we conducted investigations into the effects of altered gravitational forces on conidiation. Exposure to hypergravity (via centrifugation), simulated microgravity (via the use of a clinostat) and altered orientations (via alterations in the vector of a 1 g force) were used to examine the effects of gravity upon the circadian rhythm of conidiation.

Biological Clocks↗
PubMed1986

[Rhythms of the digestive system and the body's biological clocks].

A hierarchic system of short-period rhythms are supposed to exist in the gastro-intestinal tract (GIT). A periodical activity (PA) of the GIT was considered from the standpoint of its role in the control of intraintestinal transit. A hypothesis is proposed concerning the structure and mechanism of the PA rhythm clock. The daily interaction of own rhythms of the enterometa-sympathetic system with the food intake triggers the intramuscular oscillator, two physiologically significant signals of which (filling up of the stomach and transit to the colon) are under the control of higher nervous centers. On the basis of the intramuscular oscillator, a central also double one, is formed, and a mutual neuro-humoral interaction is established between them. Significance of this mechanism is emphasized not only for the GIT activity but as a "timer" for ultraradian rhythms as well.

Activity Cycles↗
PubMed2003

The biological clock nucleus: a multiphasic oscillator network regulated by light.

The circadian clock nucleus of the mammalian brain is composed of thousands of oscillator neurons, each driven by the cell-autonomous action of a defined set of circadian clock genes. A critical question is how these individual oscillators are organized into an internal clock that times behavior and physiology. We examined the neural organization of the suprachiasmatic nucleus (SCN) through time-lapse imaging of a short-half-life green fluorescent protein (GFP) reporter of the circadian clock gene Period 1 (Per1). Using brain slice preparations, Per1 promoter rhythms were resolved at the level of the SCN, and in individual neurons within the SCN, to determine the temporal patterns of rhythmicity resulting from exposure of mice to light/dark cycle (LD) and constant darkness (DD) conditions. Quantitative imaging and patch-clamp electrophysiology were used to define the relationship of Per1 gene expression to neurophysiological output on an individual neuron basis. We found that in both LD and DD, the overall rhythm of the clock nucleus is composed of individual cellular rhythms that peak in distinct phase groups at 3-4 hr intervals. However, the phase relationships of Per1 oscillations to locomotor activity and the phase relationships among individual neuronal oscillators within the SCN are different in LD and DD. There was a positive, linear correlation of Per1 transcription with neuronal spike frequency output, thus Per1::GFP rhythms are representative of physiological rhythmicity. Our results reveal multiple phase groupings of SCN oscillators and suggest that light regulation of oscillator interactions within the SCN underlies entrainment to the photoperiod.

Action Potentials↗
PubMed2006

Biological clocks and shift work: circadian dysregulation and potential long-term effects.

Long-term epidemiologic studies on large numbers of night and rotating shift workers have suggested an increase in the incidence of breast and colon cancer in these populations. These studies suffer from poor definition and quantification of the work schedules of the exposed subjects. Against this background, the pathophysiology of phase shift and phase adaptation is reviewed. A phase shift as experienced in night and rotating shift work involves desynchronization at the molecular level in the circadian oscillators in the central nervous tissue and in most peripheral tissues of the body. There is a change in the coordination between oscillators with transient loss of control by the master-oscillator (the Suprachiasmatic Nucleus, SCN) in the hypothalamus. The implications of the pathophysiology of phase shift are discussed for long-term health effects and for the design of ergonomic work schedules minimizing the adverse health effects upon the worker.

Adaptation, Physiological↗
PubMed1988

Does a biological clock reside in the eye of quail?

The site (intra- vs. extraocular) of the circadian clock driving an ocular melatonin rhythm in Japanese quail was investigated by alternately covering the left and right eyes of individual quail, otherwise held in constant light (LL), for 12-hr periods. This procedure exposed each eye to a light-dark (LD) 12:12 light cycle 180 degrees (12 hr) out of phase with the LD 12:12 light cycle experienced by the other eye. This protocol entrained the melatonin rhythm in the left eye of quail 180 degrees out of phase with the rhythm expressed in the right eye. These results are compatible with the hypothesis that an independent light-entrainable circadian pacemaker resides in each eye; they are incompatible with the hypothesis that a single (or functionally single) extraocular pacemaker drives the ocular melatonin rhythm in both eyes. However, the results are also compatible with a model in which two independent extraocular circadian pacemakers, each with an exclusive photic input from one eye, drive the ocular melatonin rhythm.

Animals↗
PubMed2001

Reproductive aging and mating: the ticking of the biological clock in female cockroaches.

Females are expected to have different mating preferences because of the variation in costs and benefits of mate choice both between females and within individual females over a lifetime. Workers have begun to look for, and find, the expected variation among females in expressed mating preferences. However, variation within females caused by changes in intrinsic influences has not been examined in detail. Here we show that reproductive aging caused by delayed mating resulted in reduced choosiness by female Nauphoeta cinerea, a cockroach that has reproductive cycles and gives live birth. Male willingness to mate was unaffected by variation in female age. Females who were beyond the optimal mating age, 6 days postadult molt, required considerably less courtship than their younger counterparts. Females who were older when they mated had fewer offspring per clutch and fewer clutches than females who mated young. Thus, reduced choosiness was correlated with a permanent reduction in fertility. There was no difference in overall senescence among females, and thus the reduction in clutch size did not result in the expected increased lifespan. We suggest that reproductive aging in N. cinerea, similar to aging in general, occurs because the maintenance of oocytes is costly, and selection is relaxed after the optimal mating period. Our results further suggest that selection for continued choosiness is also relaxed and supports direct selection on female choosiness and a cost to choosiness.

Aging↗
PubMed2005

Adrenal cortex -- the next biological clock?

It is well known that plasma levels of dehydroepiandrosterone (DHEA), a steroid hormone secreted by zona reticularis (ZR) of the adrenal cortex, reach the maximal values in the third decade of life and then gradually decline with age. Moreover, the DHEA deficiency is probably responsible for several functional disturbances connected with aging. It was also found that ZR reaches its definitive volume at puberty and undergoes selective atrophy during the aging. Thus, the decline of DHEA may be a simple consequence of ZR atrophy in aged subjects. A hypothesis presented here attempts to explain the mechanism of the age-related ZR atrophy and is based on the adrenal cortex cell kinetics. In the adrenal cortex the cell proliferation indices are lower when we pass from zona glomerulosa (ZG) to the inner zones and are the lowest in ZR. In contrast, the apoptotic index is the highest in ZR. It is suggested that adrenocortical cells renew from the progenitor cells located in ZG /zona fasculata boundary and /or in subcapsular layer. These cells migrate centripetally undergoing the subsequent steps of differention and consecutive divisions - and - if not die en route - reach the most central localization in ZR. In consequence, ZR includes the "oldest" adrenocortical cells which probably in majority reached the "Hayflick's number" and cannot divide. This results in the preponderance of apoptosis over proliferation leading to progressive ZR atrophy followed by a decline of secretion of ZR-derived steroid hormones.

Adrenal Cortex↗
PubMed2005

Reduced alpha-adrenoceptor responsiveness and enhanced baroreflex sensitivity in Cry-deficient mice lacking a biological clock.

To reveal the role of clock genes in generating the circadian rhythm of baroreflexes, we continuously measured mean arterial pressure and baroreflex sensitivity in free-moving normal wild-type mice, and in Cry-deficient mice which lack a circadian rhythm, in constant darkness for 24 h. In wild-type mice the mean arterial pressure was higher at night than during the day, and was accompanied by a significantly enhanced baroreflex sensitivity of -13.6 +/- 0.8 at night compared with -9.7 +/- 0.7 beats min(-1) mmHg(-1) during the day (P < 0.001). On the other hand, diurnal changes in arterial pressure disappeared in Cry-deficient mice with remarkably enhanced baroreflex sensitivity compared with wild-type mice (P < 0.001): -21.9 +/- 1.6 at night and -23.1 +/- 2.1 beats min(-1) mmHg(-1) during the day. Moreover, the mean arterial pressure response to 10 microg kg(-1) of phenylephrine, an alpha1-adrenoceptor agonist, was severely suppressed in Cry-deficient mice regardless of time, while that for the wild-type mice was 10.1 +/- 1.9 mmHg in the night, significantly lower than 22.0 +/- 3.5 mmHg in the day (P < 0.01). These results suggest that CRY genes are involved in generating the circadian rhythm of baroreflex sensitivity, partially by regulating alpha(1)-adrenoceptor-mediated vasoconstriction in peripheral vessels.

Adrenergic alpha-Agonists↗
PubMed2006

[Molecular biology of biological clock--genetic regulation of circadian rhythm and sleep].

Circadian rhythm is a universal biological property functioning in most living species on the earth from bacteria and plants to animals. The molecular mechanisms creating this rhythm have recently been elucidated and the transcriptional feedback loop regulation of 'clock genes' is regarded as essential for all species studied so far. Both mammals and insects share the similar clock genes, which highlights the long conservation of circadian rhythm at the genetic level. Sleep and arousal cycles in mammals are known to be regulated by both homeostatic and circadian processes, but the genetic machinery for sleep regulation is still unclear. Recently, it has been reported that insects also have sleep-like behavior, and we showed that insects use dopamine as a regulator of their sleep/arousal cycling, which strongly suggests the similarity of arousal regulation between insects and mammals at the molecular level. In this review, these recent advancements of the molecular understanding of circadian rhythm and sleep/arousal regulation are outlined.

Animals↗
PubMed2004

Insomnia, biological clock, and the bedtime decision: an economic perspective.

While insomnia can be a symptom of numerous mental and physical illnesses, it is frequently diagnosed as a sleep disorder in its own right, caused mainly by stressful life events or by non-synchronization of individuals' biological sleep-wake cycle with the one they choose to practice. Because of irregular work schedules, late-night entertainment, or rapid crossing of several time zones, individuals might retire to bed earlier or later than their biological bedtime, experiencing difficulties in falling asleep. The present paper develops a simple economic model of the bedtime decision, viewing the individual as a rational decision-maker who determines her insomnia level through consciously weighing the cost and benefit of deviating from her biological bedtime. The model is then used to examine the individual's response to stress, yielding a prediction which is consistent with observed behavior, although not with sleep therapists' recommendations. Finally, the model is applied to the case of transmeridian flights, explaining jet lag as a rational adjustment to a misalignment between the individual's slow-to-adapt internal clock and her external environment.

Biological Clocks↗