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At least 1,081 records · Page 60Linked to original sources
PubMed2004

Circadian rhythms in behavior and clock gene expressions in the brain of mice lacking histidine decarboxylase.

To clarify functional roles of histamine in the circadian clock system, circadian rhythms of behavior and clock gene expression in the brain were examined in the mouse lacking histidine decarboxylase (HDC-/- mouse). Wheel-running and spontaneous locomotion were recorded under light-dark cycle (LD) and constant darkness (DD). mPer1, mPer2 and mBMAL1 mRNA expression rhythms under LD and DD were measured in the suprachiasmatic nucleus (SCN), cerebral cortex and striatum by in situ hybridization. The activity levels under LD and DD in the HDC-/- mice were lower than that in the wild type regardless of activity types (wheel-running and spontaneous locomotion). The free-running period under DD was significantly longer in the HDC-/- mice than in the wild type. The 24-h profiles of mPer1, mPer2 and mBMAL1 mRNA expressions in the SCN were not different between the two genotypes. By contrast, the mPer1 and mPer2 mRNA rhythms in the other brain areas such as the cortex and striatum were significantly disrupted in the HDC-/- mice. These results suggest that histamine is involved in the circadian system especially in the output pathway or feedback route from behavior to the pacemaker in the SCN, and that mPer genes in the brain areas outside the SCN play an important role in the expression of behavioral rhythm.

ARNTL Transcription Factors↗
PubMed2005

Clock gene polymorphisms and narcolepsy in positive and negative HLA-DQB1*0602 patients.

Narcolepsy is a chronic sleep disorder. It is linked to the HLA-DQB1*0602 allele. A recent report established a genetic linkage between narcolepsy and the chromosomal region 4p13-q21 that contains the Clock gene. We studied two SNPs in the Clock gene aiming to find any association with narcolepsy. We did not find differences in genetic frequencies in the patients group. We concluded that these two SNPs are not associated with narcolepsy.

Base Sequence↗
PubMed2004

Resetting the clock: Dexras1 defines a path.

The signaling pathways by which light and activity shift the circadian clock are not well understood. In this issue of Neuron, Cheng et al. analyze mice lacking Dexras1 (a Ras family GTPase protein) and demonstrate an important role for G(i/o) signaling mediating both photic and nonphotic phase shifts of the circadian clock.

Animals↗
PubMed2006

5-HT3 receptor-mediated photic-like responses of the circadian clock in the rat.

Serotonin (5-HT) and 5-HT agonists have various resetting effects on the master clock, located in the suprachiasmatic nucleus (SCN), depending on the species. In rats, they induce photic-like effects on both locomotor activity rhythms and gene expression in the SCN. The 5-HT receptor(s) mediating these effects at circadian time 22 are localized in the SCN, most likely at a presynaptic level, on the retinohypothalamic terminals (RHT) known to convey photic information by releasing glutamate. Indeed, RHT degeneration blocks photic-like effects of a non-specific 5-HT agonist, quipazine. However, the 5-HT receptor subtype(s) involved is still unknown, although 5-HT(3) receptor activation is known to induce glutamate release. We thus analyzed the effects of selective 5-HT(3) agonist and antagonist, as well as a specific NMDA receptor antagonist, on different parameters of the clock. This study shows that the 5-HT(3) receptor mediates the resetting effects of quipazine on locomotor activity rhythms. The 5-HT(3) receptor is only partially implicated in quipazine-induced expression of c-FOS, while NMDA receptor inhibition blocks quipazine photic-like effects on both parameters. Taken together, photic-like responses produced by 5-HT stimulation in rats are likely mediated by (presynaptic?) 5-HT(3) receptor activation followed by NMDA receptor activation.

Analysis of Variance↗
PubMed2006

Diurnal pattern of clock gene expression in the hypothalamus of the newborn rabbit.

In the European rabbit (Oryctolagus cuniculus) nursing acts as a strong non-photic synchronizer of circadian rhythmicity in the newborn young. Rabbits only nurse for a few minutes once every 24 h and previous studies have shown that the pups, blind at birth, display endogenous circadian rhythms in behavior and physiology entrained by this regular daily event. As a further step toward understanding the neural organization of the rabbit's early circadian system, we investigated the expression of clock genes in the suprachiasmatic nucleus of the hypothalamus (SCN; the principal circadian pacemaker in adult mammals) across the pups' 24-h day. We used 43 pups from seven litters maintained in constant darkness and entrained non-photically by nursing at the same time each day until P7. After nursing on day 7, pups were killed in the dark at 3-h intervals so as to obtain eight groups (n=5-6 pups/group) distributed evenly across the 24 h before the next scheduled nursing. Profiles in the expression of the clock genes Per1, Per2, Cry1 and Bmal1 were determined using in situ hybridization in brain sections through the hypothalamus at the level of the SCN. We report for the first time: 1) that Per1, Per2, Cry1 and Bmal1 are all expressed in the SCN of the newborn rabbit, 2) that the expression of Per1, Per2 and Bmal1 but not Cry1 shows diurnal rhythmicity similar to that in adult mammals, and 3) that the expression of Per1, Per2 and Bmal1 is consistent with the strong entraining effect of nursing found in previous studies. Unexpectedly, and contrasting somewhat to the pattern in the SCN, we also found diurnal rhythmicity in the expression of Cry1 and Bmal1 but not of Per1 in the anterior ventromedial hypothalamic nucleus. Overall, our findings suggest that the SCN is a functional part of the newborn rabbit's circadian system and that it can be entrained by non-photic cues associated with the mother's daily nursing visit.

Age Factors↗
PubMed2006

Dexras1: shaping the responsiveness of the circadian clock.

Living organisms are endowed with an autonomous timekeeping program that not only maintains circadian rhythms of behaviour and physiology but is reset by cues from the external, cyclic environment. Intracellular signaling events that mediate entrainment of the mammalian circadian clock by photic (light) as well as non-photic inputs are only beginning to be elucidated. Dexras1 is a novel Ras-like G protein that modulates multiple signaling cascades. Genetic ablation of Dexras1 in mice (dexras1(-/-)) results in altered responsiveness of the master circadian clock to photic and non-photic cues. This review will attempt to provide mechanistic insights into the involvement of Dexras1 in biological timing processes based on its role as a modulator of signal transduction.

Animals↗
PubMed2004

Real-time imaging reveals spatiotemporal dynamics of cellular circadian clocks.

Circadian clocks have been localized to discrete sites within the nervous systems of several organisms, and in mammals to the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The clock in the SCN is composed of multiple autonomous single-cell oscillators, and new studies now allow an unprecedented look at their oscillatory activities over repeated cycles in tissue slices in vitro. Initial data reinforce the importance of intercellular membrane events for constructing a functional and reliable tissue pacemaker.

Animals↗
PubMed2003

Effect of phosphodiesterase type 4 on circadian clock gene Per1 transcription.

The induction of Per1 gene in the suprachiasmatic nucleus, the center of the circadian clock, is assumed to play significant roles in the adjustment of the internal clock. cAMP is one of the intracellular mediators which activates Per1 transcription. Here, we showed that the amount of the rat Per1 (rPer1) transcript induced by forskolin (FK) was significantly upregulated by the inhibition of phosphodiesterase type 4 (PDE4), a specific phosphodiesterase for cAMP, in rat-1 fibroblasts. Administration of rolipram, a specific inhibitor of PDE4, increased intracellular cAMP concentration, phosphorylation of cAMP response element binding protein (CREB) and enhanced rPer1 induction at their peaks. However, in the falling phase of rPer1 induction, the inhibition of PDE4 hardly affected the profile of rPer1 expression. These findings suggest the involvement of PDE4 for the regulation of rPer1 expression via cAMP metabolism at peak of the induction but little or no participation of PDE4 in the decreasing phase of the gene expression.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Respiratory oscillations in yeast: clock-driven mitochondrial cycles of energization.

Respiratory oscillations in continuous yeast cultures can be accounted for by cyclic energization of mitochondria, dictated by the demands of a temperature-compensated ultradian clock with a period of 50 min. Inner mitochondrial membranes show both ultrastructural modifications and electrochemical potential changes. Electron transport components (NADH and cytochromes c and c oxidase) show redox state changes as the organisms cycle between their energized and de-energized phases. These regular cycles are transiently perturbed by uncouplers of energy conservation, with amplitudes more affected than period; that the characteristic period is restored after only one prolonged cycle, indicates that mitochondrial energy generation is not part of the clock mechanism itself, but is responding to energetic requirement.

Activity Cycles↗
PubMed2005

Peripheral clocks and the regulation of cardiovascular and metabolic function.

Circadian rhythms generated by cell autonomous biological clocks allow for the appropriate temporal synchronization of physiology and behavior, optimizing the efficiency of biological systems. Circadian oscillators and functions have been uncovered in both central and peripheral tissues. This article describes methodology, experimental design, and technical challenges pertaining to studies of circadian rhythms in the periphery. Experimental approaches are focused upon revealing the role of peripheral clocks in cardiovascular and metabolic function using in vitro and in vivo techniques.

ARNTL Transcription Factors↗
PubMed2005

Cell culture models for oscillator and pacemaker function: recipes for dishes with circadian clocks?

Primary cell cultures of avian pinealocytes and the mammalian suprachiasmatic nucleus (SCN), immortalized cell lines derived from the SCN (SCN2.2), and fibroblasts derived from mice and rats have been employed as in vitro models to study the cellular and molecular mechanisms underlying circadian biological clocks. This article compares and contrasts these model systems and describes methods for avian pinealocyte cultures, immortalized SCN2.2 cells, and mouse fibroblast culture. Each of these culture models has advantages and disadvantages. Avian pinealocytes are photoreceptive, contain a circadian pacemaker, and produce rhythms of an easily assayed endocrine output-melatonin. However, the molecular mechanisms underlying pinealocyte function are not understood. SCN2.2 cells express metabolic and molecular rhythms and can impose rhythmicity on cocultured cells as well as rat behavior when transplanted into the brain. Yet, the entrainment pathways are not experimentally established in these cells. Fibroblast cultures are simple to produce and express molecular clock gene rhythms, but they express neither physiological rhythmicity nor pacemaker properties. The relative merits of these culture systems, as well as their impact on understanding circadian organization in vivo, are also considered.

Animals↗
PubMed2005

The circadian clock and tumor suppression by mammalian period genes.

Period (Per) genes are key circadian rhythm regulators in mammals. Expression of mouse Per (mPer) genes has a diurnal pattern in the suprachiasmatic nucleus and in peripheral tissues. Genetic ablation mPER1 and mPER2 function results in a complete loss of circadian rhythm control based on wheel-running activity in mice. In addition, these animals also display apparent premature aging and a significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma radiation, mPer2-deficient mice respond by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes, and have robust tumor occurrences. Studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response, and tumor suppression in vivo. The temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice. Genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators, confirming the critical role of circadian function in organismal homeostasis.

Animals↗
PubMed2000

FKF1, a clock-controlled gene that regulates the transition to flowering in Arabidopsis.

Plant reproduction requires precise control of flowering in response to environmental cues. We isolated a late-flowering Arabidopsis mutant, fkf1, that is rescued by vemalization or gibberellin treatment. We positionally cloned FKF1, which encodes a novel protein with a PAS domain similar to the flavin-binding region of certain photoreceptors, an F box characteristic of proteins that direct ubiquitin-mediated degradation, and six kelch repeats predicted to fold into a beta propeller. FKF1 mRNA levels oscillate with a circadian rhythm, and deletion of FKF1 alters the waveform of rhythmic expression of two clock-controlled genes, implicating FKF1 in modulating the Arabidopsis circadian clock.

Amino Acid Sequence↗
PubMed1998

double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation.

We have isolated three alleles of a novel Drosophila clock gene, double-time (dbt). Short- (dbtS) and long-period (dbtL) mutants alter both behavioral rhythmicity and molecular oscillations from previously identified clock genes, period and timeless. A third allele, dbtP, causes pupal lethality and eliminates circadian cycling of per and tim gene products in larvae. In dbtP mutants, PER proteins constitutively accumulate, remain hypophosphorylated, and no longer depend on TIM proteins for their accumulation. We propose that the normal function of DOUBLETIME protein is to reduce the stability and thus the level of accumulation of monomeric PER proteins. This would promote a delay between per/tim transcription and PER/TIM complex function, which is essential for molecular rhythmicity.

Alleles↗
PubMed1998

CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity.

Light is a major environmental signal for circadian rhythms. We have identified and analyzed cry, a novel Drosophila cryptochrome gene. All characterized family members are directly photosensitive and include plant blue light photoreceptors. We show that cry transcription is under circadian regulation, influenced by the Drosophila clock genes period, timeless, Clock, and cycle. We also show that cry protein levels are dramatically affected by light exposure. Importantly, circadian photosensitivity is increased in a cry-overexpressing strain. These physiological and genetic data therefore link a specific photoreceptor molecule to circadian rhythmicity. Taken together with the data in the accompanying paper, we propose that CRY is a major Drosophila photoreceptor dedicated to the resetting of circadian rhythms.

ARNTL Transcription Factors↗
PubMed1999

Long-lasting sensitization to the accelerating effects of amphetamine on the speed of an internal clock.

Drinking in the rat occurs in bursts of rapid licking, a high frequency rhythmic behavior controlled by a neural clock located in the brain stem. We found that 3.0 mg/kg amphetamine increased the speed of licking and shifted to the left the frequency distribution of inter-lick intervals. Repeated amphetamine treatments result in long-lasting sensitization to this effect. Thus, it appears possible to produce enduring changes in the activity of a biological interval clock (or 'stopwatch') by manipulating catecholaminergic transmission. These findings may be important for an understanding of the neural basis of normal and pathological timing behavior.

Amphetamine↗
PubMed1997

Prostaglandin D synthase (beta-trace protein): a molecular clock to trace the origin of REM sleep?

In 1965, Zuckerkandl and Pauling proposed a novel concept that some important molecules termed semantides, which carry the information of the genes or a transcript thereof, can be used as molecular clocks to trace evolutionary history. According to this concept, enzymes are designated as tertiary semantides, following genes (primary semantides) and the mRNA (secondary semantides). Based on this idea, I propose that prostaglandin D synthase (which has been demonstrated recently as identical to the beta-trace protein present in the cerebrospinal fluid of mammals) may serve as a molecular clock to trace the origin and evolution of rapid eye movement sleep in the vertebrates.

Animals↗
PubMed1998

The Drosophila CLOCK protein undergoes daily rhythms in abundance, phosphorylation, and interactions with the PER-TIM complex.

We report the in vivo characterization of the Drosophila CLOCK protein (dCLOCK), a transcription factor that is required for the expression of the circadian clock genes period (per) and timeless (tim). dCLOCK undergoes circadian fluctuations in abundance, is phosphorylated throughout a daily cycle, and interacts with PER, TIM, and/or the PER-TIM complex during the night but not during most of the day. Our results suggest that PER and TIM participate in transcriptional autoinhibition by physically interacting with dCLOCK or a dCLOCK-containing complex. Nevertheless, in the absence of PER or TIM, the levels of dCLOCK are constitutively low, indicating that PER and TIM also act as positive elements in the feedback loop by stimulating the production of dCLOCK.

Animals↗