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PubMed1994

The effects of altering extracellular potassium ion concentration on the membrane potential and circadian clock of Paramecium bursaria.

In some neural models of circadian rhythmicity, membrane potential and transmembrane flux of potassium and calcium ions appear to play important roles in the entrainment and central mechanisms of the biological clock. We wondered whether these cellular variables might be generally involved in circadian clocks, even non-neural clocks. Therefore, we tested the impact of changing extracellular potassium level on the circadian rhythm of photoaccumulation of Paramecium cells, whose membrane potential responds to changes of extracellular potassium in a manner similar to that of neurones. We found that pulse or step changes of extracellular potassium concentration did not phase-shift the circadian clock of P. bursaria cells in a phase-specific manner. Furthermore, modifying the extracellular concentration of calcium did not affect the magnitude of light-induced phase resetting. Therefore, while membrane potential and calcium fluxes may be crucial components of the circadian clock system in some organisms, especially in neural systems that involve intercellular communication, the P. bursaria data indicate that membrane potential changes are not necessarily an intrinsic component of circadian organization at the cellular level.

Animals↗
PubMed2006

Control of daily transcript oscillations in Drosophila by light and the circadian clock.

The transcriptional circuits of circadian clocks control physiological and behavioral rhythms. Light may affect such overt rhythms in two ways: (1) by entraining the clock circuits and (2) via clock-independent molecular pathways. In this study we examine the relationship between autonomous transcript oscillations and light-driven transcript responses. Transcript profiles of wild-type and arrhythmic mutant Drosophila were recorded both in the presence of an environmental photocycle and in constant darkness. Systematic autonomous oscillations in the 12- to 48-h period range were detectable only in wild-type flies and occurred preferentially at the circadian period length. However, an extensive program of light-driven expression was confirmed in arrhythmic mutant flies. Many light-responsive transcripts are preferentially expressed in the compound eyes and the phospholipase C component of phototransduction, NORPA (no receptor potential), is required for their light-dependent regulation. Although there is evidence for the existence of multiple molecular clock circuits in cyanobacteria, protists, plants, and fungi, Drosophila appears to possess only one such system. The sustained photic expression responses identified here are partially coupled to the circadian clock and may reflect a mechanism for flies to modulate functions such as visual sensitivity and synaptic transmission in response to seasonal changes in photoperiod.

Animals↗
PubMed2005

Circadian clock signaling in Arabidopsis thaliana: from gene expression to physiology and development.

The daily rotation of the earth on its axis leads to predictable periodic fluctuations of environmental conditions. Accordingly, most organisms have evolved an internal timing mechanism, the circadian clock, which is able to recognize these 24-hour rhythmic oscillations. In plants, the temporal synchronization of physiology with the environment is essential for successful plant growth and development. The intimate connection between light signaling pathways and the circadian oscillator allows the anticipation of the environmental transitions and the measurement of day-length as an indicator of changing seasons. In recent years, significant advances have been made in the genetic and molecular dissection of the plant circadian system, mostly in Arabidopsis thaliana. The overall plant clock organization is highly complex; the system seems to include several input pathways, tightly regulated central oscillators and a myriad of outputs. The molecular cloning and characterization of a number of clock components has greatly improved our view of the plant central oscillator and additional players will most likely come into place very soon. Molecular mechanisms underlying circadian clock function are also beginning to be characterized. The emerging model relies on negative feedback loops at the core of the oscillator. Additional levels of post-transcriptional and post-translational regulation also contribute to the generation and maintenance of the rhythms. Globally, these studies have shed new light on how the clock coordinates plant physiology and development with the daily and seasonal environmental cycles.

Arabidopsis↗
PubMed2005

A circadian clock and light/dark adaptation differentially regulate adenosine in the mammalian retina.

Although the purine adenosine acts as an extracellular neuromodulator in the mammalian CNS in both normal and pathological conditions and regulates sleep, the regulation of extracellular adenosine in the day and night is incompletely understood. To determine how extracellular adenosine is regulated, rabbit neural retinas were maintained by superfusion at different times of the regular light/dark and circadian cycles. The adenosine level in the superfusate, representing adenosine overflow from the retinas, and the adenosine level in retinal homogenates, representing adenosine content, were measured using HPLC with fluorescence detection in the absence or presence of blockers of adenosine transport and/or extracellular adenosine synthesis. We report that darkness, compared with illumination, increases the level of extracellular adenosine, and that a circadian clock also increases extracellular adenosine at night. In addition, we show that the darkness-evoked increase in the level of extracellular adenosine results primarily from an increase in the conversion of extracellular ATP into adenosine, but that the clock-induced increase at night results primarily from an increase in the accumulation of intracellular adenosine. We also show that a slightly hypoxic state increases adenosine content and overflow to an extent similar to that of the clock. Our findings demonstrate that the extracellular level of adenosine in the mammalian retina is differentially regulated by a circadian clock and the lighting conditions and is maximal at night under dark-adapted conditions. We conclude that adenosine is a neuromodulator involved in both circadian clock and dark-adaptive processes in the vertebrate retina.

Adaptation, Physiological↗
PubMed2003

Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis.

Melatonin-based photoperiod time-measurement and circannual rhythm generation are long-term time-keeping systems used to regulate seasonal cycles in physiology and behaviour in a wide range of mammals including man. We summarise recent evidence that temporal, melatonin-controlled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.

Animals↗
PubMed1995

Synergistic inhibition by benzodiazepine and barbiturate drugs of the clock control of ovulation in hamsters.

A surge of pituitary luteinizing hormone (LH) into the bloodstream occurs in hamsters every 4 days between 1:30 p.m. and 3 p.m. in response to a signal from a biological clock. This surge initiates behavioral estrus approximately 2 h later and ovulation approximately 12 h later. Phenobarbital at a dose > or = 100 mg/kg consistently blocks LH release. Barbiturate and benzodiazepine drugs have separate binding sites in the GABAA receptor/chloride channel complex. Binding of either drug increases GABA-mediated chloride conductance, which suppresses the postsynaptic neuron. Barbiturate binding also increases benzodiazepine binding. This suggested that these drugs might synergize to inhibit LH release. A combination of triazolam and phenobarbital at doses of 10 mg/kg injected s.c. at 1:30 p.m. inhibited ovulation and extended the 4-day vaginal cycle in all treated hamsters. Either drug dose injected alone at 1:30 p.m., or the combination at 3 p.m., was completely ineffective. Bicuculline prevented inhibition by the combination at 1:30 p.m. The clock signal for LH release may act by antagonizing GABA transmission, which may be chronically inhibiting LH release. The combination delimited a 75-min period (1:30-2:45 p.m.) within which the clock signal for LH release occurred in all individuals (ET50 = 2:08 p.m.). This period appears to arise from individuals with different but constant clock settings rather than from a 75-min variation in the clock setting of the individual.

Animals↗
PubMed1997

The ultradian clocks of eukaryotic microbes: timekeeping devices displaying a homeostasis of the period.

Temperature compensation of their period is one of the canonical characteristics of circadian rhythms, yet it is not restricted to circadian rhythms. This short review summarizes the evidence for ultradian rhythms, with periods from 1 minute to several hours, that likewise display a strict temperature compensation. They have been observed mostly in unicellular organisms in which their constancy of period at different temperatures, as well as under different growth conditions (e.g., medium type, carbon source), indicates a general homeostasis of the period. Up to eight different parameters, including cell division, cell motility, and energy metabolism, were observed to oscillate with the same periodicity and therefore appear to be under the control of the same central pacemaker. This suggests that these ultradian clocks should be considered as cellular timekeeping devices that in fast-growing cells take over temporal control of cellular functions controlled by the circadian clock in slow-growing or nongrowing cells. Being potential relatives of circadian clocks, these ultradian rhythms may serve as model systems in chronobiological research. Indeed, mutations have been found that affect both circadian and ultradian periods, indicating that the respective oscillators share some mechanistic features. In the haploid yeast Schizosaccharomyces pombe, a number of genes have been identified where mutation, deletion, or overexpression affect the ultradian clock. Since most of these genes play roles in cellular metabolism and signaling, and mutations have pleiotropic effects, it has to be assumed that the clock is deeply embedded in cellular physiology. It is therefore suggested that mechanisms ensuring temperature compensation and general homeostasis of period are to be sought in a wider context.

Acanthamoeba↗
PubMed1993

[Clock drawing task as screening for cognitive impairment in the elderly population].

This study compared the "Clock-Drawing Task" to the Mini-Mental State Test (MMST) in 834 elderly persons. A cut-off score of 20 or less on the MMST was used to determine cognitive impairment. The "Clock drawing Task" was score of 20 or less on the MMST was used to determine cognitive impairment. The "Clock drawing Task" was scored by three components; frame, numbers, and two hands. Using a criterion of completion on two or more of the three components, the sensitivity, specificity, and correct identification of the diagnosis of cognitive impairment of "Clock Drawing Task" were 89%, 65% and 83% respectively. "Clock Drawing" appears to be a practical test which can be useful for clinicians as a screening for cognitive impairment in old age.

Aged↗
PubMed1999

Differential regulation of mPER1 and mTIM proteins in the mouse suprachiasmatic nuclei: new insights into a core clock mechanism.

Recent discoveries have identified a framework for the core circadian clock mechanism in mammals. Development of this framework has been based entirely on the expression patterns of so-called "clock genes" in the suprachiasmatic nuclei (SCN), the principal clock of mammals. We now provide data concerning the protein expression patterns of two of these genes, mPer1 and mTim. Our studies show that mPER1 and mTIM are nuclear antigens expressed in the SCN and extensively throughout the forebrain. Expression of mPER1 in the SCN was rhythmic under entrained conditions and with clear circadian cycling under free-running conditions. Expression of mPER1 elsewhere in the mouse forebrain was not rhythmic. In contrast to mPER1, mTIM expression in the SCN did not vary with time in mice housed in either a light/dark cycle or in constant dim red light. The phase relationship between mPer1 RNA and mPER1 cycles in the SCN is consistent with a negative feedback model of the mammalian clock. The invariant nature of nuclear mTIM in the SCN suggests that its participation in negative feedback occurs only after mPER1 has entered the nucleus, and that the abundance of mTIM is not regulated by the circadian clock or the light/dark cycle.

Animals↗
PubMed1997

Early identification of dementia: predictive validity of the clock test.

Various clock scoring procedures have been developed in recent years as dementia screening measures. The current longitudinal study was developed to assess the predictive validity of the Clock Test (Tuokko, Hadjistavropoulos, Miller, Horton, & Beattie, 1995). Within a sample of subjects who initially did not meet dementia criteria, Clock Test scores (drawing, setting, and reading) distinguished between those who later met criteria for dementia as compared to subjects who did not. When impaired performance was identified as falling below cut-off on two or more subtests of the Clock Test, sensitivity and specificity were found to be 91% and 95% relative to time two diagnosis. Clock errors among the current sample were compared against normal control subjects from the Canadian Study of Health and Aging (CSHA). These comparative analyses attest to the relative normality of the clinic sample at the time of their initial assessment.

Journal Article↗
PubMed1993

Clock drawing as an assessment tool for dementia.

Clock drawing has recently been shown to lie useful in differentiating Alzieimer's disease patients from normal controls. Our procedure for clock drawing differed from other published reports in that a copy condition was employed and patients were asked to set clock hands to read "ten after eleven". We found both clock drawing procedures to be correlated with tests related to executive and visuospatial functioning. In both conditions, nondemented controls performed significantly better than demented patients. In the command condition there was no difference between Alzheimer patients and patients with cerebrovascular dementia. In the copy condition, patients with cerebrovascular dementia performed significantly worse than Alzheimer patients. The inclusion of a copy condition appears to greatly expand the utility of this test. Although our scoring system did not differentiate between various dementing disorders in the command condition, if clock drawing is used as a screening instrument, lack of improvement in the copy condition in comparison to the command condition may be a sign of a vascular involvement.

Journal Article↗
PubMed2002

Clock face drawing in children with attention-deficit/hyperactivity disorder.

The clock drawing test has been found to be sensitive to visual-spatial perception, graphomotor skills, verbal reasoning, and executive functioning in adult patient populations, as well as frontal lobe maturation in normal children. Our study is among the first to assess the use of clock drawing as a neuropsychological measure in the pediatric population. Participants included 41 children with attention-deficit/hyperactivity disorder (ADHD) and 41 normal controls, ages 6-12 years, matched for age, gender, and handedness. Conceptualization of time and construction of the clock face were assessed separately using a scoring system normed on school-age children in an earlier study. Children with Predominantly Inattentive Type were found to perform similarly to those with Combined Type of ADHD. However, children with ADHD, regardless of subtype, performed significantly poorer than controls. Qualitative analysis of performance revealed errors that were subsequent to poor planning during task execution, consistent with executive dysfunction commonly present in children with ADHD. Further, multiple regression analysis demonstrated that a neuropsychological measure of executive functioning was predictive of clock construction performance in children with ADHD. Constructional praxis and receptive vocabulary also were predictive of clock construction ability. Implications of these findings are discussed.

Journal Article↗
PubMed2003

The molecular workings of the Neurospora biological clock.

In Neurosporacrassa the FRQ/WC feedback loop has been shown to be central to the function of the circadian clock. Similar to other eukaryotic systems it is based on a transcription-translation PAS heterodimer type feedback. FRQ levels cycle with a period identical to that of the Neurospora circadian cycle and its expression is rapidly induced by light. A complex of White Collar 1 (WC-1) and White Collar 2 (WC-2) (the WCC) is required for the transcriptional activation of frq. The oscillation in frq message is transcriptionally regulated via a single necessary and sufficient cis-acting element in the frq promoter, the Clock-Box (CB) bound by WCC. Light-induction of frq transcription is mediated by WCC binding to two cis-acting elements (LREs) in the frq promoter. WC-1, with flavin adenine dinucleotide (FAD) as a cofactor, is the blue-light photoreceptor. The original description of a frq-null strain, frq9, (Loros et al 1986) included a description of oscillations in asexual conidial banding that occasionally appeared following 3 to 7 days of arrhythmic development now referred to as FLO for FRQ-less oscillator. Unlike the intact clock, FLO period is sensitive to media composition. We have identified a circadianly regulated gene whose mutation interferes with FLO even under temperature entrainment conditions. This same mutation affects the circadian clock in a frq+ background causing a shorter period length as well as temperature response defects. This gene may be an entry point to study the connection between the biological clock and other basic cellular mechanisms.

Circadian Rhythm↗
PubMed2005

Screening of dementia in Chinese elderly adults by the clock drawing test and the time and change test.

OBJECTIVES: To assess the usefulness, relative ease of administration, and patient acceptance of the clock drawing test as well as the time and change test for detecting dementia in Chinese elderly adults. DESIGN: Prospective case-controlled study. SETTING: Memory clinic and geriatric clinic of a district hospital, Hong Kong. PARTICIPANTS: A convenient sample of 85 subjects aged 65 years or older attending the two clinics during the period from September 2002 to June 2003. MAIN OUTCOME MEASURES: The clock drawing test scored according to Lam's method; the time and change test with modification to the making change task; and the Chinese version of the Mini-Mental State Examination. RESULTS: Demented subjects were matched with non-demented ones with respect to age, sex, educational level, and co-morbidity status. The clock drawing test had a comparable sensitivity (89.4%) but a lower specificity (47.1%) when compared with that of the Chinese version of the Mini-Mental State Examination (96.0 and 76.5%, respectively). In contrast, the time and change test had a lower sensitivity (62.7%) but higher specificity (94.1%). Both tests took significantly less time to complete than the Chinese version of the Mini-Mental State Examination. All except four subjects completed the clock drawing test while all subjects accepted the time and change test well. CONCLUSIONS: The Chinese version of the Mini-Mental State Examination is still the best among the three tests despite the longer time to completion. The clock drawing test may be a good alternative to the Mini-Mental State Examination as an effective screening test for dementia when time does not permit. The time and change test, although time-saving, is not suitable to be used alone because of its low sensitivity.

Aged↗
PubMed1986

Regulation of the circadian clock in the Aplysia eye: mimicry of neural action by serotonin.

In Aplysia, activity of efferent fibers in the optic nerve can influence the circadian clock in the eye. In addition, serotonin (5-HT) is present in the eye and influences the function of the clock. Accordingly, we hypothesized that 5-HT is the transmitter of the optic efferents, and tested the prediction that exogenous 5-HT would mimic the action of the optic efferents on the clock. We also tested the prediction that the action of the efferents would be prevented by blocking synaptic secretions with high Mg2+, low Ca2+ (HMLC). Activity of the optic efferents enhances clock resetting in response to the onset of darkness. We used this neural enhancement as a measure of neural action on the eye clock. We found that HMLC blocked neural enhancement. Serotonin enhanced resetting to the same extent as efferent activity. Enhancement by 5-HT did not summate with neural enhancement. High concentrations of 5-HT ([5-HT] greater than or equal to 6 X 10(-4) did not cause enhancement. High concentrations of 5-HT also blocked neural enhancement. Enhancement by 5-HT depended on the phase of drug application, much as neural enhancement depends on the phase of neural activity. Enhancement by 5-HT depended on day length in a manner similar to the enhancement by neural activity. HMLC did not block the facilitatory action of 5-HT. Several other transmitters that may be active in the eye did not enhance resetting.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

[The clock test: a simple method to assess dementia].

AIM: to validate an easy and simple test to measure cognitive function: the clock drawing test. STUDY DESIGN: 138 hospitalized and free living elders (96 female, mean age 77.9 years) were studied. They were requested to draw a clock, using standardized instructions. The drawings were independently analyzed and scored by the authors. The Mini Mental State test was used as reference and the scores of both tests were correlated. RESULTS: there was a correlation of 0.73 between the scores of the clock drawing and Mini Mental State tests. Using a score of 7 points in tye clock drawing and 26 points in the Mini Mental State test as cut of points for the diagnosis of dementia, the former's sensitivity and specificity was 0.82 and 0.71 respectively. CONCLUSIONS: the clock drawing test appears as a simple and effective test for the initial assessment of cognitive functions in patients with suspected dementia.

Aged↗
PubMed1998

A myosin III from Limulus eyes is a clock-regulated phosphoprotein.

The lateral eyes of the horseshoe crab Limulus polyphemus undergo dramatic daily changes in structure and function that lead to enhanced retinal sensitivity and responsiveness to light at night. These changes are controlled by a circadian neural input that alters photoreceptor and pigment cell shape, pigment migration, and phototransduction. Clock input to the eyes also regulates photomechanical movements within photoreceptors, including membrane shedding. The biochemical mechanisms underlying these diverse effects of the clock on the retina are unknown, but a major biochemical consequence of activating clock input to the eyes is a rise in the concentration of cAMP in photoreceptors and the phosphorylation of a 122 kDa visual system-specific protein. We have cloned and sequenced cDNA encoding the clock-regulated 122 kDa phosphoprotein and show here that it is a new member of the myosin III family. We report that Limulus myosin III is similar to other unconventional myosins in that it binds to calmodulin in the absence of Ca2+; it is novel in that it is phosphorylated within its myosin globular head, probably by cAMP-dependent protein kinase. The protein is present throughout the photoreceptor, including the region occupied by the photosensitive rhabdom. We propose that the phosphorylation of Limulus myosin III is involved in one or more of the structural and functional changes that occur in Limulus eyes in response to clock input.

Amino Acid Sequence↗
PubMed1998

[Understanding the action of the circadian clock: from phenomenologic ideas to molecular activity].

The focus of the present review is to present recent studies of the mammalian circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The main questions in circadian neuroscience are: how many oscillators are implicated, how are their daily oscillations generated and synchronized to the external environment and how does the central clock send timed signals to the whole organism. The review is introduced by a presentation of circadian system properties and by a description of the responses to manipulations of the main entraining factor, i.e. the light-dark cycle. The anatomy of the SCN and its major afferents from the retina (glutamate, Substance P), raphe (serotonin) and intergeniculate leaflet (neuropeptide Y) of the thalamus are presented with a special emphasis on the interaction of these inputs with the circadian timekeeping mechanism. The arguments related to the issue of whether the retina contain an endogenous oscillator are exposed. What is known of the endogenous mechanism(s) of this small structure containing 10,000 or so "self-oscillating neurons" is reviewed through: i) the anatomical distribution and functional significance of clock-peptides (VIP, PHI, GRP, VP or SS), ii) the putative involvement of the SCN astrocytic population in coordinating neuronal activities, iii) the various aspects of cellular activity (electrical activity, energy metabolism, protein or peptide synthesis) and iv) the participation of immediate early genes in light-driven phase shifts. The present understanding of molecular timekeeping mechanism is exposed in light of the growing list of candidate clock-genes described within the SCN as well as in peripheral tissues of mammals and also in the clock-systems of phylogenetically lower species. Efferents from the SCN are also discussed with an interest toward understanding how the central circadian information is transmitted to the rest of the brain in order to impulse or/and coordinate the numerous rhythmic activities of the organism. Finally, cellular disturbances in peptide expression or content, reduction in the amplitude of a given functional index or even astrocytic proliferation are viewed along the line of pathologies observed with aging.

Afferent Pathways↗