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PubMed1996

Daily rhythms in cells of the fly's optic lobe: taking time out from the circadian clock.

Considerable progress has recently been reported in locating the cellular basis and molecular mechanisms of the circadian clock in the fruitfly, Drosophila melanogaster. To advance beyond the clock, towards the outputs that lie between the clock itself and the circadian rhythms in behaviour that it regulates, will present new challenges. This is because most behaviours are generated by complex neuronal circuits, which are themselves difficult to unravel. Recently described anatomical changes in the optic lobe of the related housefly, Musca domestica, exhibit a circadian rhythm that is, by contrast, relatively easy to assay. This rhythm is apparently controlled by at least two sets of diffuse modulatory neurones. One of these, immunoreactive to the peptide pigment-dispersing hormone, also expresses in Drosophila the product of the period (per) gene, the most widely studied of the so-called clock genes that are essential for the correct expression of circadian rhythmicity. The second, called LBO5HT, is immunoreactive to 5-HT, a widely invoked transmitter system in insect circadian rhythms. The identification of these elements, and a widening cascade of events which their actions apparently trigger, opens up new opportunities to examine old problems in the regulation of circadian rhythms in the nervous system.

Animals↗
PubMed2003

Parieto-frontal networks for clock drawing revealed with fMRI.

We studied the neural substrates of clock drawing using functional magnetic resonance imaging in 18 right-handed volunteers. In the test condition, subjects were required to draw the hands of a clock corresponded to the time presented acoustically. In the control task, they drew horizontal and vertical lines after reciting silently the numerals of three figures presented acoustically. In group analyses, comparison between the test and control condition revealed brain areas related to clock drawing; bilateral posterior parietal cortices with a right side dominance, bilateral dorsal premotor areas, the left pre-supplementary motor area, the left ventral prefrontal cortex, the left precentral gyrus, and bilateral cerebellum. In particular, the posterior parietal cortex and the dorsal premotor area, which were strongly activated in all 18 subjects examined in individual analyses, appear to be the main constituent of the parieto-frontal cortical networks for clock drawing.

Acoustic Stimulation↗
PubMed2001

Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock.

The clock gene double-time (dbt) encodes an ortholog of casein kinase Iepsilon that promotes phosphorylation and turnover of the PERIOD protein. Whereas the period (per), timeless (tim), and dClock (dClk) genes of Drosophila each contribute cycling mRNA and protein to a circadian clock, dbt RNA and DBT protein are constitutively expressed. Robust circadian changes in DBT subcellular localization are nevertheless observed in clock-containing cells of the fly head. These localization rhythms accompany formation of protein complexes that include PER, TIM, and DBT, and reflect periodic redistribution between the nucleus and the cytoplasm. Nuclear phosphorylation of PER is strongly enhanced when TIM is removed from PER/TIM/DBT complexes. The varying associations of PER, DBT and TIM appear to determine the onset and duration of nuclear PER function within the Drosophila clock.

Animals↗
PubMed2003

Clock drawing test in institutionalized patients with schizophrenia compared with Alzheimer's disease patients.

The impaired performance of Alzheimer's disease (AD) patients on the clock drawing test (CDT) relative to age-matched normal controls is a well-documented finding in the literature. On the other hand, there is sparse information regarding the use of this test in schizophrenia. We examined three groups of subjects matched for gender and education: institutionalized patients with schizophrenia (n = 32), patients with AD (n = 32), and normal controls (n = 36). The CDT ("free-drawn", "pre-drawn", and three "examiner" conditions) and Mini-Mental State Examination (MMSE) were administered to all participants. In patients with schizophrenia, symptom severity was assessed with the Brief Psychiatric Rating Scale (BPRS). Patients with schizophrenia were significantly younger than AD patients and normal controls (56.78 versus 71.41 and 66.25, respectively), and normal controls had significantly higher MMSE scores than patients with schizophrenia and AD (27.58 versus 20.75 and 18.44, respectively). In all of the clock conditions, the two patient groups performed significantly poorer than the normal controls, with the exception of the "pre-drawn" clock in which AD patients also performed worse than patients with schizophrenia. Age and duration of illness did not correlate significantly with CDT scores. When MMSE scores were used as a covariate, all significant differences on the CDT among the three groups disappeared, with the exception of the "pre-drawn" clock (AD patients had lower scores than both control and schizophrenia groups). In patients with schizophrenia, scores on the BPRS were not related with any CDT variable. Institutionalized patients with schizophrenia and AD patients showed similar deficits on a neuropsychological test sensitive to changes in visual-analytic function, attention, receptive language, and executive functions such as planning, organization, and simultaneous processing.

Aged↗
PubMed2000

Functional independence of circadian clocks that regulate plant gene expression.

BACKGROUND: Circadian clocks regulate the gene expression, metabolism and behaviour of most eukaryotes, controlling an orderly succession of physiological processes that are synchronised with the environmental day/night cycle. Central circadian pacemakers that control animal behaviour are located in the brains of insects and rodents, but the location of such a pacemaker has not been determined in plants. Peripheral plant and animal tissues also maintain circadian rhythms when isolated in culture, indicating that these tissues contain circadian clocks. The degree of autonomy that the multiple, peripheral circadian clocks have in the intact organism is unclear. RESULTS: We used the bioluminescent luciferase reporter gene to monitor rhythmic expression from three promoters in transgenic Arabidopsis and tobacco plants. The rhythmic expression of a single gene could be set at up to three phases in different anatomical locations of a single plant, by applying light/dark treatments to restricted tissue areas. The initial phases were stably maintained after the entraining treatments ended, indicating that the circadian oscillators in intact plants are autonomous. This result held for all the vegetative plant organs and for promoters expressed in all major cell types. The rhythms of one organ were unaffected by entrainment of the rest of the plant, indicating that phase-resetting signals are also autonomous. CONCLUSIONS: Higher plants contain a spatial array of autonomous circadian clocks that regulate gene expression without a localised pacemaker. Circadian timing in plants might be less accurate but more flexible than the vertebrate circadian system.

Arabidopsis↗
PubMed2000

All in good time: the Arabidopsis circadian clock.

Biological time-keeping mechanisms have fascinated researchers since the movement of leaves with a daily rhythm was first described >270 years ago. The circadian clock confers a approximately 24-hour rhythm on a range of processes including leaf movements and the expression of some genes. Molecular mechanisms and components underlying clock function have been described in recent years for several animal and prokaryotic organisms, and those of plants are beginning to be characterized. The emerging model of the Arabidopsis clock has mechanistic parallels with the clocks of other model organisms, which consist of positive and negative feedback loops, but the molecular components appear to be unique to plants.

Animals↗
PubMed2003

Differential regulation of Period 2 and Period 3 expression during development of the zebrafish circadian clock.

Circadian ( approximately 24h) clocks are endogenous time-keeping systems that drive the daily biological rhythms observed in most living organisms. The oscillation is generated by a transcriptional/translational autoregulatory feedback loop that is reset by external time cues such as the light/dark cycle and which in turn controls rhythms in physiology and behavior through downstream clock-controlled genes (Nature 417 (2002) 329). Genetic and biochemical analysis of Drosophila and mammalian clock genes has provided a comprehensive model for the molecular oscillator that generates these rhythms, but the ontogeny of this oscillator remains poorly understood. A circadian oscillator involving the clock genes Per3 and Rev-erb alpha was identified during early development in zebrafish (Science 289 (2000) 297). Here, we report the isolation of zebrafish Per2 and show the presence of a Per2 maternal mRNA in early embryos as for Per3. However, Per2 rhythmic expression occurs late during embryogenesis as compared to that of Per3. Furthermore, our data indicate that Per2 is not required during embryogenesis for the rhythmicity of physiological outputs such as melatonin synthesis. In addition, Per2 but not Per3 is constitutively expressed in the developing olfactory bulb and pituitary. This differential spatio-temporal expression patterns suggest specific roles for Per2 and Per3 in the establishment of the embryonic circadian system.

Amino Acid Sequence↗
PubMed2006

The Clock Reading Test: validation of an instrument for the diagnosis of dementia and disorders of visuo-spatial cognition.

BACKGROUND: The 12-item Clock Reading Test (CRT) allows a fine-graded assessment of clock-reading ability. It has a strong focus on visuo-spatial processing and requires no executive processing. This study evaluated the reliability, validity, sensitivity and specificity of the CRT for the diagnosis of dementia and visuo-spatial dysfunction. METHODS: The CRT, the Clock Drawing Test (CDT) and other tests were applied to groups of 200 subjects with dementia, 105 subjects with mild cognitive impairment (MCI), 20 subjects with focal parietal lesions and 64 elderly control subjects. RESULTS: The CRT was found to be reliable and sensitive for the detection of cognitive impairment in parietal lesions, Alzheimer-, mixed- and Lewy Body dementia. Normal subjects and patients with MCI, frontotemporal dementia or cerebral small vessel disease showed little or no impairment. CONCLUSION: CRT and CDT are clock-processing tests with different demand profiles. They can supplement each other in the neuropsychological diagnosis of dementia and visuo-spatial dysfunction.

Aged↗
PubMed1982

Interaural and monaural clicks and clocks: tempo difference versus attention switching.

We describe a quantitative model capable of explaining the results of all reported investigations of the counting of interaural and monaural click sequencies. The model is developed by means of three convergent operations: (a) reanalyzing absolute-estimation data of apparent repetition rates of interaural and monaural sequences, (b) deriving interaural and monaural counting times from numerosity-judgement data, and (c) analyzing the time that observers needed to respond to the end of interaural and monaural sequences. The combined evidence demonstrates that the perceived onset asynchrony (POA) between interaural events is 24 msec longer than that between monaural events. The model has three components: (a) a "stimulus clock," which represents the stimulus onset synchrony (SOA) between events; (b) a "memory clock," which represents the POA between events, and (c) a "counting clock," which represents the counter increment time. The transfer functions between the three clocks are deduced from empirical data. Other proposals to explain interaural click counting results (attention switching, streaming by locus, counterincrement deficit) are discussed and rejected.

Attention↗
PubMed2004

Effect of arousal on internal clock speed in real action and mental imagery.

The possible implication of an internal clock as a mechanism accounting for the temporal homology between actual and mental walking is studied. To observe this phenomenon, stressful sound stimuli were used to increase arousal, which is known to activate the internal clock. Seventeen participants performed three tasks: (1) a time production task, used as a reference task reflecting the internal clock speed; (2) an actual walking task; and (3) a mental walking task, all three in two sound conditions (no noise and noise). The results showed a significant effect of arousal on time in each task. The effect of noise, increasing the arousal level, was greater in time production and mental imagery tasks than in real action. In addition, the percentages of change between the two sound conditions for actual and mental walking time were not statistically different. These findings are further evidence of the existence of a timing process common to actual and mental walking. The data are consistent with the implication of an internal clock in both actual and mental walking.

Adult↗
PubMed1989

Stimulated activity mediates phase shifts in the hamster circadian clock induced by dark pulses or benzodiazepines.

A number of environmental and pharmacological stimuli capable of inducing phase shifts and/or period changes in the circadian clock of mammals have now been identified. Agents that can alter circadian clocks provide a means for investigating the cellular and neural mechanisms responsible for their generation, regulation and entrainment. Two stimuli that have been used to probe the basis of circadian rhythmicity are pulses of darkness on a background of constant light and injections of short-acting benzodiazepines, such as triazolam. Surprisingly, these two very different stimuli have remarkably similar phase-shifting effects on the circadian clock of hamsters. The observation that a short-term increase in locomotor activity occurs when the circadian activity rhythm of hamsters is shifted by dark pulses or triazolam injections, coupled with the finding that activity bouts themselves are capable of shifting this rhythm, raises the possibility that dark pulses or triazolam alter the circadian clock by inducing acute hyperactivity. Here we demonstrate that the phase-advancing and phase-delaying effects of dark pulses or triazolam on the circadian activity rhythm can be totally suppressed by immobilization of the animals during treatment. These results indicate that behavioural events mediate the phase-shifting effects of both dark pulses and triazolam on the circadian activity rhythm and question present hypotheses regarding the pathways by which light-dark information and pharmacological agents influence circadian pacemakers.

Activity Cycles↗
PubMed2001

CONSTANS mediates between the circadian clock and the control of flowering in Arabidopsis.

Flowering is often triggered by exposing plants to appropriate day lengths. This response requires an endogenous timer called the circadian clock to measure the duration of the day or night. This timer also controls daily rhythms in gene expression and behavioural patterns such as leaf movements. Several Arabidopsis mutations affect both circadian processes and flowering time; but how the effect of these mutations on the circadian clock is related to their influence on flowering remains unknown. Here we show that expression of CONSTANS (CO), a gene that accelerates flowering in response to long days, is modulated by the circadian clock and day length. Expression of a CO target gene, called FLOWERING LOCUS T (FT), is restricted to a similar time of day as expression of CO. Three mutations that affect circadian rhythms and flowering time alter CO and FT expression in ways that are consistent with their effects on flowering. In addition, the late flowering phenotype of such mutants is corrected by overexpressing CO. Thus, CO acts between the circadian clock and the control of flowering, suggesting mechanisms by which day length regulates flowering time.

Arabidopsis↗
PubMed2000

Light induces chromatin modification in cells of the mammalian circadian clock.

The mammalian circadian clock resides in neurons of the hypothalamic suprachiasmatic nucleus (SCN). Light entrains phase resetting of the clock using the retino-hypothalamic tract, via release of glutamate. Nighttime light exposure causes rapid, transient induction of clock and immediate-early genes implicated in phase-shifting the pacemaker. Here we show that a nighttime light pulse caused phosphorylation of Ser10 in histone H3's tail, in SCN clock cells. The effect of light was specific, and the kinetics of H3 phosphorylation were characteristic of the early response, paralleling c-fos and Per1 induction. Using fos-lacZ transgenic mice, we found that H3 phosphorylation and Fos induction occurRed in the same SCN neurons. Systemic treatment with the GABAB receptor agonist baclofen prevented light-induced c-fos and Per1 expression and H3 phosphorylation, indicating that one signaling pathway governs both events. Our results suggest that dynamic chromatin remodeling in the SCN occurs in response to a physiological stimulus in vivo.

Animals↗
PubMed2003

Role for antisense RNA in regulating circadian clock function in Neurospora crassa.

The prevalence of antisense RNA in eukaryotes is not known and only a few naturally occurring antisense transcripts have been assigned a function. However, the recent identification of a large number of putative antisense transcripts strengthens the view that antisense RNAs might affect a wider variety of processes than previously thought. Here we show that in the model organism Neurospora crassa entrainment of the circadian clock, which is critical for the correct temporal expression of genes and their products, is controlled partly by an antisense RNA arising from a clock component locus. In a wild-type strain, levels of antisense frequency (frq) transcripts cycle in antiphase to sense frq transcripts in the dark, and are inducible by light. In mutant strains in which the induction of antisense frq RNA by light is abolished, the time of the internal clock is delayed relative to the wild-type strain, and resetting of the clock by light is altered. These data provide an unexpected link between antisense RNA and circadian timing and provide a new example of a eukaryotic cellular process regulated by naturally occurring antisense RNA.

Circadian Rhythm↗
PubMed2004

Instability of Hes7 protein is crucial for the somite segmentation clock.

During somitogenesis, a pair of somites buds off from the presomitic mesoderm every 2 hours in mouse embryos, suggesting that somite segmentation is controlled by a biological clock with a 2-hour cycle. Expression of the basic helix-loop-helix factor Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; this is proposed to be the molecular basis for the somite segmentation clock. If the proposal is correct, this clock should depend crucially on the short lifetime of Hes7. To address the biological importance of Hes7 instability, we generated mice expressing mutant Hes7 with a longer half-life (approximately 30 min compared with approximately 22 min for wild-type Hes7) but normal repressor activity. In these mice, somite segmentation and oscillatory expression became severely disorganized after a few normal cycles of segmentation. We simulated this effect mathematically using a direct autorepression model. Thus, instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock.

Animals↗
PubMed2006

Molecular genetics of the fruit-fly circadian clock.

The circadian clock percolates through every aspect of behaviour and physiology, and has wide implications for human and animal health. The molecular basis of the Drosophila circadian clock provides a model system that has remarkable similarities to that of mammals. The various cardinal clock molecules in the fly are outlined, and compared to those of their actual and 'functional' homologues in the mammal. We also focus on the evolutionary tinkering of these clock genes and compare and contrast the neuronal basis for behavioural rhythms between the two phyla.

Animals↗
PubMed1993

Constitutive, light-responsive and circadian clock-responsive factors compete for the different l box elements in plant light-regulated promoters.

The l box is a conserved regulatory motif which is found upstream of plant genes (rbcS, cab and nia) whose transcription is regulated by light and the circadian clock. Gel retardation and UV cross-linking assays were used to resolve two different groups of I box binding factors (IBFs) in tomato nuclear extracts. Active components of the first group (IBF-1) recognize the l box of the light-responsive rbcS promoter; one factor within this group, IBF-1a, also recognizes the adjacent G box, which has been shown previously to bind a different class of plant transcription factors, the G box binding factors (GBFs). To the limit of experimental resolution, IBF-1a and GBF compete for the same nucleotides on the G box. Nevertheless, these two activities are biochemically and immunologically distinct. The relative abundance of IBF-1a shows a vast decrease in dark-adapted plants. Factors in the second group (IBF-2), recognize the l box of the nia promoter, which is regulated both by light and the circadian clock; one factor within this group, IBF-2a, also binds the l box of a second promoter showing similar regulation, the cab promoter. The IBF-2a binding sites on the cab and nia promoters show extensive homology to a circadian clock-responsive promoter element from wheat. The abundance of IBF-2a is diurnally regulated and shows a dramatic induction around the onset of the light period. Transfer of the plants in continuous darkness demonstrates that this induction is under the control of a circadian clock.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2005

[How many pieces to build a circadian clock?].

Biological rhythms represent a fundamental property of various living organisms. In particular, circadian rhythms, i.e. rhythms with a period close to 24 hours, help organisms to adapt to environmental daily rhythms. Although various factors can entrain or reset rhythms, they persist even in the absence of external timing cue, showing that their generation is endogenous. Indeed, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be the main circadian clock in mammals. Isolated SCN neurons have been shown to display circadian rhythms, and in each cell, a set of genes, called "clock genes", are devoted to the generation and regulation of rhythms. Recently, it has become obvious that the clock located in the SCN is not homogenous, but is rather composed of multiple functional components somewhat reminiscent of its neurochemical organization. The significance and implications of these findings are still poorly understood but pave the way for future exciting studies. Here, current knowledge concerning these distinct neuronal populations and the ways through which synchronization could be achieved, as well as the potential role of neuropeptides in both photic and non-photic resetting of the clock, are summarized. Finally, we discuss the role of the SCN within the circadian system, which also includes oscillators located in various tissues and cell types.

Animals↗