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At least 649 records · Page 36Linked to original sources
PubMed1994

A possible glial role in the mammalian circadian clock.

The primary mammalian circadian clock is located within the suprachiasmatic nuclei (SCN), but the cellular organization of the clock is not yet known. We investigated the potential role of glial cells in the clock mechanism by determining whether disrupting glial activity affects the in vitro circadian rhythm of neuronal activity and the in vivo circadian activity rhythm in rats. We used two agents (octanol and halothane) that block gap junctions, and one (fluorocitrate) that inhibits glial metabolism. All three agents disrupted the circadian pattern of neuronal activity. Octanol flattened the rhythm at the highest concentration (200 microM) and induced a small phase delay at a lower concentration (66 microM). Halothane and fluorocitrate induced ultradian rhythmicity. Fluorocitrate injected into the SCN of an intact rat induced arrhythmicity for about 1 week, after which the rhythm reappeared with a 1.6 h delay. These results suggest that glia play an important role in the SCN circadian clock.

1-Octanol↗
PubMed1991

Rapid reentrainment of the circadian clock itself, but not the measurable activity rhythms to a new light-dark cycle in the rat.

Experiments were performed to determine if the circadian clock reentrains more quickly to an 8-hour phase shift in light-dark (LD) cycles than does the overt rhythm of activity. To investigate the reentrainment of the clock itself to an 8-hour advance or delay in the LD cycle, the rats were released into constant darkness only two or three days after a shift in LD cycle, and the amount of the phase shift of the clock itself was estimated from where free-running rhythm started by backward extrapolation. If the circadian clock could rapidly reset itself to the new LD cycle, it was predicted that the free-running rhythm of activity would start from near the dark period of the new LD cycle rather than the preceding one. When rats were released into constant darkness three days after the LD cycle was advanced by 8 hours, the activity of the free-running rhythm started near time of dark period of the new LD cycle in all rats (n = 16). When rats (n = 24) were released into constant darkness two days after the LD cycle was advanced by 8 hours, 12 rats started the activity near time of dark period of the new LD cycle, while 9 rats started the activity near time of dark period of the preceding LD cycle. The remaining 3 rats showed the activity of the free-running rhythm near intermediate phase (transient phase). On the other hand, when the rats were not released into constant darkness after LD cycle was advanced by 8 hours, it took 6.4 days for activity rhythm to reentrain to the advanced LD cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Hypothesis: the central oscillator of the circadian clock is a controlled chaotic attractor.

Controlled chaos may be important for the generation of rhythmic behaviour in living systems. A model is proposed in which the central circadian oscillator is a chaotic attractor. Whereas a limit cycle mechanism (previously invoked to explain circadian clocks as well as ultradian clocks and cell division cycles) can provide only a single stable periodic orbit, a chaotic attractor can generate rich dynamic behaviour. Control by feedback makes accessible a selected stabilized orbit; this can be chosen so as to optimize system performance. Such a system can accommodate a wide variety of requirements, e.g. that a single clock mutation can affect both period and temperature compensation, and the generation of higher periods from an ultradian oscillator. Simultaneous operation of more than one clock (with differing periods) may require a high-dimension chaotic attractor. Attractive features of such a model include versatility of period selection (e.g. as in the per mutants of Drosophila) and the use of control elements of the type already well known in metabolic circuitry.

Animals↗
PubMed1995

Anterior-inferior (5 o'clock) portal for shoulder arthroscopy.

The present study describes an anterior-inferior portal for arthroscopic shoulder instrumentation at the 5 o'clock position along the glenoid rim. An anterior-inferior portal was established in 14 cadaver shoulders. The portal was created in an inside-to-outside fashion, with the humerus maximally adducted, directing the guide rod as far lateral as possible. Using the described technique, a 5 o'clock portal travels through the subscapularis and lateral to the conjoined tendon. Distance between the portal and the musculocutaneous nerve was 22.9 +/- 4.9 mm (mean +/- SD), and 24.4 +/- 5.7 mm between the portal and the axillary nerve. Previously described portals were either at, or above the 3 o'clock position, resulting in an acute, difficult angle of approach to the glenoid neck. Through a combination of proper arm positioning and rod insertion technique, the 5 o'clock portal can be created safely and is of great potential utility for arthroscopic shoulder stabilization procedures.

Arthroscopy↗
PubMed2004

Entrainment dissociates transcription and translation of a circadian clock gene in neurospora.

Circadian systems coordinate the daily sequence of events in cells, tissues, and organisms. In constant conditions, the biological clock oscillates with its endogenous period, whereas it is synchronized to the 24 hr light:dark cycle in nature. Here, we investigate light entrainment of Neurospora crassa to photoperiods that mimic seasonal changes. Clock gene (frequency, or frq) RNA levels directly reflect the light environment in all photoperiods, whereas the FRQ protein follows neither RNA levels nor light transitions. Induction of frq RNA and protein can be dissociated by as much as 6 hr, depending on photoperiod. The phase of entrainment at the physiological level (e.g., asexual spore development) correlates with FRQ protein. Thus, a dissociation of transcription, translation, and protein stability is fundamental to circadian entrainment of Neurospora. Our findings suggest that simple feedback models are insufficient to explain the molecular circadian mechanisms under entrained conditions and that clock control of light input pathways involves posttranscriptional regulation. The regulators mediating the dissociation between RNA and protein levels are still unknown and will be the key to understanding both circadian timing at the molecular level and how the clock exerts control over many cellular processes.

Acclimatization↗
PubMed2005

Structural and functional features of transcription factors controlling the circadian clock.

Most organisms adapt the timing of their physiology to the cyclic changes of the environment with the use of intrinsic time-keeping systems called circadian clocks. Central features of the molecular clock mechanism are transcription- and translation-based negative feedback loops: clock genes and their products interact to generate oscillation of specific transcripts and proteins, and, ultimately, circadian rhythmicity and behavior. Various transcription factors constitute the molecular clock, and the signal transduction cascades governing their function appear to be crucial for the fine-tuning of the circadian cycle.

Animals↗
PubMed2006

A nondiapausing variant of the flesh fly, Sarcophaga bullata, that shows arrhythmic adult eclosion and elevated expression of two circadian clock genes, period and timeless.

We describe a variant of the flesh fly, Sarcophaga bullata, which fails to enter pupal diapause in response to short daylength and low temperatures. This fly also has an arrhythmic adult eclosion pattern: rather than eclosing in early photophase, the variant ecloses arrhythmically throughout the photophase and scotophase. The loss of both diapause (photoperiodic response) and the gating of adult eclosion (presumably a circadian response) suggests that the same clock system is involved in these two responses. An examination of the expression patterns of the clock genes period and timeless demonstrates that both genes are present in the nondiapausing variant, but surprisingly, both genes are expressed at higher levels. This abnormality we observe, possibly the consequence of an upstream clock gene malfunction or a malfunction of the autoregulatory loop, results in disruption of a component of the clock system that is apparently needed for both photoperiodism and circadian rhythmicity.

Animals↗
PubMed2004

Modeling the mammalian circadian clock: sensitivity analysis and multiplicity of oscillatory mechanisms.

We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.

ARNTL Transcription Factors↗
PubMed2006

Altered expression profiles of clock genes hPer1 and hPer2 in peripheral blood mononuclear cells of cancer patients undergoing surgery.

Patients undergoing surgery often develop symptoms of circadian rhythm disorders such as insomnia or delirium. However, the effect of surgery on the biological clock remains unknown. The present study examines the expression of clock genes in peripheral blood mononuclear cells (PBMCs) and measures plasma hormone concentrations in patients with esophageal cancer and early gastric cancer who underwent surgery. Six blood samples per day were collected from 9 patients with esophageal cancer before and after esophagectomy and from 9 patients with early gastric cancer before and after laparoscopy-assisted distal gastrectomy (LADG). The expression profiles of hPer1 and hPer2 mRNAs in PBMCs were determined by real-time RT-PCR. Plasma melatonin and cortisol concentrations were measured by radioimmunoassay. Plasma melatonin levels decreased in both groups throughout the day and plasma cortisol levels changed after surgery. The acrophase of clock gene expression was altered after surgery as follows: hPer1, from 6:19+/-1:50 to 13:59+/-0:59 (p=0.0003) and from 7:47+/-1:27 to 12:33+/-1:30 (p=0.0043) and hPer2, from 5:01+/-2:59 to 19:30+/-2:15 (p<0.0001) and from 6:49+/-1:59 to 13:39+/-3:06 (p=0.0171) in patients with esophageal and early gastric cancer, respectively. The post-operative phase change of hPer2 was more prominent after esophagectomy than after LADG. Our results suggest that surgical stress affects the peripheral clock as well as endogenous hormones in humans.

Cell Cycle Proteins↗
PubMed2006

Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats.

A role for thyroid hormones in the regulation of the rhythmic expression of circadian clock genes is suggested by the finding that surgical removal of the thyroid gland alters circadian behavioral and endocrine rhythms in rodents. Virtually nothing is known about the role of thyroid hormones in the regulation of clock genes responsible for the generation of circadian rhythmicity. To study this issue, we assessed in rats the effect of thyroidectomy/parathyrodectomy (TPX) on the expression of the clock protein, PER2, in the suprachiasmatic nucleus (SCN), the master circadian clock, and in a number of key limbic forebrain structures, the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA) and the dentate gyrus (DG). TPX significantly altered the normal daily pattern of PER2 expression in the BNSTov and CEA, but had no effect on PER2 expression in the SCN, BLA and DG. Thus, although thyroid hormones modulate PER2 expression in the brain, the effect is tissue specific and therefore likely not to be mediated by a direct effect of the hormone on gene expression.

Amygdala↗
PubMed2004

Molecular clock-like evolution of human immunodeficiency virus type 1.

The molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1.

Evolution, Molecular↗
PubMed1998

Neuropeptide Y blocks serotonergic phase shifts of the suprachiasmatic circadian clock in vitro.

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) can be reset in vitro by various neurochemical stimuli. This study investigated the phase-shifting properties of neuropeptide Y (NPY) and serotonin (5-HT) agonists when applied alone, as well as their combined effects on clock resetting. These neurotransmitters have both been shown to advance the SCN clock in vitro when applied during the daytime. By monitoring the SCN neuronal activity rhythm in vitro, I first confirm that the 5HT1A/5HT7 agonist (+)DPAT maximally advances the SCN clock when applied at zeitgeber time 6 (ZT6). Conversely, NPY only phase advances the neuronal activity rhythm when applied at ZT 10. This effect occurs through stimulation of Y2 receptors. NPY, again acting through Y2 receptors, blocks (+)DPAT-induced phase shifts at ZT 6, while neither (+)DPAT nor 5-HT affect NPY-induced phase shifts at ZT 10. NPY appears to block (+)DPAT-induced phase shifts by preventing increases in cyclic AMP. These data are the first to demonstrate in vitro interactions between daytime resetting stimuli in the rat, and provide critical insights into mechanisms controlling circadian clock phase.

Animals↗
PubMed1999

Protein kinase C inhibition and activation phase advances the hamster circadian clock.

The mammalian circadian clock is located in the suprachiasmatic nuclei (SCN). Clock function can be detected by the measurement of the circadian change in cellular firing rate of SCN cells in vitro. We investigated the effects of protein kinase C (PKC) inhibition and activation on this rhythm of firing rate in hamster SCN neurons. PKC inhibition by chelerythrine chloride application phase advances the in vitro circadian rhythm during the late subjective night and early subjective morning, Zeitgeber time (ZT) 20-24 and ZT 0-4. No effect of PKC inhibition on clock phase was seen during ZT 6-18. Activation of PKC via phorbol 12-myristate 13-acetate (PMA) phase advanced the clock at all phases tested. Thus, at some circadian phases both inhibition and activation of PKC can advance circadian rhythms.

Alkaloids↗
PubMed2001

Adenosine A1 receptors regulate the response of the hamster circadian clock to light.

Circadian rhythms are synchronized to the environmental light-dark cycle by daily, light-induced adjustments in the phase of a biological clock located in the suprachiasmatic nucleus. Ambient light alters the phase of the clock via a direct, glutamatergic projection from retinal ganglion cells. We investigated the hypothesis that adenosine A1 receptors modulate the phase adjusting effect of light on the circadian clock. Systemic administration of the selective adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), significantly (p<0.05) attenuated light-induced phase delays and advances of the circadian activity rhythm. Selective agonists for the adenosine A2A and adenosine A3 receptors were without effect. The inhibitory effect of CHA on light-induced phase advances was dose-dependent (0.025-1.0 mg/kg, ED(50)=0.3 mg/kg), and this effect was blocked in a dose-dependent (0.005-1.0 mg/kg) manner by the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Injection of CHA (10 microM) into the region of the suprachiasmatic nucleus significantly attenuated light-induced phase advances, and this effect was also blocked by DPCPX (100 microM). The results suggest that adenosine A1 receptors located in the region of the suprachiasmatic nucleus regulate the response of the circadian clock to the phase-adjusting effects of light.

Adenosine↗
PubMed2001

Photoperiodic time measurement in insects and mites: a critical evaluation of the oscillator-clock hypothesis.

The validity of the oscillator-clock hypothesis for photoperiodic time measurement in insects and mites is questioned on the basis of a re-interpretation of available experimental evidence. The possible role of the circadian system in photoperiodism in arthropods is critically reviewed. Apart from the outcome of kinetic experiments, based on diel and non-diel light/dark cycles, evidence from various genetic and physiological experiments is discussed in relation to the oscillator-clock hypothesis. The conclusion is that photoperiodic time measurement in insects and mites is performed by a non-circadian 'hourglass' clock. Experimental evidence suggests a non-clock role for the circadian system in the photoperiodic mechanism of insects and mites.

Journal Article↗
PubMed1991

Quantitative genetic variation and developmental clocks.

It is well-known that most genetic variation affects quantitative traits, and natural or artificial selection can act to change quantitative features of organisms more rapidly than qualitative ones. Surprisingly, variability is not confined to outbred species, but also occurs in inbred mice at a much higher rate than expected from known mutation rates. The size and shape of organisms and their constituent parts are, at least in part, controlled by the number of cell divisions, and there is published evidence for the existence of developmental clocks, which may count cell divisions. A molecular model for a developmental clock was previously proposed. It depends on the DNA methylation of repeated sequences of DNA, where the methylation of each additional sequence is tied to DNA synthesis and therefore cell division. The number of repeats specifies the number of divisions which will occur before a signal is produced which can activate or inactivate one or more genes. It is known that crossing over occurs between sister chromatids, and where tandemly repeated sequences occur unequal exchange can generate a larger or smaller number of repeats. An example of this is seen in the well-known variability of "minisatellite" sequences in human DNA. Unequal sister chromatid exchange can occur in mitotic and meiotic cells in the germ line, and in the case of developmental clock sequences could generate variation in clock length which in turn would directly affect quantitative traits. These events can be regarded as a special case of molecular drive during evolution.

Animals↗
PubMed1997

Cellular construction of a circadian clock: period determination in the suprachiasmatic nuclei.

The circadian clock in the suprachiasmatic nuclei is composed of multiple, single-cell circadian oscillators (clock cells). We now test the hypothesis that the circadian period in behavior is determined by the mean period that arises from the coupling of clock cells with diverse circadian periods. For these studies, we monitored firing rate rhythms of individual suprachiasmatic nuclei neurons on fixed multielectrode plates and exploited the altered circadian periods expressed by heterozygous and homozygous tau mutant hamsters. The results show that circadian period in the whole animal is determined by averaging widely dispersed periods of individual clock cells. The data also demonstrate that the tau mutation affects circadian function in a cell-autonomous manner.

Animals↗
PubMedDate not supplied

The use of clock tests in schizophrenia.

Though clock drawing tests are well recognized as measures of cognitive function, there is little data on the performance of patients with schizophrenia. We compared 24 patients with schizophrenia to 24 healthy, age-matched controls on clock drawing, copying, and reading. Patients with schizophrenia performed significantly worse on clock drawing and copying despite the fact that the groups had similar scores on the MMSE. Worse performance was associated with higher scores on the BPRS. Clock drawing and copying may be useful for the assessment of cognition in schizophrenia, and the monitoring of cognitive changes associated with antipsychotic medication.

Adult↗