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PubMed2006

Influence of photoperiodic history on clock genes and the circadian pacemaker in the rat retina.

The influence of seasonal lighting conditions on expression of clock genes and the circadian pacemaker was investigated in the rat retina. For this purpose, the 24-h profiles of nine clock genes (bmal1, clock, per1, per2, per3, dec1, dec2, cry1 and cry 2) and the arylalkylamine N-acetyltransferase gene as an indicator of the circadian pacemaker output were compared between light-dark periods of 8 : 16 and 16 : 8 h. The photoperiod influenced the daily patterns of the amount of transcript for per1, per3, dec2 and arylalkylamine N-acetyltransferase. This indicates that photoperiodic information modulates clock gene expression in addition to the circadian pacemaker of the retina. Under constant darkness, photoperiod-dependent changes in the daily profile of the level of transcript persisted for the arylalkylamine N-acetyltransferase gene but not for any of the clock genes. Hence, quantitative expression of each clock gene is influenced by the photoperiod only under the acute light-dark cycle, whereas the pacemaker is capable of storing photoperiodic information from past cycles.

Analysis of Variance↗
PubMed2006

Trans-pineal microdialysis in the Djungarian hamster (Phodopus sungorus): a tool to study seasonal changes of circadian clock activities.

The Djungarian hamster is a highly seasonal small mammal. The rhythmic secretion of melatonin by the pineal gland is under control of the circadian clock, conveying the photoperiodic message to the organism. Trans-pineal microdialysis permits the in vivo study of this well-defined and precise clock output by measuring melatonin release directly in the pineal gland. The aim of this study was to adapt this method to the Djungarian hamster in order to monitor clock properties during photoperiodic changes. Male adult Djungarian hamsters were kept in a long photoperiod (LD 16:8) and melatonin release was measured hourly during the dark period for several weeks. Melatonin showed a regular secretion between ZT 17 and ZT 23.5 whereas the amplitude became stable only after the third day of perfusion. To test how quickly changes in melatonin profile can be measured, 15-min light pulses were given at different time points throughout the scotophase. Light-pulses immediately interrupted melatonin secretion at any time point during the scotophase and the temporal resolution for measurement could be reduced to 30 min. In accordance with studies in the rat, long-term effects of light on the clock could only be observed when a light pulse was administered in the second half of the night. For the first time we established a method to measure precisely a direct and reliable clock-output in a highly seasonal species which allows us now to study the circadian and seasonal properties of the clock in detail.

Animals↗
PubMed2006

JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS.

Organisms ranging from bacteria to humans synchronize their internal clocks to daily cycles of light and dark. Photic entrainment of the Drosophila clock is mediated by proteasomal degradation of the clock protein TIMELESS (TIM). We have identified mutations in jetlag-a gene coding for an F-box protein with leucine-rich repeats-that result in reduced light sensitivity of the circadian clock. Mutant flies show rhythmic behavior in constant light, reduced phase shifts in response to light pulses, and reduced light-dependent degradation of TIM. Expression of JET along with the circadian photoreceptor cryptochrome (CRY) in cultured S2R cells confers light-dependent degradation onto TIM, thereby reconstituting the acute response + of the circadian clock to light in a cell culture system. Our results suggest that JET is essential for resetting the clock by transmitting light signals from CRY to TIM.

Amino Acid Sequence↗
PubMed2004

Genome-wide molecular clock and horizontal gene transfer in bacterial evolution.

We describe a simple theoretical framework for identifying orthologous sets of genes that deviate from a clock-like model of evolution. The approach used is based on comparing the evolutionary distances within a set of orthologs to a standard intergenomic distance, which was defined as the median of the distribution of the distances between all one-to-one orthologs. Under the clock-like model, the points on a plot of intergenic distances versus intergenomic distances are expected to fit a straight line. A statistical technique to identify significant deviations from the clock-like behavior is described. For several hundred analyzed orthologous sets representing three well-defined bacterial lineages, the alpha-Proteobacteria, the gamma-Proteobacteria, and the Bacillus-Clostridium group, the clock-like null hypothesis could not be rejected for approximately 70% of the sets, whereas the rest showed substantial anomalies. Subsequent detailed phylogenetic analysis of the genes with the strongest deviations indicated that over one-half of these genes probably underwent a distinct form of horizontal gene transfer, xenologous gene displacement, in which a gene is displaced by an ortholog from a different lineage. The remaining deviations from the clock-like model could be explained by lineage-specific acceleration of evolution. The results indicate that although xenologous gene displacement is a major force in bacterial evolution, a significant majority of orthologous gene sets in three major bacterial lineages evolved in accordance with the clock-like model. The approach described here allows rapid detection of deviations from this mode of evolution on the genome scale.

Evolution, Molecular↗
PubMed2006

Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor.

The circadian timing system and the cell division cycle are frequently deregulated in cancer. The therapeutic relevance of the reciprocal interactions between both biological rhythms was investigated using Seliciclib, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Mice bearing Glasgow osteosarcoma received Seliciclib (300 mg/kg/d orally) or vehicle for 5 days at Zeitgeber time (ZT) 3, 11, or 19. On day 6, tumor mRNA 24-hour expression patterns were determined for clock genes (Per2, Rev-erbalpha, and Bmal1) and clock-controlled cell cycle genes (c-Myc, Wee1, cyclin B1, and CDK1) with quantitative reverse transcription-PCR. Affinity chromatography on immobilized Seliciclib identified CDK1/CDK2 and extracellular signal-regulated kinase (ERK) 1/ERK2, CDK7/CDK9, and casein kinase CK1epsilon as Seliciclib targets, which respectively regulate cell cycle, transcription, and circadian clock in Glasgow osteosarcoma. Seliciclib reduced tumor growth by 55% following dosing at ZT3 or ZT11 and by 35% at ZT19 compared with controls (P < 0.001). Tolerability was also best at ZT3. Mean transcriptional activity of Rev-erbalpha, Per2, and Bmal1 was arrhythmic in the tumors of untreated mice. Seliciclib induced rhythmic clock gene expression patterns with physiologic phase relations only after ZT3 dosing. c-Myc and Wee1 mRNAs displayed synchronous circadian rhythms in the tumors of control mice receiving vehicle only but not in those of mice given the drug. Seliciclib further enhanced Wee1 expression irrespective of dosing time, an effect that reinforced G(2)-M gating. Seliciclib also inhibited CK1epsilon, which determines circadian period length. The coordination of clock gene expression patterns in tumor cells was associated with best antitumor activity of Seliciclib. The circadian clock and its upstream regulators represent relevant targets for CDKIs.

Animals↗
PubMed2001

MPer1 and mper2 are essential for normal resetting of the circadian clock.

Mammalian Per1 and Per2 genes are involved in the mechanism of the circadian clock and are inducible by light. A light pulse can evoke a change in the onset of wheel-running activity in mice by shifting the onset of activity to earlier times (phase advance) or later times (phase delays) thereby advancing or delaying the clock (clock resetting). To assess the role of mouse Per (mPer) genes in circadian clock resetting, mice carrying mutant mPer1 or mPer2 genes were tested for responses to a light pulse at ZT 14 and ZT 22, respectively. The authors found that mPer1 mutants did not advance and mPer2 mutants did not delay the clock. They conclude that the mammalian Per genes are not only light-responsive components of the circadian oscillator but also are involved in resetting of the circadian clock.

Animals↗
PubMed1993

Clock-drawing test and unilateral spatial neglect.

We investigated the ability of 25 patients with left unilateral spatial neglect to make a clock face by putting numbers inside a printed circle. Impairment seen in this clock-drawing test did not parallel neglect severity as judged by results of the line-cancellation and line-bisection tests, as well as the copying of a daisy. The score for clock drawing correlated highly with the verbal WAIS score. Most neglect patients with a verbal IQ of 87 or more could draw a clock face fairly well and used planning in placing the numbers 12, 3, 6, and 9 before the others. In clock drawing, verbal intelligence may compensate for left unilateral spatial neglect. We therefore recommend use of the line-cancellation and line-bisection tests, as well as the copying test, but do not recommend use of the clock-drawing test in the diagnosis of left unilateral spatial neglect.

Aged↗
PubMed2002

The clock drawing test is a poor screen for very mild dementia.

OBJECTIVE: To determine whether performance on the clock drawing test varies as a function of dementia severity and particularly whether it differentiates cognitively normal older adults from those with very mild dementia. METHODS: Clock drawings were obtained during the initial clinical assessments of 75 participants in a longitudinal study of healthy aging and dementia of the Alzheimer type (15 cognitively normal, 25 with very mild dementia, 21 with mild dementia, and 14 with moderate to severe dementia, as staged by the Clinical Dementia Rating). Each clock drawing later was judged blindly and independently by two raters according to six commonly used sets of scoring criteria. RESULTS: The same pattern of results was obtained for all six scoring methods. Inter-rater reliability was consistently high. Spearman correlations indicated that as dementia severity increased, clock drawing performance decreased. Analyses of variance revealed that although those with mild or moderate/severe dementia performed significantly worse on the clock drawing test than did individuals who had very mild dementia or who were cognitively normal, the latter two groups did not differ significantly. Sensitivity and specificity analyses revealed that all methods could distinguish between normal aging and dementia of at least mild severity. However, sensitivity for detecting very mild dementia was poor. CONCLUSION: Although the clock drawing test can be scored reliably and can differentiate cognitively normal older adults from those with at least mild dementia of the Alzheimer type, it does not appear to be a useful screening instrument for detecting very mild dementia.

Aged↗
PubMed2005

Factors reducing the expected deflection in initial orientation in clock-shifted homing pigeons.

To orient from familiar sites, homing pigeons can rely on both an olfactory map and visual familiar landmarks. The latter can in principle be used in two different ways: either within a topographical map exploited for piloting or in a so-called mosaic map associated with a compass bearing. One way to investigate the matter is to put the compass and the topographical information in conflict by releasing clock-shifted pigeons from familiar locations. Although the compass orientation is in general dominant over a piloting strategy, a stronger or weaker tendency to correct towards the home direction by clock-shifted pigeons released from very familiar sites has often been observed. To investigate which factors are involved in the reduction of the deviation due to clock-shift, we performed a series of releases with intact and anosmic pigeons from familiar sites in unshifted and clock-shifted conditions and a series of releases from the same sites with naive clock-shifted birds. Our data suggest that the following factors have a role in reducing deviation due to the clock-shift: familiarity with the release site, the lack of olfactory information and some unknown site-dependent features.

Animals↗
PubMed2005

PRR5 (PSEUDO-RESPONSE REGULATOR 5) plays antagonistic roles to CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1) in Arabidopsis thaliana.

In general, the clock (or oscillator) is central to circadian rhythms in many organisms. In the model higher plant Arabidopsis thaliana, the best candidates for clock components are CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1) and LHY (LATE ELONGATED HYPOCOTYL), which are homologous Myb-related transcription factors. It is also believed that TOC1 (TIMING OF CAB EXPRESSION 1) is another component of the central oscillator. In this connection, we have been characterizing a small family of proteins, designated ARABIDOPSIS PSEUDO-RESPONSE REGULATOR (PRR1, PRR3, PRR5, PRR7, and PRR9), based on the fact that one of the members (PRR1) is identical to TOC1. Nevertheless, it is not yet certain whether other PRR family members are also implicated in clock function per se. To address this issue, in this study we examined a functional interaction between the CCA1 clock component and one of the PRR family members, PRR5, by employing transgenic lines overexpressing both the CCA1 and PRR5 genes. Evidence will be provided that PRR5 plays an antagonistic role(s) to the putative CCA1 clock component.

Arabidopsis↗
PubMed1976

Clock control of human performance on avoidance and fixed-interval schedules.

The avoidance and fixed-interval performances of human subjects were studied in two experiments. Addition of time-correlated stimuli (added clock) improved behavioral efficiency, since response rates decreased without decreases in reinforcement rates. Response-dependent display of the clock maintained a second, observing response and reductions in clock duration weakened such observing behavior. Generally, the reinforcing properties of the clock were more apparent with the avoidance than with the fixed-interval schedule, a finding attributed to temporal cues already provided by delivery of the fixed-interval reinforcers. Reduced rates of the main response when the clock was dependent on an observing response were more than offset by rates of the observing response in the majority of subjects. Thus, the results do not support an interpretation of the reinforcing properties of added clocks simply in terms of work reduction.

Journal Article↗
PubMed1994

The ten point clock test: a quick screen and grading method for cognitive impairment in medical and surgical patients.

OBJECTIVE: The objective of this study was to evaluate the clinical utility of the ten point clock test in screening for and grading cognitive deficits in medical and surgical patients. METHOD: The setting was the hospital and clinics of Virginia Mason Medical Center, a tertiary referral center. Consecutive samples of hospitalized patients, and clinic outpatients--with and without a dementia--were administered the ten point clock test as well as a number of other neuropsychological tests and measures of cognitive impairment. RESULTS: Clock scores correlated with neuropsychological test scores and with the mini-mental state examination. They were stable from rater to rater, and from day to day in stable patients. The mean clock score of elderly outpatient controls was 8.5, significantly different from the mean of 5.5 scored by patients with a dementia. A cut off score of seven identified 76 percent of outpatients with dementia and 78 percent of elderly controls. Clock scores correlated well with nurses' ratings of their inpatients' cognitive deficits (Spearman's rs = -0.61). The test was easy to administer, even to hospitalized patients. CONCLUSIONS: The ten point clock test is reliable, valid, and useful as a quick screen and grading method for cognitive deficits in medical and surgical patients.

Adult↗
PubMed2001

Dissociation between light-induced phase shift of the circadian rhythm and clock gene expression in mice lacking the pituitary adenylate cyclase activating polypeptide type 1 receptor.

The circadian clock located in the suprachiasmatic nucleus (SCN) organizes autonomic and behavioral rhythms into a near 24 hr time that is adjusted daily to the solar cycle via a direct projection from the retina, the retinohypothalamic tract (RHT). This neuronal pathway costores the neurotransmitters PACAP and glutamate, which seem to be important for light-induced resetting of the clock. At the molecular level the clock genes mPer1 and mPer2 are believed to be target for the light signaling to the clock. In this study, we investigated the possible role of PACAP-type 1 receptor signaling in light-induced resetting of the behavioral rhythm and light-induced clock gene expression in the SCN. Light stimulation at early night resulted in larger phase delays in PACAP-type 1 receptor-deficient mice (PAC1(-)/-) compared with wild-type mice accompanied by a marked reduction in light-induced mPer1, mPer2, and c-fos gene expression. Light stimulation at late night induced mPer1 and c-fos gene expression in the SCN to the same levels in both wild type and PAC1(-)/- mice. However, in contrast to the phase advance seen in wild-type mice, PAC1(-)/- mice responded with phase delays after photic stimulation. These data indicate that PAC1 receptor signaling participates in the gating control of photic sensitivity of the clock and suggest that mPer1, mPer2, and c-fos are of less importance for light-induced phase shifts at night.

Activity Cycles↗
PubMed2002

"Clockness" in the detection of dementia: a semantic-conceptual effect.

We studied aspects of clock cognition that might underlie the sensitivity of the CDT in screening for dementia of the Alzheimer type (DAT). Two groups, 15 patients with mild-moderate DAT and 15 controls, were assessed with the CDT and specially designed tests of clock-related cognition. Patients were impaired on the CDT, but they did not differ from controls in copying a clock face or selecting the correct representation of a given time. Patients were worse than controls at distinguishing between clock and nonclock objects, detecting anomalies in clocks, and in setting time irrespective of response format. These findings suggest that semantic-conceptual aspects of clock-related cognition are important in discriminating between patients with DAT and controls.

Aged↗
PubMed2006

Rhythmic clock gene expression in heart, kidney and some brain nuclei involved in blood pressure control in hypertensive TGR(mREN-2)27 rats.

Hypertensive TGR(mREN-2)27 rats exerting inverted blood pressure (BP) profile were used to study clock gene expression in structures responsible for BP control. TGR and control Sprague Dawley male rats were synchronized to the light:dark cycle 12:12 with food and water ad libitum. Daily rhythm in per2, bmal1, clock and dbp expression in the suprachiasmatic nucleus (SCN), rostral ventrolateral medulla (RVLM), nucleus of the solitary tract (NTS), heart and kidney was determined in both groups. Sampling occurred in regular 4 h intervals when rats of both strains were 11-weeks-old. Blood pressure and relative heart weight were significantly elevated in TGR rats in comparison with control. Expression of bmal1 and clock was up regulated in SCN of TGR rats but daily rhythm in per2 and dbp expression was similar in both groups. Mesor of per2 expression in RVLM was significantly higher in TGR than in control rats. In NTS of TGR rats expression of per2 was phase delayed by 3.5 h in comparison with control and bmal1 did not exert rhythmic pattern. Our study provided the first evidence about modified function of central and peripheral circadian oscillators in TGR rats at the level of clock gene expression. Expression of clock genes exerted up regulation in SCN and RVLM and down regulation in NTS. Circadian oscillators in selected brain structures were influenced more than oscillators in the heart and kidney by additional renin gene. Interactions of RAS and circadian system probably contribute to the development of inverted BP profile in TGR rats.

ARNTL Transcription Factors↗
PubMed2006

Keeping time without a clock.

The accepted dogma in circadian biology is that the transcription factor CLOCK lies at the heart of the molecular clock that drives behavioral and molecular rhythms. In this issue of Neuron, the generation of CLOCK-deficient mice with only subtle clock defects by DeBruyne et al. shakes up this view of the mammalian clock.

Animals↗
PubMed1999

A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock.

We examined the transcriptional regulation of the clock-controlled arginine vasopressin gene in the suprachiasmatic nuclei (SCN). A core clock mechanism in mouse SCN appears to involve a transcriptional feedback loop in which CLOCK and BMAL1 are positive regulators and three mPeriod (mPer) genes are involved in negative feedback. We show that the RNA rhythm of each mPer gene is severely blunted in Clock/Clock mice. The vasopressin RNA rhythm is abolished in the SCN of Clock/Clock animals, leading to markedly decreased peptide levels. Luciferase reporter gene assays show that CLOCK-BMAL1 heterodimers act through an E box enhancer in the vasopressin gene to activate transcription; this activation can be inhibited by the mPER and mTIM proteins. These data indicate that the transcriptional machinery of the core clockwork directly regulates a clock-controlled output rhythm.

3T3 Cells↗
PubMed1999

mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop.

We determined that two mouse cryptochrome genes, mCry1 and mCry2, act in the negative limb of the clock feedback loop. In cell lines, mPER proteins (alone or in combination) have modest effects on their cellular location and ability to inhibit CLOCK:BMAL1 -mediated transcription. This suggested cryptochrome involvement in the negative limb of the feedback loop. Indeed, mCry1 and mCry2 RNA levels are reduced in the central and peripheral clocks of Clock/Clock mutant mice. mCRY1 and mCRY2 are nuclear proteins that interact with each of the mPER proteins, translocate each mPER protein from cytoplasm to nucleus, and are rhythmically expressed in the suprachiasmatic circadian clock. Luciferase reporter gene assays show that mCRY1 or mCRY2 alone abrogates CLOCK:BMAL1-E box-mediated transcription. The mPER and mCRY proteins appear to inhibit the transcriptional complex differentially.

3T3 Cells↗