WorldWideScience

Sample records for hippocampal clock gene

  1. Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A-deficient rats.

    Science.gov (United States)

    Navigatore-Fonzo, Lorena S; Delgado, Silvia M; Golini, Rebeca S; Anzulovich, Ana C

    2014-04-01

    The main external time giver is the day-night cycle; however, signals from feeding and the activity/rest cycles can entrain peripheral clocks, such as the hippocampus, in the absence of light. Knowing that vitamin A and its derivatives, the retinoids, may act as regulators of the endogenous clock activity, we hypothesized that the nutritional deficiency of vitamin A may influence the locomotor activity rhythm as well as the endogenous circadian patterns of clock genes in the rat hippocampus. Locomotor activity was recorded during the last week of the treatment period. Circadian rhythms of clock genes expression were analyzed by reverse transcription-polymerase chain reaction in hippocampus samples that were isolated every 4 hours during a 24-hour period. Reduced glutathione (GSH) levels were also determined by a kinetic assay. Regulatory regions of clock PER2, CRY1, and CRY2 genes were scanned for RXRE, RARE, and RORE sites. As expected, the locomotor activity pattern of rats shifted rightward under constant dark conditions. Clock genes expression and GSH levels displayed robust circadian oscillations in the rat hippocampus. We found RXRE and RORE sites on regulatory regions of clock genes. Vitamin A deficiency dampened rhythms of locomotor activity as well as modified endogenous rhythms of clock genes expression and GSH levels. Thus, vitamin A may have a role in endogenous clock functioning and participate in the circadian regulation of the cellular redox state in the hippocampus, a peripheral clock with relevant function in memory and learning. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Circadian clock genes, ovarian development and diapause

    Directory of Open Access Journals (Sweden)

    Bradshaw William E

    2010-09-01

    Full Text Available Abstract Insects, like most organisms, have an internal circadian clock that oscillates with a daily rhythmicity, and a timing mechanism that mediates seasonal events, including diapause. In research published in BMC Biology, Ikeno et al. show that downregulation of the circadian clock genes period and cycle affects expression of ovarian diapause in the insect Riptortus pedestris. They interpret these important results as support for Erwin Bünning's (1936 hypothesis that the circadian clock constitutes the basis of photoperiodism. However, their observations could also be the result of pleiotropic effects of the individual clock genes. See research article http://www.biomedcentral.com/1741-7007/8/116

  3. Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters.

    Science.gov (United States)

    Ikeno, Tomoko; Nelson, Randy J

    2015-02-01

    In the hippocampus of Siberian hamsters, dendritic length and dendritic complexity increase in the CA1 region whereas dendritic spine density decreases in the dentate gyrus region at night. However, the underlying mechanism of the diurnal rhythmicity in hippocampal neuronal remodeling is unknown. In mammals, most daily rhythms in physiology and behaviors are regulated by a network of circadian clocks. The central clock, located in the hypothalamus, controls melatonin secretion at night and melatonin modifies peripheral clocks by altering expression of circadian clock genes. In this study, we examined the effects of acute melatonin treatment on the circadian clock system as well as on morphological changes of hippocampal neurons. Male Siberian hamsters were injected with melatonin in the afternoon; 4 h later, mRNA levels of hypothalamic and hippocampal circadian clock genes and hippocampal neuron dendritic morphology were assessed. In the hypothalamus, melatonin treatment did not alter Period1 and Bmal1 expression. However, melatonin treatment increased both Period1 and Bmal1 expression in the hippocampus, suggesting that melatonin affected molecular oscillations in the hippocampus. Melatonin treatment also induced rapid remodeling of hippocampal neurons; melatonin increased apical dendritic length and dendritic complexity in the CA1 region and reduced the dendritic spine density in the dentate gyrus region. These data suggest that structural changes in hippocampal neurons are regulated by a circadian clock and that melatonin functions as a nighttime signal to coordinate the diurnal rhythm in neuronal remodeling. © 2014 Wiley Periodicals, Inc.

  4. Clock Genes Control Cortical Critical Period Timing

    OpenAIRE

    Kobayashi, Yohei; Ye, Zhanlei; Hensch, Takao K.

    2015-01-01

    Circadian rhythms control a variety of physiological processes, but whether they may also time brain development remains largely unknown. Here, we show that circadian clock genes control the onset of critical period plasticity in the neocortex. Within visual cortex of Clock-deficient mice, the emergence of circadian gene expression was dampened, and the maturation of inhibitory parvalbumin (PV)-cell networks slowed. Loss of visual acuity in response to brief monocular deprivation was concomit...

  5. Clock genes control cortical critical period timing.

    Science.gov (United States)

    Kobayashi, Yohei; Ye, Zhanlei; Hensch, Takao K

    2015-04-08

    Circadian rhythms control a variety of physiological processes, but whether they may also time brain development remains largely unknown. Here, we show that circadian clock genes control the onset of critical period plasticity in the neocortex. Within visual cortex of Clock-deficient mice, the emergence of circadian gene expression was dampened, and the maturation of inhibitory parvalbumin (PV) cell networks slowed. Loss of visual acuity in response to brief monocular deprivation was concomitantly delayed and rescued by direct enhancement of GABAergic transmission. Conditional deletion of Clock or Bmal1 only within PV cells recapitulated the results of total Clock-deficient mice. Unique downstream gene sets controlling synaptic events and cellular homeostasis for proper maturation and maintenance were found to be mis-regulated by Clock deletion specifically within PV cells. These data demonstrate a developmental role for circadian clock genes outside the suprachiasmatic nucleus, which may contribute mis-timed brain plasticity in associated mental disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Circadian clock genes in Drosophila: recent developments.

    Science.gov (United States)

    Subramanian, P; Balamurugan, E; Suthakar, G

    2003-08-01

    Circadian rhythms provide a temporal framework to living organisms and are established in a majority of eukaryotes and in a few prokaryotes. The molecular mechanisms of circadian clock is constantly being investigated in Drosophila melanogaster. The core of the clock mechanism was described by a transcription-translation feedback loop model involving period (per), timeless (tim), dclock and cycle genes. However, recent research has identified multiple feedback loops controlling rhythm generation and expression. Novel mutations of timeless throw more light on the functions of per and tim products. Analysis of pdf neuropeptide gene (expressed in circadian pacemaker cells in Drosophila), indicate that PDF acts as the principal circadian transmitter and is involved in output pathways. The product of cryptochrome is known to function as a circadian photoreceptor as well as component of the circadian clock. This review focuses on the recent progress in the field of molecular rhythm research in the fruit fly. The gene(s) and the gene product(s) that are involved in the transmission of environmental information to the clock, as well as the timing signals from the clock outward to cellular functions are remain to be determined.

  7. Breast cancer risk, nightwork, and circadian clock gene polymorphisms

    National Research Council Canada - National Science Library

    Truong, Thérèse; Liquet, Benoît; Menegaux, Florence; Plancoulaine, Sabine; Laurent-Puig, Pierre; Mulot, Claire; Cordina-Duverger, Emilie; Sanchez, Marie; Arveux, Patrick; Kerbrat, Pierre; Richardson, Sylvia; Guénel, Pascal

    2014-01-01

    ...) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs...

  8. Novel candidate genes associated with hippocampal oscillations.

    NARCIS (Netherlands)

    Jansen, R.; Timmerman, J.; Loos, M.; Spijker, S.; van Ooyen, A.; Brussaard, A.B.; Mansvelder, H.D.; Smit, A.B.; de Gunst, M.; Linkenkaer-Hansen, K.

    2011-01-01

    The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD

  9. Circadian expression of clock genes and clock-controlled genes in the rat retina

    NARCIS (Netherlands)

    Kamphuis, Willem; Cailotto, Cathy; Dijk, Frederike; Bergen, Arthur; Buijs, Ruud M.

    2005-01-01

    The circadian expression patterns of genes encoding for proteins that make up the core of the circadian clock were measured in rat retina using real-time quantitative PCR (qPCR). Transcript levels of several genes previously used for normalization of qPCR assays were determined and the effect of

  10. Clock Genes: Critical Modulators of Breast Cancer Risk

    National Research Council Canada - National Science Library

    Kennaway, David J; Butler, Lisa M; Tilley, Wayne D

    2005-01-01

    .... Circadian rhythms are regulated by a panel of specific transcription factors, called clock genes, and our current understanding of endogenous cellular rhythmicity is that both positive and negative...

  11. Clock genes show circadian rhythms in salivary glands.

    Science.gov (United States)

    Zheng, L; Seon, Y J; McHugh, J; Papagerakis, S; Papagerakis, P

    2012-08-01

    Circadian rhythms are endogenous self-sustained oscillations with 24-hour periods that regulate diverse physiological and metabolic processes through complex gene regulation by "clock" transcription factors. The oral cavity is bathed by saliva, and its amount and content are modified within regular daily intervals. The clock mechanisms that control salivary production remain unclear. Our objective was to evaluate the expression and periodicity of clock genes in salivary glands. Real-time quantitative RT-PCR, in situ hybridization, and immunohistochemistry were performed to show circadian mRNA and protein expression and localization of key clock genes (Bmal1, Clock, Per1, and Per2), ion and aqua channel genes (Ae2a, Car2, and Aqp5), and salivary gland markers. Clock gene mRNAs and clock proteins were found differentially expressed in the serous acini and duct cells of all major salivary glands. The expression levels of clock genes and Aqp5 showed regular oscillatory patterns under both light/dark and complete-dark conditions. Bmla1 overexpression resulted in increased Aqp5 expression levels. Analysis of our data suggests that salivary glands have a peripheral clock mechanism that functions both in normal light/dark conditions and in the absence of light. This finding may increase our understanding of the control mechanisms of salivary content and flow.

  12. Diurnal oscillations of soybean circadian clock and drought responsive genes.

    Directory of Open Access Journals (Sweden)

    Juliana Marcolino-Gomes

    Full Text Available Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis-elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i drought stress affects gene expression of circadian clock components and (ii several stress responsive genes display diurnal oscillation in soybeans.

  13. Clock genes of Mammalian cells: practical implications in tissue culture.

    Science.gov (United States)

    Kaeffer, Bertrand; Pardini, Lissia

    2005-01-01

    The clock genes family is expressed by all the somatic cells driving central and peripheral circadian rhythms through transcription/translation feedback loops. The circadian clock provides a local time for a cell and a way to integrate the normal environmental changes to smoothly adapt the cellular machinery to new conditions. The central circadian rhythm is retained in primary cultures by neurons of the suprachiasmatic nuclei. The peripheral circadian rhythms of the other somatic cells are progressively dampened down up to loss unless neuronal signals of the central clock are provided for re-entrainment. Under typical culture conditions (obscurity, 37 +/- 1 degrees C, 5-7% CO(2)), freshly explanted peripheral cells harbor chaotic expression of clock genes for 12-14 h and loose, coordinated oscillating patterns of clock components. Cells of normal or cancerous phenotypes established in culture harbor low levels of clock genes idling up to the re-occurrence of new synchronizer signals. Synchronizers are physicochemical cues (like thermic oscillations, short-term exposure to high concentrations of serum or single medium exchange) able to re-induce molecular oscillations of clock genes. The environmental synchronizers are integrated by response elements located in the promoter region of period genes that drive the central oscillator complex (CLOCK:BMAL1 and NPAS2:BMAL1 heterodimers). Only a few cell lines from different species and lineages have been tested for the existence or the functioning of a circadian clockwork. The best characterized cell lines are the immortalized SCN2.2 neurons of rat suprachiasmatic nuclei for the central clock and the Rat-1 fibroblasts or the NIH/3T3 cells for peripheral clocks. Isolation methods of fragile cell phenotypes may benefit from research on the biological clocks to design improved tissue culture media and new bioassays to diagnose pernicious consequences for health of circadian rhythm alterations.

  14. Transcriptional oscillation of canonical clock genes in mouse peripheral tissues

    Directory of Open Access Journals (Sweden)

    Nakahata Yasukazu

    2004-10-01

    Full Text Available Abstract Background The circadian rhythm of about 24 hours is a fundamental physiological function observed in almost all organisms from prokaryotes to humans. Identification of clock genes has allowed us to study the molecular bases for circadian behaviors and temporal physiological processes such as hormonal secretion, and has prompted the idea that molecular clocks reside not only in a central pacemaker, the suprachiasmatic nuclei (SCN of hypothalamus in mammals, but also in peripheral tissues, even in immortalized cells. Furthermore, previous molecular dissection revealed that the mechanism of circadian oscillation at a molecular level is based on transcriptional regulation of clock and clock-controlled genes. Results We systematically analyzed the mRNA expression of clock and clock-controlled genes in mouse peripheral tissues. Eight genes (mBmal1, mNpas2, mRev-erbα, mDbp, mRev-erbβ, mPer3, mPer1 and mPer2; given in the temporal order of the rhythm peak showed robust circadian expressions of mRNAs in all tissues except testis, suggesting that these genes are core molecules of the molecular biological clock. The bioinformatics analysis revealed that these genes have one or a combination of 3 transcriptional elements (RORE, DBPE, and E-box, which are conserved among human, mouse, and rat genome sequences, and indicated that these 3 elements may be responsible for the biological timing of expression of canonical clock genes. Conclusions The observation of oscillatory profiles of canonical clock genes is not only useful for physiological and pathological examination of the circadian clock in various organs but also important for systematic understanding of transcriptional regulation on a genome-wide basis. Our finding of the oscillatory expression of canonical clock genes with a temporal order provides us an interesting hypothesis, that cyclic timing of all clock and clock-controlled genes may be dependent on several transcriptional elements

  15. Clock gene variation in Tachycineta swallows

    Science.gov (United States)

    Dor, Roi; Cooper, Caren B; Lovette, Irby J; Massoni, Viviana; Bulit, Flor; Liljesthrom, Marcela; Winkler, David W

    2012-01-01

    Many animals use photoperiod cues to synchronize reproduction with environmental conditions and thereby improve their reproductive success. The circadian clock, which creates endogenous behavioral and physiological rhythms typically entrained to photoperiod, is well characterized at the molecular level. Recent work provided evidence for an association between Clock poly-Q length polymorphism and latitude and, within a population, an association with the date of laying and the length of the incubation period. Despite relatively high overall breeding synchrony, the timing of clutch initiation has a large impact on the fitness of swallows in the genus Tachycineta. We compared length polymorphism in the Clock poly-Q region among five populations from five different Tachycineta species that breed across a hemisphere-wide latitudinal gradient (Fig. 1). Clock poly-Q variation was not associated with latitude; however, there was an association between Clock poly-Q allele diversity and the degree of clutch size decline within breeding seasons. We did not find evidence for an association between Clock poly-Q variation and date of clutch initiation in for any of the five Tachycineta species, nor did we found a relationship between incubation duration and Clock genotype. Thus, there is no general association between latitude, breeding phenology, and Clock polymorphism in this clade of closely related birds. Figure 1 Photos of Tachycineta swallows that were used in this study: A) T. bicolor from Ithaca, New York, B) T. leucorrhoa from Chascomús, Argentina, C) T. albilinea from Hill Bank, Belize, D) T. meyeni from Puerto Varas, Chile, and E) T. thalassina from Mono Lake, California, Photographers: B: Valentina Ferretti; A, C-E: David Winkler. PMID:22408729

  16. Circadian clock genes as modulators of sensitivity to genotoxic stress.

    Science.gov (United States)

    Antoch, Marina P; Kondratov, Roman V; Takahashi, Joseph S

    2005-07-01

    A broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex. Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with

  17. Deregulated expression of the clock genes in gliomas.

    Science.gov (United States)

    Chen, Z; Liu, P; Li, C; Luo, Y; Chen, I; Liang, W; Chen, X; Feng, Y; Xia, H; Wang, F

    2013-02-01

    Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored. Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of the most important clock genes, clock, in 67 gliomas.Our results revealed that asynchronized expression of the clock gene was found in cancerous tissues in comparison with paired non-cancerous tissues. The expression levels of clock mRNA in grade III or IV glioma was significantly different from the surrounding non-tumor tissues (P  0.05). The intensity of immunoactivity for Clock in highgrade gliomas was significantly higher than that of low-grade gliomas (r = -0.403, P 5 0.012 ,  0.05). The expression of PCNA (Proliferating Cell Nuclear Antigen) protein in highgrade gliomas was significantly higher than that of low-grade gliomas (P control of normal circadian rhythm, thus benefiting the survival of glioma cells and promoting carcinogenesis.

  18. Breast cancer risk, nightwork, and circadian clock gene polymorphisms.

    Science.gov (United States)

    Truong, Thérèse; Liquet, Benoît; Menegaux, Florence; Plancoulaine, Sabine; Laurent-Puig, Pierre; Mulot, Claire; Cordina-Duverger, Emilie; Sanchez, Marie; Arveux, Patrick; Kerbrat, Pierre; Richardson, Sylvia; Guénel, Pascal

    2014-08-01

    Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case-control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs in RORA (rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 in CLOCK, and with CLOCK, RORA, and NPAS2 in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (P=0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction between PER1 and nightwork in breast cancer in the whole sample (P=0.024), although the effect was not statistically significant after correcting for multiple testing (P=0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk. © 2014 Society for Endocrinology.

  19. Conservation of Arabidopsis thaliana circadian clock genes in Chrysanthemum lavandulifolium.

    Science.gov (United States)

    Fu, Jianxin; Yang, Liwen; Dai, Silan

    2014-07-01

    In Arabidopsis, circadian clock genes play important roles in photoperiod pathway by regulating the daytime expression of CONSTANS (CO), but related reports for chrysanthemum are notably limited. In this study, we isolated eleven circadian clock genes, which lie in the three interconnected negative and positive feedback loops in a wild diploid chrysanthemum, Chrysanthemum lavandulifolium. With the exception of ClELF3, ClPRR1 and ClPRR73, most of the circadian clock genes are expressed more highly in leaves than in other tested tissues. The diurnal rhythms of these circadian clock genes are similar to those of their homologs in Arabidopsis. ClELF3 and ClZTL are constitutively expressed at all time points in both assessed photoperiods. The expression succession from morning to night of the PSEUDO RESPONSE REGULATOR (PRR) gene family occurs in the order ClPRR73/ClPRR37, ClPRR5, and then ClPRR1. ClLHY is expressed during the dawn period, and ClGIs is expressed during the dusk period. The peak expression levels of ClFKF1 and ClGIs are synchronous in the inductive photoperiod. However, in the non-inductive night break (NB) condition or non-24 h photoperiod, the peak expression level of ClFKF1 is significantly changed, indicating that ClFKF1 itself or the synchronous expression of ClFKF1 and ClGIs might be essential to initiate the flowering of C. lavandulifolium. This study provides the first extensive evaluation of circadian clock genes, and it presents a useful foundation for dissecting the functions of circadian clock genes in C. lavandulifolium. Copyright © 2014. Published by Elsevier Masson SAS.

  20. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    Directory of Open Access Journals (Sweden)

    Astha Malik

    Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte

  1. Clock gene expression in the murine gastrointestinal tract: endogenous rhythmicity and effects of a feeding regimen.

    Science.gov (United States)

    Hoogerwerf, Willemijntje A; Hellmich, Helen L; Cornélissen, Germaine; Halberg, Franz; Shahinian, Vahakn B; Bostwick, Jonathon; Savidge, Tor C; Cassone, Vincent M

    2007-10-01

    Based on observations that the gastrointestinal tract is subject to various 24-hour rhythmic processes, it is conceivable that some of these rhythms are under circadian clock gene control. We hypothesized that clock genes are present in the gastrointestinal tract and that they are part of a functional molecular clock that coordinates rhythmic physiologic functions. The effects of timed feeding and vagotomy on temporal clock gene expression (clock, bmal1, per1-3, cry1-2) in the gastrointestinal tract and suprachiasmatic nucleus (bmal, per2) of C57BL/6J mice were examined using real-time polymerase chain reaction and Western blotting (BMAL, PER2). Colonic clock gene localization was examined using immunohistochemistry (BMAL, PER1-2). Clock immunoreactivity was observed in the myenteric plexus and epithelial crypt cells. Clock genes were expressed rhythmically throughout the gastrointestinal tract. Timed feeding shifted clock gene expression at the RNA and protein level but did not shift clock gene expression in the central clock. Vagotomy did not alter gastric clock gene expression compared with sham-treated controls. The murine gastrointestinal tract contains functional clock genes, which are molecular core components of the circadian clock. Daytime feeding in nocturnal rodents is a strong synchronizer of gastrointestinal clock genes. This synchronization occurs independently of the central clock. Gastric clock gene expression is not mediated through the vagal nerve. The presence of clock genes in the myenteric plexus and epithelial cells suggests a role for clock genes in circadian coordination of gastrointestinal functions such as motility, cell proliferation, and migration.

  2. Deregulated expression of circadian clock genes in gastric cancer.

    Science.gov (United States)

    Hu, Ming-Luen; Yeh, Kun-Tu; Lin, Pai-Mei; Hsu, Cheng-Ming; Hsiao, Hui-Hua; Liu, Yi-Chang; Lin, Hugo You-Hsien; Lin, Sheng-Fung; Yang, Ming-Yu

    2014-04-06

    Gastric cancer (GC), an aggressive malignant tumor of the alimentary tract, is a leading cause of cancer-related death. Circadian rhythm exhibits a 24-hour variation in physiological processes and behavior, such as hormone levels, metabolism, gene expression, sleep and wakefulness, and appetite. Disruption of circadian rhythm has been associated with various cancers, including chronic myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However, the expression of circadian clock genes in GC remains unexplored. In this study, the expression profiles of eight circadian clock genes (PER1, PER2, PER3, CRY1, CRY2, CKIϵ, CLOCK, and BMAL1) of cancerous and noncancerous tissues from 29 GC patients were investigated using real-time quantitative reverse-transcriptase polymerase chain reaction and validated through immunohistochemical analysis. We found that PER2 was significantly up-regulated in cancer tissues (p clock genes exist in GC and circadian rhythm disturbance may be associated with the development of GC.

  3. Phenotypic effects of genetic variability in human clock genes on ...

    Indian Academy of Sciences (India)

    Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep ...

  4. Altered expression pattern of clock genes in a rat model of depression

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Bouzinova, Elena; Fahrenkrug, Jan

    2016-01-01

    of clock gene expression in depressive patients many studies have reported single-nucleotide polymorphisms in clock genes in these patients. METHODS: In the present study we investigated whether a depression-like state in rats associates with alternations of the diurnal expression of clock genes......: The present results suggest that altered expression of investigated clock genes are likely to associate with the induction of a depression-like state in the CMS model...

  5. Genetic polymorphism at the CLOCK gene locus and major depression.

    Science.gov (United States)

    Desan, P H; Oren, D A; Malison, R; Price, L H; Rosenbaum, J; Smoller, J; Charney, D S; Gelernter, J

    2000-06-12

    Genetic analysis in both mouse and Drosophila has indicated that the product of the CLOCK gene is an essential component of a circadian rhythm timing system. A single nucleotide polymorphism (SNP), T3111C, in the 3' flanking region of the human CLOCK gene has been identified. Homozygotes or heterozygotes for the 3111C allele have been reported to have higher mean scores on a measure of evening preference for activity (vs. morning preference) than subjects homozygous for the 3111T allele. Since major depression is hypothesized to be closely linked to circadian rhythms, we explored whether this polymorphism might be related to susceptibility to major depression. We also ascertained allele frequency in an African-American control population, to begin to evaluate population variation at this locus. CLOCK T3111C allele frequencies were determined in 280 European American (EA) subjects, 143 with a history of major depression and 137 screened controls, and in 58 African American (AA) screened control subjects, using a polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. There was no significant difference between EA depressed and control subjects in allele frequency. There was a significant difference in allele frequency between EA and AA subjects, demonstrating a potential for population stratification. In none of these groups were significant deviations from Hardy-Weinberg equilibrium found. The present data do not support an association between CLOCK gene alleles at the T3111C locus and major depression.

  6. Oscillation of Clock and Clock Controlled Genes Induced by Serum Shock in Human Breast Epithelial and Breast Cancer Cells: Regulation by Melatonin

    Science.gov (United States)

    Xiang, S.; Mao, L.; Duplessis, T.; Yuan, L.; Dauchy, R.; Dauchy, E.; Blask, D.E.; Frasch, T.; Hill, S.M.

    2012-01-01

    This study investigates differences in expression of clock and clock-controlled genes (CCGs) between human breast epithelial and breast cancer cells and breast tumor xenografts in circadian intact rats and examines if the pineal hormone melatonin influences clock gene and CCG expression. Oscillation of clock gene expression was not observed under standard growth conditions in vitro, however, serum shock (50% horse serum for 2 h) induced oscillation of clock gene and CCG expression in MCF-10A cells, which was repressed or disrupted in MCF-7 cells. Melatonin administration following serum shock differentially suppressed or induced clock gene (Bmal1 and Per2) and CCG expression in MCF10A and MCF-7 cells. These studies demonstrate the lack of rhythmic expression of clock genes and CCGs of cells in vitro and that transplantation of breast cancer cells as xenografts into circadian competent hosts re-establishes a circadian rhythm in the peripheral clock genes of tumor cells. PMID:23012497

  7. Circadian intraocular pressure rhythm is generated by clock genes.

    Science.gov (United States)

    Maeda, Ari; Tsujiya, Sosuke; Higashide, Tomomi; Toida, Kazunori; Todo, Takeshi; Ueyama, Tomoko; Okamura, Hitoshi; Sugiyama, Kazuhisa

    2006-09-01

    The present study in a mouse model was undertaken to reveal the role of the circadian clock genes Cry1 and Cry2 in generation of 24-hour intraocular pressure (IOP) rhythm. IOP was measured at eight time points daily (circadian time [CT] 0, 3, 6, 9, 12, 15, 18, and 21 hours), using a microneedle method in four groups of C57BL/6J mice (groups 1 and 3, wild-type; groups 2 and 4, Cry-deficient [Cry1-/-Cry2-/-]). During the IOP measurements, mice in groups 1 and 2 were maintained in a 12-hour light-dark cycle (LD), whereas mice in groups 3 and 4 were kept in a constant darkness (DD) that started 24 to 48 hours before the measurements. Circadian IOP variations in each group were evaluated by one-way analysis of variance (ANOVA) and Scheffé tests. In wild-type mice living in LD conditions, pressures measured in the light phase were significantly lower than those in the dark phase. This daily rhythm was maintained under DD conditions with low pressure in the subjective day and high pressure in the subjective night. In contrast, Cry-deficient mice did not show significant circadian changes in IOP, regardless of environmental light conditions. These findings demonstrate that clock oscillatory mechanisms requiring the activity of core clock genes are essential for the generation of a circadian rhythm of intraocular pressure.

  8. Regulation of clock-controlled genes in mammals.

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    Full Text Available The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs.Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCKratioBMAL1, DBP, HLF, E4BP4, CREB, RORalpha and the recently described regulators HSF1, STAT3, SP1 and HNF-4alpha. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1 and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1 are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including

  9. Regulation of Clock-Controlled Genes in Mammals

    Science.gov (United States)

    Kielbasa, Szymon M.; Heine, Markus; Dame, Christof; Kramer, Achim; Herzel, Hanspeter

    2009-01-01

    The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs) suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs. Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCK∶BMAL1, DBP, HLF, E4BP4, CREB, RORα and the recently described regulators HSF1, STAT3, SP1 and HNF-4α. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1) and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1) are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo) gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine

  10. Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes.

    Science.gov (United States)

    Yu, Elizabeth A; Weaver, David R

    2011-05-01

    The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer.

  11. Localized gene transfer into organotypic hippocampal slice cultures and acute hippocampal slices

    DEFF Research Database (Denmark)

    Casaccia-Bonnefil, P; Benedikz, Eirikur; Shen, H

    1993-01-01

    that directs expression of E. coli beta-galactosidase (beta-gal), were microapplied into stratum pyramidale or stratum granulosum of slice cultures. Twenty-four hours later, a cluster of transduced cells expressing beta-gal was observed at the microapplication site. Gene transfer by microapplication was both...... effective and rapid. The titer of the HSVlac stocks was determined on NIH3T3 cells. Eighty-three percent of the beta-gal forming units successfully transduced beta-gal after microapplication to slice cultures. beta-Gal expression was detected as rapidly as 4 h after transduction into cultures of fibroblasts...... or hippocampal slices. The rapid expression of beta-gal by HSVlac allowed efficient transduction of acute hippocampal slices. Many genes have been transduced and expressed using HSV vectors; therefore, this microapplication method can be applied to many neurobiological questions....

  12. A role for clock genes in sleep homeostasis.

    Science.gov (United States)

    Franken, Paul

    2013-10-01

    The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Interactions of polymorphisms in different clock genes associated with circadian phenotypes in humans

    Directory of Open Access Journals (Sweden)

    Mario Pedrazzoli

    2010-01-01

    Full Text Available Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1 in people with extreme diurnal preferences (morning or evening. We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.

  14. Circadian expression of clock- and tumor suppressor genes in human oral mucosa.

    Science.gov (United States)

    Zieker, Derek; Jenne, Isabel; Koenigsrainer, Ingmar; Zdichavsky, Marty; Nieselt, Kay; Buck, Katharina; Zieker, Judith; Beckert, Stefan; Glatzle, Joerg; Spanagel, Rainer; Koenigsrainer, Alfred; Northoff, Hinnak; Loeffler, Markus

    2010-01-01

    Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. Imbalance of these rhythms has been associated with cancerogenesis in humans. To further elucidate the role circadian clocks have in cellular growth control, tumor suppression and cancer treatment, it is revealing to know how clock genes and clock-controlled genes are regulated in healthy humans. Therefore comparative microarray analyses were conducted investigating the relative mRNA expression of clock genes throughout a 24-hour period in cell samples obtained from oral mucosa of eight healthy diurnally active male study participants. Differentially expressed selected genes of interest were additionally evaluated using qRT-PCR. Microarray analysis revealed 33 significant differentially regulated clock genes and clock- controlled genes, throughout a one day period (6.00h, 12.00h, 18.00h, 24.00h). Hereof were 16 clock genes and 17 clock- controlled genes including tumor suppressor- and oncogenes. qRT-PCR of selected genes of interest, such as hPER2, hCRY1, hBMAL1, hCCRN4L and hSMAD5 revealed significant circadian regulations. Our study revealed a proper circadian regulation profile of several clock- and tumor suppressor genes at defined points in time in the participants studied. These findings could provide important information regarding genes displaying the same expression profile in the gastrointestinal tract amounting to a physiological expression profile of healthy humans. In the future asynchronous regulations of those genes might be an additional assistant method to detect derivations distinguishing normal from malignant tissue or assessing risk factors for cancer. Copyright 2010 S. Karger AG, Basel.

  15. Clock gene expression in different synovial cells of patients with rheumatoid arthritis and osteoarthritis

    NARCIS (Netherlands)

    Becker, Tatjana; Tohidast-Akrad, Makiyeh; Humpeler, Susanne; Gerlag, Danielle M.; Kiener, Hans-Peter; Zenz, Peter; Steiner, Günter; Ekmekcioglu, Cem

    2014-01-01

    Patients with rheumatoid arthritis (RA) show modulated circadian rhythms of inflammatory cytokines and cortisol, which may be associated with a modified expression of clock genes. The expression of major clock genes was previously studied in synovial tissues and fibroblasts of patients with RA and

  16. Daily rhythmicity of clock gene transcripts in atlantic cod fast skeletal muscle.

    Science.gov (United States)

    Lazado, Carlo C; Kumaratunga, Hiruni P S; Nagasawa, Kazue; Babiak, Igor; Giannetto, Alessia; Fernandes, Jorge M O

    2014-01-01

    The classical notion of a centralized clock that governs circadian rhythmicity has been challenged with the discovery of peripheral oscillators that enable organisms to cope with daily changes in their environment. The present study aimed to identify the molecular clock components in Atlantic cod (Gadus morhua) and to investigate their daily gene expression in fast skeletal muscle. Atlantic cod clock genes were closely related to their orthologs in teleosts and tetrapods. Synteny was conserved to varying degrees in the majority of the 18 clock genes examined. In particular, aryl hydrocarbon receptor nuclear translocator-like 2 (arntl2), RAR-related orphan receptor A (rora) and timeless (tim) displayed high degrees of conservation. Expression profiling during the early ontogenesis revealed that some transcripts were maternally transferred, namely arntl2, cryptochrome 1b and 2 (cry1b and cry2), and period 2a and 2b (per2a and per2b). Most clock genes were ubiquitously expressed in various tissues, suggesting the possible existence of multiple peripheral clock systems in Atlantic cod. In particular, they were all detected in fast skeletal muscle, with the exception of neuronal PAS (Per-Arnt-Single-minded) domain-containing protein (npas1) and rora. Rhythmicity analysis revealed 8 clock genes with daily rhythmic expression, namely arntl2, circadian locomotor output cycles kaput (clock), npas2, cry2, cry3 per2a, nuclear receptor subfamily 1, group D, member 1 (nr1d1), and nr1d2a. Transcript levels of the myogenic genes myogenic factor 5 (myf5) and muscleblind-like 1 (mbnl1) strongly correlated with clock gene expression. This is the first study to unravel the molecular components of peripheral clocks in Atlantic cod. Taken together, our data suggest that the putative clock system in fast skeletal muscle of Atlantic cod has regulatory implications on muscle physiology, particularly in the expression of genes related to myogenesis.

  17. Daily rhythmicity of clock gene transcripts in atlantic cod fast skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Carlo C Lazado

    Full Text Available The classical notion of a centralized clock that governs circadian rhythmicity has been challenged with the discovery of peripheral oscillators that enable organisms to cope with daily changes in their environment. The present study aimed to identify the molecular clock components in Atlantic cod (Gadus morhua and to investigate their daily gene expression in fast skeletal muscle. Atlantic cod clock genes were closely related to their orthologs in teleosts and tetrapods. Synteny was conserved to varying degrees in the majority of the 18 clock genes examined. In particular, aryl hydrocarbon receptor nuclear translocator-like 2 (arntl2, RAR-related orphan receptor A (rora and timeless (tim displayed high degrees of conservation. Expression profiling during the early ontogenesis revealed that some transcripts were maternally transferred, namely arntl2, cryptochrome 1b and 2 (cry1b and cry2, and period 2a and 2b (per2a and per2b. Most clock genes were ubiquitously expressed in various tissues, suggesting the possible existence of multiple peripheral clock systems in Atlantic cod. In particular, they were all detected in fast skeletal muscle, with the exception of neuronal PAS (Per-Arnt-Single-minded domain-containing protein (npas1 and rora. Rhythmicity analysis revealed 8 clock genes with daily rhythmic expression, namely arntl2, circadian locomotor output cycles kaput (clock, npas2, cry2, cry3 per2a, nuclear receptor subfamily 1, group D, member 1 (nr1d1, and nr1d2a. Transcript levels of the myogenic genes myogenic factor 5 (myf5 and muscleblind-like 1 (mbnl1 strongly correlated with clock gene expression. This is the first study to unravel the molecular components of peripheral clocks in Atlantic cod. Taken together, our data suggest that the putative clock system in fast skeletal muscle of Atlantic cod has regulatory implications on muscle physiology, particularly in the expression of genes related to myogenesis.

  18. Expression of core clock genes in colorectal tumour cells compared with normal mucosa

    DEFF Research Database (Denmark)

    Fonnes, S; Donatsky, A M; Gögenur, I

    2015-01-01

    AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its...... expression of colorectal cancer cells compared with healthy mucosa cells from specimens analysed by real-time or quantitative real-time polymer chain reaction. The expression of the core clock genes Period, Cryptochrome, Bmal1 and Clock in colorectal tumours were compared with healthy mucosa and correlated...... with clinicopathological features and survival. RESULTS: Seventy-four articles were identified and 11 studies were included. Overall, gene expression of Period was significantly decreased in colorectal cancer cells compared with healthy mucosa cells. This tendency was also seen in the gene expression of Clock. Other core...

  19. Circadian clock genes and risk of fatal prostate cancer.

    Science.gov (United States)

    Markt, Sarah C; Valdimarsdottir, Unnur A; Shui, Irene M; Sigurdardottir, Lara G; Rider, Jennifer R; Tamimi, Rulla M; Batista, Julie L; Haneuse, Sebastien; Flynn-Evans, Erin; Lockley, Steven W; Czeisler, Charles A; Stampfer, Meir J; Launer, Lenore; Harris, Tamara; Smith, Albert Vernon; Gudnason, Vilmundur; Lindstrom, Sara; Kraft, Peter; Mucci, Lorelei A

    2015-01-01

    Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels. We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes. None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels. We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.

  20. The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

    Energy Technology Data Exchange (ETDEWEB)

    Bluhm, A.P.C.; Obeid, N.N.; Castrucci, A.M.L.; Visconti, M.A. [Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-05-25

    Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression.

  1. Deleting the Arntl clock gene in the granular layer of the mouse cerebellum

    DEFF Research Database (Denmark)

    Bering, Tenna; Carstensen, Mikkel Bloss; Rath, Martin Fredensborg

    2017-01-01

    The suprachiasmatic nucleus houses the central circadian clock and is characterized by the timely regulated expression of clock genes. However, neurons of the cerebellar cortex also contain a circadian oscillator with circadian expression of clock genes being controlled by the suprachiasmatic...... is involved in circadian physiology and food anticipation, we therefore by use of Cre-LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located...... nucleus. It has been suggested that the cerebellar circadian oscillator is involved in food anticipation, but direct molecular evidence of the role of the circadian oscillator of the cerebellar cortex is currently unavailable. To investigate the hypothesis that the circadian oscillator of the cerebellum...

  2. Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms.

    Science.gov (United States)

    Bunney, Blynn G; Bunney, William E

    2013-06-15

    A significant subset of both major depressive disorder and bipolar disorder patients rapidly (within 24 hours) and robustly improves with the chronotherapeutic intervention of sleep deprivation therapy (SDT). Major mood disorder patients are reported to have abnormal circadian rhythms including temperature, hormonal secretion, mood, and particularly sleep. These rhythms are modulated by the clock gene machinery and its products. It is hypothesized that SDT resets abnormal clock gene machinery, that relapse of depressive symptoms during recovery night sleep reactivates abnormal clock gene machinery, and that supplemental chronotherapies and medications can block relapse and help stabilize circadian-related improvement. The central circadian clock genes, BMAL1/CLOCK (NPAS2), bind to Enhancer Boxes to initiate the transcription of circadian genes, including the period genes (per1, per2, per3). It is suggested that a defect in BMAL1/CLOCK (NPAS2) or in the Enhancer Box binding contributes to altered circadian function associated, in part, with the period genes. The fact that chronotherapies, including SDT and sleep phase advance, are dramatically effective suggests that altered clock gene machinery may represent a core pathophysiological defect in a subset of mood disorder patients. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  3. Gene-environment effects on hippocampal neurodevelopment

    DEFF Research Database (Denmark)

    Rosenthal, Eva Helga

    Mental disorders like schizophrenia and autism put a heavy load on today’s societies, creating a steady call for revealing underlying disease mechanisms and the development of effective treatments. The etiology of major psychiatric illnesses is complex involving gene by environment susceptibility...... factors. Hence, a deeper understanding is needed of how cortical neurodevelopmental deficiencies can arise from such gene-environment interactions. The convergence of genetic and environmental risk factors is a recent field of research. It is now clear that disease, infection and stress factors may...

  4. A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.

    Directory of Open Access Journals (Sweden)

    Michael J McCarthy

    Full Text Available Circadian rhythm abnormalities in bipolar disorder (BD have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS. At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity. Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

  5. Molecular clocks and evolutionary relationships: possible distortions due to horizontal gene flow.

    Science.gov (United States)

    Syvanen, M

    1987-01-01

    This paper discusses recent evidence suggesting that genetic information from one species occasionally transfers to another remotely related species. Besides addressing the issue of whether or not the molecular data are consistent with a wide-spread influence of horizontal gene transfer, the paper shows that horizontal gene flow would not necessarily preclude a linear molecular clock or change the rate of molecular evolution (assuming the neutral allele theory). A pervasive influence of horizontal gene transfer is more than just consistent with the data of molecular evolution, it also provides a unique explanation for a number of possibly conflicting phylogenies and contradictory clocks. This phenomenon might explain why some protein clocks are linear while the superoxide dismutase clock is not, how the molecular data on the phylogeny of apes and Australian song birds are not necessarily in conflict with those based on morphology, and, finally, why the mycoplasmas have an accelerated molecular clock.

  6. A Survey of Genomic Studies Supports Association of Circadian Clock Genes with Bipolar Disorder Spectrum Illnesses and Lithium Response

    Science.gov (United States)

    McCarthy, Michael J.; Nievergelt, Caroline M.; Kelsoe, John R.; Welsh, David K.

    2012-01-01

    Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian “clock genes” associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential “core” clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies. PMID:22384149

  7. IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function.

    Science.gov (United States)

    Pardo, Joaquín; Abba, Martin C; Lacunza, Ezequiel; Ogundele, Olalekan M; Paiva, Isabel; Morel, Gustavo R; Outeiro, Tiago F; Goya, Rodolfo G

    2017-06-22

    In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28 months old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo adenovector-injected counterparts. From the differentially expressed genes, 81 were down and 138 upregulated. From those genes, a list of functionally relevant genes, concerning hippocampal IGF-I expression, synaptic plasticity as well as neuronal function was identified. Our results provide an initial glimpse at the molecular mechanisms underlying the neuroprotective actions of IGF-I in the aging brain. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Assignment of circadian function for the Neurospora clock gene frequency

    NARCIS (Netherlands)

    Merrow, Martha; Brunner, Michael; Roenneberg, Till

    1999-01-01

    Circadian clocks consist of three elements: entrainment pathways (inputs), the mechanism generating the rhythmicity (oscillator), and the output pathways that control the circadian rhythms. It is difficult to assign molecular clock components to any one of these elements. Experiments show that

  9. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells.

    Science.gov (United States)

    Arjona, Alvaro; Sarkar, Dipak K

    2005-06-15

    A growing body of knowledge is revealing the critical role of circadian physiology in the development of specific pathological entities such as cancer. NK cell function participates in the immune response against infection and malignancy. We have reported previously the existence of a physiological circadian rhythm of NK cell cytolytic activity in rats, suggesting the existence of circadian mechanisms subjacent to NK cell function. At the cellular level, circadian rhythms are originated by the sustained transcriptional-translational oscillation of clock genes that form the cellular clock apparatus. Our aim in this study was to investigate the presence of molecular clock mechanisms in NK cells as well as the circadian expression of critical factors involved in NK cell function. For that purpose, we measured the circadian changes in the expression of clock genes (Per1, Per2, Bmal1, Clock), Dbp (a clock-controlled output gene), CREB (involved in clock signaling), cytolytic factors (granzyme B and perforin), and cytokines (IFN-gamma and TNF-alpha) in NK cells enriched from the rat spleen. The results obtained from this study demonstrate for the first time the existence of functional molecular clock mechanisms in NK cells. Moreover, the circadian expression of cytolytic factors and cytokines in NK cells reported in this study emphasizes the circadian nature of NK cell function.

  10. Estradiol differently affects melanin synthesis of malignant and normal melanocytes: a relationship with clock and clock-controlled genes.

    Science.gov (United States)

    Poletini, Maristela Oliveira; de Assis, Leonardo Vinicius Monteiro; Moraes, Maria Nathalia; Castrucci, Ana Maria de Lauro

    2016-10-01

    Melanin production within melanocytes is regulated, among others, by estradiol, whose effects on melanogenesis are still not completely elucidated. Here we show that although 10(-7) M 17β-estradiol (E2) increased tyrosinase mRNA levels in B16-F10 malignant melanocytes, there was a transient decrease and abolishment of the temporal variation of melanin content. Both parameters were much higher in the malignant than in normal Melan-a cells. Considering that silencing clock machinery in human melanocytes increases melanogenesis, we investigated clock gene expression in those cell lines. Except for Melan-a Bmal1 and B16-F10 Per2 expression of control cells, Per1, Per2, and Bmal1 expression increased independently of cell type or E2 treatment after 24 h. However, melanoma cells showed a marked increase in Per1 and Bma11 expression in response to E2 at the same time points, what may rule out E2 as a synchronizer agent since the expression of those genes were not in antiphase. Next, we investigated the expression of Xpa, a clock-controlled gene, which in Melan-a cells, peaked at 18 h, and E2 treatment shifted this peak to 24 h, whereas B16-F10 Xpa expression peaked at 24 h in both control and E2 group, and it was higher compared to Melan-a cells in both groups. Therefore, malignant and normal melanocytes display profound differences on core elements of the local clock, and how they respond to E2, what is most probably determinant of the differences seen on melanin synthesis and Tyrosinase and Xpa expression. Understanding these processes at the molecular level could bring new strategies to treat melanoma.

  11. Altered clock gene expression in obese visceral adipose tissue is associated with metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Clock gene expression was associated with different components of metabolic syndrome (MS in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21-25 kg/m2; n = 21 and morbidly obese women (BMI >40 kg/m2; n = 28. The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.

  12. The relevance of hippocampal subfield integrity and clock drawing test performance for the diagnosis of Alzheimer's disease and mild cognitive impairment.

    Science.gov (United States)

    Hirjak, Dusan; Sambataro, Fabio; Remmele, Barbara; Kubera, Katharina M; Schröder, Johannes; Seidl, Ulrich; Thomann, Anne K; Maier-Hein, Klaus H; Wolf, Robert C; Thomann, Philipp A

    2017-08-31

    The clock drawing test (CDT) is one of the worldwide most used screening tests for Alzheimer's disease (AD). MRI studies have identified temporo-parietal regions being involved in CDT impairment. However, the contributions of specific hippocampal subfields and adjacent extrahippocampal structures to CDT performance in AD and mild cognitive impairment (MCI) have not been investigated so far. It is unclear whether morphological alterations or CDT score, or a combination of both, are able to predict AD. 38 AD patients, 38 MCI individuals and 31 healthy controls underwent neuropsychological assessment and MRI at 3 Tesla. FreeSurfer 5.3 was used to perform hippocampal parcellation. We used a collection of statistical methods to better understand the relationship between CDT and hippocampal formation. We also tested the clinical feasibility of this relationship when predicting AD. Impaired CDT performance in AD was associated with widespread atrophy of the cornu ammonis, presubiculum, and subiculum, whereas MCI subjects showed CDT-related alterations of the CA4-dentate gyrus and subiculum. CDT correlates in AD and MCI showed regional and quantitative overlap. Importantly, CDT score was the best predictor of AD. Our findings lend support for an involvement of different hippocampal subfields in impaired CDT performance in AD and MCI. CDT seems to be more efficient than subfield imaging for predicting AD.

  13. Altered expression pattern of clock genes in a rat model of depression

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Bouzinova, Elena; Fahrenkrug, Jan

    2016-01-01

    BACKGROUND: Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation...... of clock gene expression in depressive patients many studies have reported single-nucleotide polymorphisms in clock genes in these patients. METHODS: In the present study we investigated whether a depression-like state in rats associates with alternations of the diurnal expression of clock genes....... The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes; Per1, Per2 and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at 4 h sampling interval within 24 h. We...

  14. Evolution of the CLOCK and BMAL1 genes in a subterranean rodent species (Lasiopodomys mandarinus).

    Science.gov (United States)

    Sun, Hong; Zhang, Yifeng; Shi, Yuhua; Li, Yangwei; Li, Wei; Wang, Zhenlong

    2017-11-12

    Lasiopodomys mandarinus, a subterranean rodent, spends its entire life underground. To test whether the CLOCK and BMAL1 genes of L. mandarinus have undergone adaptive evolution to underground darkness, we cloned and analyzed their complete cDNA sequences, using Lasiopodomys brandtii as a control. The phylogenetic trees of the CLOCK and BMAL1 genes were similar to the trees of the conserved Cyt b gene,further, L. mandarinus clustered with L. brandtii and Microtus ochrogaster in the phylogenetic tree. The Q-rich region of the CLOCK gene in L. mandarinus was different from that of other subterranean rodents. Using phylogenetic analysis maximum likelihood (PAML), the ω value (ωimportant functionality of the TAD, which is putatively of functional relevance to CLOCK protein activity. The present findings provide novel insights into adaptation to underground darkness, at the gene level, in subterranean rodents. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Interactions of polymorphisms in different clock genes associated with circadian phenotypes in humans

    National Research Council Canada - National Science Library

    Pedrazzoli, Mario; Secolin, Rodrigo; Esteves, Luiz Otávio Bastos; Pereira, Danyella Silva; Koike, Bruna Del Vechio; Louzada, Fernando Mazzili; Lopes-Cendes, Iscia; Tufik, Sergio

    2010-01-01

    Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes...

  16. Messenger RNA expression of chicken CLOCK gene in the response to Campylobacter jejuni inoculation.

    Science.gov (United States)

    Liu, Xiaoyi; Liu, Liying; Zhang, Maozhi; Yang, Ning; Qi, Yukai; Sun, Yu; Li, Xianyao

    2015-09-01

    Campylobacter jejuni (C. jejuni) is a leading cause of human bacterial gastroenteritis worldwide. Previous research has shown that circadian rhythm plays a critical role in host response to C. jejuni colonization. The CLOCK gene is one of the core genes regulating circadian rhythms and shows significant expression on 7 d post-C. jejuni inoculation. The objective of this study was to investigate temporal and spatial expression of chicken CLOCK gene post-C. jejuni inoculation. Cecal and splenic RNA were isolated from 2 distinct chicken breeds and used to compare the mRNA expression of CLOCK gene between inoculated and noninoculated chickens within each breed and between breeds within each of inoculated and noninoculated groups. Our results showed that the CLOCK gene was significantly down-regulated at 20 h postinoculation (hpi) in cecum and spleen in Jiningbairi chicken. CLOCK gene was significantly down-regulated at 4 and 16 hpi and up-regulated at 8 hpi in cecum and spleen in specific pathogen free white leghorn noninoculated chicken. The findings suggested that expression of CLOCK gene was significantly changed post C. jejuin inoculation. This change was affected by genetic background, tissue, and time points postinoculation. © 2015 Poultry Science Association Inc.

  17. Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells

    Energy Technology Data Exchange (ETDEWEB)

    Shimizu, Takashi, E-mail: shimizut@obihiro.ac.jp [Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Hirai, Yuko; Murayama, Chiaki; Miyamoto, Akio [Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Miyazaki, Hitoshi [Gene Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8572 (Japan); Miyazaki, Koyomi [Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) Central 6, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8566 (Japan)

    2011-08-19

    Highlights: {yields} Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression. {yields}Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom. {yields} Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. {yields}Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. {yields} The expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. -- Abstract: Circadian Clock genes are associated with the estrous cycle in female animals. Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression in follicle-stimulating hormone FSH-treated granulosa cells. Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom, whereas Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. Similarly, expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. Our data provide a new insight that Per2 and Clock have different action on ovarian granulosa cell functions.

  18. Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation

    OpenAIRE

    ALEXANDER, MELANNIE; Burch, James B.; Steck, Susan E.; Chen, Chin-Fu; Hurley, Thomas G.; Cavicchia, Philip; Ray, Meredith; Shivappa, Nitin; GUESS, JACLYN; Zhang, Hongmei; Youngstedt, Shawn D; Creek, Kim E.; Lloyd, Stephen; Yang, Xiaoming; H?bert, James R.

    2014-01-01

    Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the ?period? (PER) clock genes, which have t...

  19. Glucocorticoids affect 24 h clock genes expression in human adipose tissue explant cultures.

    Directory of Open Access Journals (Sweden)

    Purificación Gómez-Abellán

    Full Text Available to examine firstly whether CLOCK exhibits a circadian expression in human visceral (V and subcutaneous (S adipose tissue (AT in vitro as compared with BMAL1 and PER2, and secondly to investigate the possible effect of the glucocorticoid analogue dexamethasone (DEX on positive and negative clock genes expression.VAT and SAT biopsies were obtained from morbid obese women (body mass index ≥ 40 kg/m(2 (n = 6. In order to investigate rhythmic expression pattern of clock genes and the effect of DEX on CLOCK, PER2 and BMAL1 expression, control AT (without DEX and AT explants treated with DEX (2 hours were cultured during 24 h and gene expression was analyzed at the following times: 10:00 h, 14:00 h, 18:00 h, 22:00 h, 02:00 h and 06:00 h, using qRT-PCR.CLOCK, BMAL1 and PER2 expression exhibited circadian patterns in both VAT and SAT explants that were adjusted to a typical 24 h sinusoidal curve. PER2 expression (negative element was in antiphase with respect to CLOCK and in phase with BMAL1 expression (both positive elements in the SAT (situation not present in VAT. A marked effect of DEX exposure on both positive and negative clock genes expression patterns was observed. Indeed, DEX treatment modified the rhythmicity pattern towards altered patterns with a period lower than 24 hours in all genes and in both tissues.24 h patterns in CLOCK and BMAL1 (positive clock elements and PER2 (negative element mRNA levels were observed in human adipose explants. These patterns were altered by dexamethasone exposure.

  20. The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons

    Directory of Open Access Journals (Sweden)

    Jeff R. Jones

    2016-08-01

    Full Text Available The brain’s biological clock, the suprachiasmatic nucleus (SCN, exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping.

  1. The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons.

    Science.gov (United States)

    Jones, Jeff R; McMahon, Douglas G

    2016-01-01

    The brain's biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping.

  2. Trojan Horse Strategy for Non-invasive Interference of Clock Gene in the Oyster Crassostrea gigas.

    Science.gov (United States)

    Payton, Laura; Perrigault, Mickael; Bourdineaud, Jean-Paul; Marcel, Anjara; Massabuau, Jean-Charles; Tran, Damien

    2017-08-01

    RNA interference is a powerful method to inhibit specific gene expression. Recently, silencing target genes by feeding has been successfully carried out in nematodes, insects, and small aquatic organisms. A non-invasive feeding-based RNA interference is reported here for the first time in a mollusk bivalve, the pacific oyster Crassostrea gigas. In this Trojan horse strategy, the unicellular alga Heterocapsa triquetra is the food supply used as a vector to feed oysters with Escherichia coli strain HT115 engineered to express the double-stranded RNA targeting gene. To test the efficacy of the method, the Clock gene, a central gene of the circadian clock, was targeted for knockout. Results demonstrated specific and systemic efficiency of the Trojan horse strategy in reducing Clock mRNA abundance. Consequences of Clock disruption were observed in Clock-related genes (Bmal, Tim1, Per, Cry1, Cry2, Rev.-erb, and Ror) and triploid oysters were more sensitive than diploid to the interference. This non-invasive approach shows an involvement of the circadian clock in oyster bioaccumulation of toxins produced by the harmful alga Alexandrium minutum.

  3. Mining for novel candidate clock genes in the circadian regulatory network.

    Science.gov (United States)

    Bhargava, Anuprabha; Herzel, Hanspeter; Ananthasubramaniam, Bharath

    2015-11-14

    Most physiological processes in mammals are temporally regulated by means of a master circadian clock in the brain and peripheral oscillators in most other tissues. A transcriptional-translation feedback network of clock genes produces near 24 h oscillations in clock gene and protein expression. Here, we aim to identify novel additions to the clock network using a meta-analysis of public chromatin immunoprecipitation sequencing (ChIP-seq), proteomics and protein-protein interaction data starting from a published list of 1000 genes with robust transcriptional rhythms and circadian phenotypes of knockdowns. We identified 20 candidate genes including nine known clock genes that received significantly high scores and were also robust to the relative weights assigned to different data types. Our scoring was consistent with the original ranking of the 1000 genes, but also provided novel complementary insights. Candidate genes were enriched for genes expressed in a circadian manner in multiple tissues with regulation driven mainly by transcription factors BMAL1 and REV-ERB α,β. Moreover, peak transcription of candidate genes was remarkably consistent across tissues. While peaks of the 1000 genes were distributed uniformly throughout the day, candidate gene peaks were strongly concentrated around dusk. Finally, we showed that binding of specific transcription factors to a gene promoter was predictive of peak transcription at a certain time of day and discuss combinatorial phase regulation. Combining complementary publicly-available data targeting different levels of regulation within the circadian network, we filtered the original list and found 11 novel robust candidate clock genes. Using the criteria of circadian proteomic expression, circadian expression in multiple tissues and independent gene knockdown data, we propose six genes (Por, Mtss1, Dgat2, Pim3, Ppp1r3b, Upp2) involved in metabolism and cancer for further experimental investigation. The availability of

  4. Association between circadian clock genes and diapause incidence in Drosophila triauraria.

    Directory of Open Access Journals (Sweden)

    Hirokazu Yamada

    Full Text Available Diapause is an adaptive response triggered by seasonal photoperiodicity to overcome unfavorable seasons. The photoperiodic clock is a system that controls seasonal physiological processes, but our knowledge about its physiological mechanisms and genetic architecture remains incomplete. The circadian clock is another system that controls daily rhythmic physiological phenomena. It has been argued that there is a connection between the two clocks. To examine the genetic connection between them, we analyzed the associations of five circadian clock genes (period, timeless, Clock, cycle and cryptochrome with the occurrence of diapause in Drosophila triauraria, which shows a robust reproductive diapause with clear photoperiodicity. Non-diapause strains found in low latitudes were compared in genetic crosses with the diapause strain, in which the diapause trait is clearly dominant. Single nucleotide polymorphism and deletion analyses of the five circadian clock genes in backcross progeny revealed that allelic differences in timeless and cryptochrome between the strains were additively associated with the differences in the incidence of diapause. This suggests that there is a molecular link between certain circadian clock genes and the occurrence of diapause.

  5. Association between Circadian Clock Genes and Diapause Incidence in Drosophila triauraria

    Science.gov (United States)

    Yamada, Hirokazu; Yamamoto, Masa-Toshi

    2011-01-01

    Diapause is an adaptive response triggered by seasonal photoperiodicity to overcome unfavorable seasons. The photoperiodic clock is a system that controls seasonal physiological processes, but our knowledge about its physiological mechanisms and genetic architecture remains incomplete. The circadian clock is another system that controls daily rhythmic physiological phenomena. It has been argued that there is a connection between the two clocks. To examine the genetic connection between them, we analyzed the associations of five circadian clock genes (period, timeless, Clock, cycle and cryptochrome) with the occurrence of diapause in Drosophila triauraria, which shows a robust reproductive diapause with clear photoperiodicity. Non-diapause strains found in low latitudes were compared in genetic crosses with the diapause strain, in which the diapause trait is clearly dominant. Single nucleotide polymorphism and deletion analyses of the five circadian clock genes in backcross progeny revealed that allelic differences in timeless and cryptochrome between the strains were additively associated with the differences in the incidence of diapause. This suggests that there is a molecular link between certain circadian clock genes and the occurrence of diapause. PMID:22164210

  6. Association between genetic variants of the clock gene and obesity and sleep duration.

    Science.gov (United States)

    Valladares, Macarena; Obregón, Ana María; Chaput, Jean-Philippe

    2015-12-01

    Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.

  7. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    Directory of Open Access Journals (Sweden)

    Zhu Zhu

    2016-01-01

    Full Text Available Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice by altering exposure to light. C57 BL/6J mice (C57 mice and ApoE-KO mice (ApoE-KO mice exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1 levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

  8. Altered behavioral rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene.

    Science.gov (United States)

    Cermakian, N; Monaco, L; Pando, M P; Dierich, A; Sassone-Corsi, P

    2001-08-01

    A group of specialized genes has been defined to govern the molecular mechanisms controlling the circadian clock in mammals. Their expression and the interactions among their products dictate circadian rhythmicity. Three genes homologous to Drosophila period exist in the mouse and are thought to be major players in the biological clock. Here we present the generation of mice in which the founding member of the family, Per1, has been inactivated by homologous recombination. These mice present rhythmicity in locomotor activity, but with a period almost 1 h shorter than wild-type littermates. Moreover, the expression of clock genes in peripheral tissues appears to be delayed in Per1 mutant animals. Importantly, light-induced phase shifting appears conserved. The oscillatory expression of clock genes and the induction of immediate-early genes in response to light in the master clock structure, the suprachiasmatic nucleus, are unaffected. Altogether, these data demonstrate that Per1 plays a distinct role within the Per family, as it may be involved predominantly in peripheral clocks and/or in the output pathways of the circadian clock.

  9. Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.

    Science.gov (United States)

    Kunieda, Takeshige; Minamino, Tohru; Katsuno, Taro; Tateno, Kaoru; Nishi, Jun-ichiro; Miyauchi, Hideyuki; Orimo, Masayuki; Okada, Sho; Komuro, Issei

    2006-03-03

    Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity.

  10. Achilles is a circadian clock-controlled gene that regulates immune function in Drosophila.

    Science.gov (United States)

    Li, Jiajia; Terry, Erin E; Fejer, Edith; Gamba, Diana; Hartmann, Natalie; Logsdon, Joseph; Michalski, Daniel; Rois, Lisa E; Scuderi, Maria J; Kunst, Michael; Hughes, Michael E

    2017-03-01

    The circadian clock is a transcriptional/translational feedback loop that drives the rhythmic expression of downstream mRNAs. Termed "clock-controlled genes," these molecular outputs of the circadian clock orchestrate cellular, metabolic, and behavioral rhythms. As part of our on-going work to characterize key upstream regulators of circadian mRNA expression, we have identified a novel clock-controlled gene in Drosophila melanogaster, Achilles (Achl), which is rhythmic at the mRNA level in the brain and which represses expression of antimicrobial peptides in the immune system. Achilles knock-down in neurons dramatically elevates expression of crucial immune response genes, including IM1 (Immune induced molecule 1), Mtk (Metchnikowin), and Drs (Drosomysin). As a result, flies with knocked-down Achilles expression are resistant to bacterial challenges. Meanwhile, no significant change in core clock gene expression and locomotor activity is observed, suggesting that Achilles influences rhythmic mRNA outputs rather than directly regulating the core timekeeping mechanism. Notably, Achilles knock-down in the absence of immune challenge significantly diminishes the fly's overall lifespan, indicating a behavioral or metabolic cost of constitutively activating this pathway. Together, our data demonstrate that (1) Achilles is a novel clock-controlled gene that (2) regulates the immune system, and (3) participates in signaling from neurons to immunological tissues. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Role of circadian gene Clock during differentiation of mouse pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Chao Lu

    2016-09-01

    Full Text Available Abstract Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs. However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs. These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b. After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.

  12. Role of circadian gene Clock during differentiation of mouse pluripotent stem cells.

    Science.gov (United States)

    Lu, Chao; Yang, Yang; Zhao, Ran; Hua, Bingxuan; Xu, Chen; Yan, Zuoqin; Sun, Ning; Qian, Ruizhe

    2016-11-01

    Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs). These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b). After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.

  13. Effect of monochromatic light on circadian rhythmic expression of clock genes in the hypothalamus of chick.

    Science.gov (United States)

    Jiang, Nan; Wang, Zixu; Cao, Jing; Dong, Yulan; Chen, Yaoxing

    2017-08-01

    To clarify the effect of monochromatic light on circadian clock gene expression in chick hypothalamus, a total 240 newly hatched chickens were reared under blue light (BL), green light (GL), red light (RL) and white light (WL), respectively. On the post-hatched day 14, 24-h profiles of seven core clock genes (cClock, cBmal1, cBmal2, cCry1, cCry2, cPer2 and cPer3) were measured at six time points (CT 0, CT 4, CT 8, CT 12, CT 16, CT 20, circadian time). We found all these clock genes expressed with a significant rhythmicity in different light wavelength groups. Meanwhile, cClock and cBmal1 showed a high level under GL, and followed a corresponding high expression of cCry1. However, RL decreased the expression levels of these genes. Be consistent with the mRNA level, CLOCK and BMAL1 proteins also showed a high level under GL. The CLOCK-like immunoreactive neurons were observed not only in the SCN, but also in the non-SCN brain region such as the nucleus anterior medialis hypothalami, the periventricularis nucleus, the paraventricular nucleus and the median eminence. All these results are consistent with the auto-regulatory circadian feedback loop, and indicate that GL may play an important role on the circadian time generation and development in the chick hypothalamus. Our results also suggest that the circadian clock in the chick hypothalamus such as non-SCN brain region were involved in the regulation of photo information. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Functional circadian clock genes are essential for the overwintering diapause of the Northern house mosquito, Culex pipiens

    OpenAIRE

    Meuti, Megan E.; Stone, Mary; Ikeno, Tomoko; Denlinger, David L.

    2015-01-01

    The short day lengths of late summer are used to program the overwintering adult diapause (dormancy) of the Northern house mosquito, Culex pipiens. Here, we investigated the role of clock genes in initiating this diapause and asked whether the circadian cycling of clock gene expression persists during diapause. We provide evidence that the major circadian clock genes continue to cycle throughout diapause and after diapause has been terminated. RNA interference (RNAi) was used to knock down th...

  15. Passive cigarette smoking changes the circadian rhythm of clock genes in rat intervertebral discs.

    Science.gov (United States)

    Numaguchi, Shumpei; Esumi, Mariko; Sakamoto, Mika; Endo, Michiko; Ebihara, Takayuki; Soma, Hirotoki; Yoshida, Akio; Tokuhashi, Yasuaki

    2016-01-01

    We aimed to elucidate the molecular changes in intervertebral discs (IVDs) caused by passive smoking. Rats were subjected to 8 weeks of passive smoking; thereafter, their lumbar vertebrae were harvested. The annulus fibrosus and cartilage endplate (AF/CEP) were harvested together, and the nucleus pulposus (NP) was isolated separately. The expression of 27,342 rat genes was analyzed. In 3 "nonsmoking" rats, 96 of 112 genes whose expression varied ≥10-fold between the AF/CEP and NP were more highly expressed in the AF/CEP. With these differentially expressed genes, we uncovered novel AF/CEP and NP marker genes and indicated their possible novel functions. Although passive smoking induced less marked alteration in the gene expression profiles of both the AF/CEP and NP, multiple clock-related genes showed altered expression. These genes were expressed with a circadian rhythm in IVD cells, and most genes showed a phase shift of -6 to -9 h induced by passive smoking. Some clock-related genes showed abolished oscillation in the NP. Passive smoking also changed the expression levels of proteases and protease inhibitors and reduced the expression of NP marker genes. Thus, passive smoking induces changes in the circadian rhythm of a peripheral clock (IVD clock) that might be involved in molecular events related to IVD degeneration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  16. Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder.

    Science.gov (United States)

    Rybakowski, Janusz K; Dmitrzak-Weglarz, Monika; Dembinska-Krajewska, Daria; Hauser, Joanna; Akiskal, Karen K; Akiskal, Hagop H

    2014-04-01

    Previously, we found correlations between lithium efficacy in bipolar disorder and temperamental dimensions of the TEMPS-A and also genes involved in the regulation of biological rhythms ("clock" genes). Here, were attempted to investigate an association between multiple, single nucleotide polymorphisms (SNPs) of four clock genes (CLOCK, ARNTL, TIM, PER3) and temperamental dimensions of the TEMPS-A, in bipolar patients. The study included 70 patients with bipolar disorder (20 males, 50 females), with a mean age of 59±12 years. The TEMPS-A questionnaire, 110 questions version, was used assessing five temperament domains: depressive, cyclothymic, hyperthymic, irritable and anxious. Genotyping was done for 9 SNPs of the CLOCK gene, 18 SNPs of the ARNTL gene, 6 SNPs of the TIM gene and 5 SNPs of the PER3 gene. An association with hyperthymic temperament was found for three, and with anxious temperament for four SNPs of the ARTL gene. An association of cyclothymic temperament was found with two SNPs of the TIM gene and of depressive temperament with one SNP of the PER3 gene. No association was observed with SNPs of the CLOCK gene. Relatively small number of patients studied and insufficient correction for multiple testing. These results may suggest that the ARNTL, TIM and PER3 genes may be associated with temperamental dimensions measured by the TEMPS-A, each of this gene being specific to given temperamental dimension. Of special interest may be the polymorphisms of ARNTL gene also connected with predisposition to bipolar mood disorder and/or lithium response. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Disruption of clock gene expression in human colorectal liver metastases

    NARCIS (Netherlands)

    S.A. Huisman (Sander); K.R. Ahmadi (Kourosh); J.N.M. IJzermans (Jan); C. Verhoef (Kees); G.T.J. van der Horst (Gijsbertus); R.W.F. de Bruin (Ron)

    2016-01-01

    textabstractThe circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an

  18. Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

    Science.gov (United States)

    Lin, Changpo; Tang, Xiao; Xu, Lirong; Qian, Ruizhe; Shi, Zhenyu; Wang, Lixin; Cai, Tingting; Yan, Dong; Fu, Weiguo; Guo, Daqiao

    2017-07-10

    The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions. Seven health donors' normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits. The circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs. The results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

  19. The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus.

    Science.gov (United States)

    Kudo, Takashi; Block, Gene D; Colwell, Christopher S

    2015-01-01

    The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca(2+)]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca(2+)]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca(2+)]i-activated channel is one of the targets. © The Author(s) 2015.

  20. The effect of Wolbachia on diapause, fecundity, and clock gene expression in Trichogramma brassicae (Hymenoptera: Trichogrammatidae).

    Science.gov (United States)

    Rahimi-Kaldeh, Somayeh; Ashouri, Ahmad; Bandani, Alireza; Tomioka, Kenji

    2017-11-01

    The short day lengths of late summer in moderate regions are used to induce diapause in various insects. Many studies have shown the maternal effect of photoperiod on diapause induction of Trichogramma wasps, but there is no study to show the relationship between photoperiodic regimes and clock genes in these useful biological control agents. Here, we investigated the role of photoperiods on diapause, fecundity, and clock gene expression (clk, cyc, cry2, per, and timeout) in asexual and sexual Trichogramma brassicae as a model insect to find any differences between two strains. Asexual strain was infected by Wolbachia, an endosymbiont bacterium. The diapause percentage was significantly higher under short days (8 h in sexual and 12 h in the asexual T. brassicae), although the diapause percentage of the sexual strain was significantly higher than the asexual one in all the photoperiods. The ANOVA revealed no significant changes between different photoperiods in the clock gene expression in the sexual strain but significant photoperiodic changes in clk, cyc, and timeout in the asexual strain. Our results showed that the mRNA levels of clock genes of asexual T. brassicae were significantly lower than those of sexual strain. The fecundity was significantly higher in the asexual strain. These results suggest that Wolbachia infection makes disturbance on the clock gene expression which consequently reduces the percentage of diapause but increases the fecundity in asexual T. brassicae.

  1. An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

    DEFF Research Database (Denmark)

    Haukvik, Unn Kristin; Saetre, Peter; McNeil, Thomas

    2010-01-01

    Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent...

  2. Diabetic retinopathy alters light-induced clock gene expression and dopamine levels in the mouse retina.

    Science.gov (United States)

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M; Bennis, Mohamed; Dkhissi-Benyahya, Ouria

    2016-01-01

    Diabetic retinopathy is one of the most common consequences of diabetes that affects millions of working-age adults worldwide and leads to progressive degeneration of the retina, visual loss, and blindness. Diabetes is associated with circadian disruption of the central and peripheral circadian clocks, but the mechanisms responsible for such alterations are unknown. Using a streptozotocin (STZ)-induced model of diabetes, we investigated whether diabetes alters 1) the circadian regulation of clock genes in the retina and in the central clocks, 2) the light response of clock genes in the retina, and/or 3) light-driven retinal dopamine (DA), a major output marker of the retinal clock. To quantify circadian expression of clock and clock-controlled genes, retinas and suprachiasmatic nucleus (SCN) from the same animals were collected every 4 h in circadian conditions, 12 weeks post-diabetes. Induction of Per1, Per2, and c-fos mRNAs was quantified in the retina after the administration of a pulse of monochromatic light (480 nm, 1.17×10(14) photons/cm(2)/s, 15 min) at circadian time 16. Gene expression was assessed with real-time reverse transcription PCR (RT-PCR). Pooled retinas from the control and STZ-diabetic mice were collected 2 h after light ON and light OFF (Zeitgeber time (ZT)2 and ZT14), and DA and its metabolite were analyzed with high-performance liquid chromatography (HPLC). We found variable effects of diabetes on the expression of clock genes in the retina and only slight differences in phase and/or amplitude in the SCN. c-fos and Per1 induction by a 480 nm light pulse was abolished in diabetic animals at 12 weeks post-induction of diabetes in comparison with the control mice, suggesting a deficit in light-induced neuronal activation of the retinal clock. Finally, we quantified a 56% reduction in the total number of tyrosine hydroxylase (TH) immunopositive cells, associated with a decrease in DA levels during the subjective day (ZT2). These findings

  3. Diabetic retinopathy alters light-induced clock gene expression and dopamine levels in the mouse retina

    Science.gov (United States)

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M.; Bennis, Mohamed

    2016-01-01

    Purpose Diabetic retinopathy is one of the most common consequences of diabetes that affects millions of working-age adults worldwide and leads to progressive degeneration of the retina, visual loss, and blindness. Diabetes is associated with circadian disruption of the central and peripheral circadian clocks, but the mechanisms responsible for such alterations are unknown. Using a streptozotocin (STZ)-induced model of diabetes, we investigated whether diabetes alters 1) the circadian regulation of clock genes in the retina and in the central clocks, 2) the light response of clock genes in the retina, and/or 3) light-driven retinal dopamine (DA), a major output marker of the retinal clock. Methods To quantify circadian expression of clock and clock-controlled genes, retinas and suprachiasmatic nucleus (SCN) from the same animals were collected every 4 h in circadian conditions, 12 weeks post-diabetes. Induction of Per1, Per2, and c-fos mRNAs was quantified in the retina after the administration of a pulse of monochromatic light (480 nm, 1.17×1014 photons/cm2/s, 15 min) at circadian time 16. Gene expression was assessed with real-time reverse transcription PCR (RT–PCR). Pooled retinas from the control and STZ-diabetic mice were collected 2 h after light ON and light OFF (Zeitgeber time (ZT)2 and ZT14), and DA and its metabolite were analyzed with high-performance liquid chromatography (HPLC). Results We found variable effects of diabetes on the expression of clock genes in the retina and only slight differences in phase and/or amplitude in the SCN. c-fos and Per1 induction by a 480 nm light pulse was abolished in diabetic animals at 12 weeks post-induction of diabetes in comparison with the control mice, suggesting a deficit in light-induced neuronal activation of the retinal clock. Finally, we quantified a 56% reduction in the total number of tyrosine hydroxylase (TH) immunopositive cells, associated with a decrease in DA levels during the subjective day (ZT2

  4. The role of clock genes in the etiology of Major Depressive Disorder.

    Science.gov (United States)

    Buoli, Massimiliano; Serati, Marta; Grassi, Silvia; Pergoli, Laura; Cantone, Laura; Altamura, A Carlo; Bollati, Valentina

    2017-11-07

    Circadian rhythms are largely dysregulated in Major Depressive Disorder (MDD). The present review provides a summary of the findings about the role of clock genes in the etiology of MDD. A careful search of articles on Pubmed, PsycINFO, Isi Web of Knowledge was performed in order to obtain a comprehensive review about the topic. The studies reported contrasting results about the association of different single nucleotide polymorphisms (SNPs) in clock genes and MDD. The most consistent result reported the association between SNP rs2287161 of CRY1 and MDD development. Most of the published papers on the topic show bias as a prevalence of Asian ethnicity or not blinded conditions of laboratory experiments with respect to subjects' conditions (healthy controls or MDD). Further epigenetic and genome-wide studies are necessary to have a more clear idea about the role of clock genes in the etiology of MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock"

    NARCIS (Netherlands)

    Wu, Ying-Hui; Fischer, David F.; Kalsbeek, Andries; Garidou-Boof, Marie-Laure; van der Vliet, Jan; van Heijningen, Caroline; Liu, Rong-Yu; Zhou, Jiang-Ning; Swaab, Dick F.

    2006-01-01

    The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease

  6. Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock".

    NARCIS (Netherlands)

    Wu, Y.-H.; Fischer, D.F.; Kalsbeek, A.; Garidou-Boof, M.-L.; Vliet, J. van der; Heijningen, C. van; Liu, R.-Y.; Zhou, J.-N.; Swaab, D.F.

    2006-01-01

    The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease

  7. Investigation of Seasonal and Latitudinal Effects on the Expression of Clock Genes in Drosophila

    Science.gov (United States)

    Hosseini, Seyede Sanaz; Nazarimehr, Fahimeh; Jafari, Sajad

    The primary goal in this work is to develop a dynamical model capturing the influence of seasonal and latitudinal variations on the expression of Drosophila clock genes. To this end, we study a specific dynamical system with strange attractors that exhibit changes of Drosophila activity in a range of latitudes and across different seasons. Bifurcations of this system are analyzed to peruse the effect of season and latitude on the behavior of clock genes. Existing experimental data collected from the activity of Drosophila melanogaster corroborate the dynamical model.

  8. Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Polona Lavtar

    Full Text Available Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02 distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001 and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002. The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

  9. The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration.

    Science.gov (United States)

    Stokes, Kyle; Cooke, Abrial; Chang, Hanna; Weaver, David R; Breault, David T; Karpowicz, Phillip

    2017-07-01

    The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied. We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture. The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway. Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology.

  10. Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures.

    Science.gov (United States)

    Petrenko, Volodymyr; Saini, Camille; Perrin, Laurent; Dibner, Charna

    2016-11-11

    Circadian clocks are functional in all light-sensitive organisms, allowing for an adaptation to the external world by anticipating daily environmental changes. Considerable progress in our understanding of the tight connection between the circadian clock and most aspects of physiology has been made in the field over the last decade. However, unraveling the molecular basis that underlies the function of the circadian oscillator in humans stays of highest technical challenge. Here, we provide a detailed description of an experimental approach for long-term (2-5 days) bioluminescence recording and outflow medium collection in cultured human primary cells. For this purpose, we have transduced primary cells with a lentiviral luciferase reporter that is under control of a core clock gene promoter, which allows for the parallel assessment of hormone secretion and circadian bioluminescence. Furthermore, we describe the conditions for disrupting the circadian clock in primary human cells by transfecting siRNA targeting CLOCK. Our results on the circadian regulation of insulin secretion by human pancreatic islets, and myokine secretion by human skeletal muscle cells, are presented here to illustrate the application of this methodology. These settings can be used to study the molecular makeup of human peripheral clocks and to analyze their functional impact on primary cells under physiological or pathophysiological conditions.

  11. Evidence for clock genes circadian rhythms in human full-term placenta.

    Science.gov (United States)

    Pérez, Silvia; Murias, Lucía; Fernández-Plaza, Catalina; Díaz, Irene; González, Celestino; Otero, Jesús; Díaz, Elena

    2015-01-01

    Biological rhythms are driven by endogenous biological clocks; in mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This master pacemaker can synchronize other peripheral oscillators in several tissues such as some involved in endocrine or reproductive functions. The presence of an endogenous placental clock has received little attention. In fact, there are no studies in human full-term placentas. To test the existence of an endogenous pacemaker in this tissue we have studied the expression of circadian locomoter output cycles kaput (Clock), brain and muscle arnt-like (Bmal)1, period (Per)2, and cryptochrome (Cry)1 mRNAs at 00, 04, 08, 12, 16, and 20 hours by qPCR. The four clock genes studied are expressed in full-term human placenta. The results obtained allow us to suggest that a peripheral oscillator exists in human placenta. Data were analyzed using Fourier series where only the Clock and Bmal1 expression shows a circadian rhythm.

  12. Role of monochromatic light on daily variation of clock gene expression in the pineal gland of chick.

    Science.gov (United States)

    Jiang, Nan; Wang, Zixu; Cao, Jing; Dong, Yulan; Chen, Yaoxing

    2016-11-01

    The avian pineal gland is a master clock that can receive external photic cues and translate them into output rhythms. To clarify whether a shift in light wavelength can influence the circadian expression in chick pineal gland, a total of 240 Arbor Acre male broilers were exposed to white light (WL), red light (RL), green light (GL) or blue light (BL). After 2weeks light illumination, circadian expressions of seven core clock genes in pineal gland and the level of melatonin in plasma were examined. The results showed after illumination with monochromatic light, 24h profiles of all clock gene mRNAs retained circadian oscillation, except that RL tended to disrupt the rhythm of cCry2. Compared to WL, BL advanced the acrophases of the negative elements (cCry1, cCry2, cPer2 and cPer3) by 0.1-1.5h and delayed those of positive elements (cClock, cBmal1 and cBmal2) by 0.2-0.8h. And, RL advanced all clock genes except cClock and cPer2 by 0.3-2.1h, while GL delayed all clock genes by 0.5-1.5h except cBmal2. Meanwhile, GL increased the amplitude and mesor of positive and reduced both parameters of negative clock genes, but RL showed the opposite pattern. Although the acrophase of plasma melatonin was advanced by both GL and RL, the melatonin level was significantly increased in GL and decreased in RL. This tendency was consistent with the variations in the positive clock gene mRNA levels under monochromatic light and contrasted with those of negative clock genes. Therefore, we speculate that GL may enhance positive clock genes expression, leading to melatonin synthesis, whereas RL may enhance negative genes expression, suppressing melatonin synthesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression.

    Science.gov (United States)

    Partonen, Timo; Treutlein, Jens; Alpman, Asude; Frank, Josef; Johansson, Carolina; Depner, Martin; Aron, Liviu; Rietschel, Marcella; Wellek, Stefan; Soronen, Pia; Paunio, Tiina; Koch, Andreas; Chen, Ping; Lathrop, Mark; Adolfsson, Rolf; Persson, Maj-Liz; Kasper, Siegfried; Schalling, Martin; Peltonen, Leena; Schumann, Gunter

    2007-01-01

    Multiple lines of evidence suggest that the circadian clock contributes to the pathogenesis of winter depression or seasonal affective disorder (SAD). We hypothesized that sequence variations in three genes, including Per2, Arntl, and Npas2, which form a functional unit at the core of the circadian clock, predispose to winter depression. In silico analysis of the biological effects of allelic differences suggested the target single-nucleotide polymorphisms (SNPs) to be analyzed in a sample of 189 patients and 189 matched controls. The most relevant SNP in each gene was identified for the interaction analysis and included in the multivariate assessment of the combined effects of all three SNPs on the disease risk. SAD was associated with variations in each of the three genes in gene-wise logistic regression analysis. In combination analysis of variations of Per2, Arntl, and Npas2, we found additive effects and identified a genetic risk profile for the disorder. Carriers of the risk genotype combination had the odds ratio of 4.43 of developing SAD as compared with the remaining genotypes, and of 10.67 as compared with the most protective genotype combination. Variations in the three circadian clock genes Per2, Arntl, and Npas2 are associated with the disease, supporting the hypothesis that the circadian clock mechanisms contribute to winter depression.

  14. Clock and clock-controlled genes are differently expressed in the retina, lamina and in selected cells of the visual system of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Milena eDamulewicz

    2015-09-01

    Full Text Available The retina and the first optic neuropil (lamina of Drosophila show circadian rhythms in various processes. To learn about the regulation of circadian rhythms in the retina and lamina and in two cell types, glial and the lamina L2 interneurons, we examined expression of the following clock genes; per, tim, clk, and cry and clock-controlled genes; Atp, nrv2, brp, Pdfr. We found that the expression of gene studied is specific for the retina and lamina. The rhythms of per and tim expression in the retina and glial cells are similar to that observed in the whole head and in clock neurons, while they differ in the lamina and L2 cells. In both the retina and lamina, CRY seems to be a repressor of clk expression. In L2 interneurons per expression is not cyclic indicating the other function of PER in those cells than in the circadian molecular clock. In contrast to per and tim, the pattern of clk and cry expression is similar in both the retina and lamina. The retina holds the autonomous oscillators but the expression of cry and clock-controlled genes, Atp and nrv2, is also regulated by inputs from the pacemaker transmitted by PDF and ITP neuropeptides.

  15. The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit

    Directory of Open Access Journals (Sweden)

    Pascale Bouchard-Cannon

    2013-11-01

    Full Text Available The subgranular zone (SGZ of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

  16. Overall alteration of circadian clock gene expression in the chestnut cold response.

    Directory of Open Access Journals (Sweden)

    Cristian Ibañez

    Full Text Available Cold acclimation in woody plants may have special features compared to similar processes in herbaceous plants. Recent studies have shown that circadian clock behavior in the chestnut tree (Castanea sativa is disrupted by cold temperatures and that the primary oscillator feedback loop is not functional at 4 degrees C or in winter. In these conditions, CsTOC1 and CsLHY genes are constantly expressed. Here, we show that this alteration also affects CsPRR5, CsPRR7 and CsPRR9. These genes are homologous to the corresponding Arabidopsis PSEUDO-RESPONSE REGULATOR genes, which are also components of the circadian oscillator feedback network. The practically constant presence of mRNAs of the 5 chestnut genes at low temperature reveals an unknown aspect of clock regulation and suggests a mechanism regulating the transcription of oscillator genes as a whole.

  17. Obesity-induced changes in hepatic and placental clock gene networks in rat pregnancy.

    Science.gov (United States)

    Crew, Rachael C; Waddell, Brendan J; Mark, Peter J

    2018-01-01

    Maternal obesity induces pregnancy complications and disturbs fetal development, but the specific mechanisms underlying these outcomes are unclear. Circadian rhythms are implicated in metabolic complications associated with obesity, and maternal metabolic adaptations to pregnancy. Accordingly, obesity-induced circadian dysfunction may drive adverse outcomes in obese pregnancy. This study investigated whether maternal obesity alters the rhythmic expression of clock genes and associated nuclear receptors across maternal, fetal, and placental tissues. Wistar rats were maintained on a cafeteria (CAF) diet prior to and throughout gestation to induce maternal obesity. Maternal and fetal liver and placental labyrinth zone (LZ) were collected at four-hourly time points across days 15-16 and 21-22 of gestation (term = 23 days). Gene expression was analyzed by RT-qPCR. Expression of the accessory clock gene Nr1d1 was rhythmic in the maternal and fetal liver and LZ of chow-fed controls, but in each case CAF feeding reduced peak Nr1d1 expression. Obesity resulted in a phase advance (approx. 1.5 h) in the rhythms of several clock genes and Ppar-delta in maternal liver. Aside from Nr1d1, expression of clock genes was mostly arrhythmic in LZ and fetal liver, and was unaffected by the CAF diet. In conclusion, maternal obesity suppressed Nr1d1 expression across maternal, fetal, and placental compartments and phase-advanced the rhythms of maternal hepatic clock genes. Given the key role of Nr1d1 in regulating metabolic, vascular, and inflammatory processes, our data suggest that disruptions to rhythmic Nr1d1 expression in utero may contribute to programmed health complications in offspring of obese pregnancies. © The Author(s) 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Dissecting Daily and Circadian Expression Rhythms of Clock-Controlled Genes in Human Blood

    NARCIS (Netherlands)

    K. Lech (Karolina); K. Ackermann (Katrin); V.L. Revell (Victoria); O.S.C.A.R. Lao; D.J. Skene (Debra); M.H. Kayser (Manfred)

    2016-01-01

    textabstractThe identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human

  19. Clock Genes and Altered Sleep–Wake Rhythms: Their Role in the Development of Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Annaëlle Charrier

    2017-04-01

    Full Text Available In mammals, the circadian clocks network (central and peripheral oscillators controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder. However, the underlying mechanisms of these associations remain to be ascertained and the cause–effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep–wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders. First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep–wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

  20. Nucleotide sequences of immunoglobulin eta genes of chimpanzee and orangutan: DNA molecular clock and hominoid evolution

    Energy Technology Data Exchange (ETDEWEB)

    Sakoyama, Y.; Hong, K.J.; Byun, S.M.; Hisajima, H.; Ueda, S.; Yaoita, Y.; Hayashida, H.; Miyata, T.; Honjo, T.

    1987-02-01

    To determine the phylogenetic relationships among hominoids and the dates of their divergence, the complete nucleotide sequences of the constant region of the immunoglobulin eta-chain (C/sub eta1/) genes from chimpanzee and orangutan have been determined. These sequences were compared with the human eta-chain constant-region sequence. A molecular clock (silent molecular clock), measured by the degree of sequence divergence at the synonymous (silent) positions of protein-encoding regions, was introduced for the present study. From the comparison of nucleotide sequences of ..cap alpha../sub 1/-antitrypsin and ..beta..- and delta-globulin genes between humans and Old World monkeys, the silent molecular clock was calibrated: the mean evolutionary rate of silent substitution was determined to be 1.56 x 10/sup -9/ substitutions per site per year. Using the silent molecular clock, the mean divergence dates of chimpanzee and orangutan from the human lineage were estimated as 6.4 +/- 2.6 million years and 17.3 +/- 4.5 million years, respectively. It was also shown that the evolutionary rate of primate genes is considerably slower than those of other mammalian genes.

  1. CLOCK Gene Variants Associate with Sleep Duration in Two Independent Populations

    NARCIS (Netherlands)

    Allebrandt, Karla V.; Teder-Laving, Maris; Akyol, Mahmut; Pichler, Irene; Mueller-Myhsok, Bertram; Pramstaller, Peter; Merrow, Martha; Meitinger, Thomas; Metspalu, Andreas; Roenneberg, Till; Müller-Myhsok, Bertram

    2010-01-01

    Background: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. Methods: Sleep duration was assessed in

  2. Toward the beginning of time: circadian rhythms in metabolism precede rhythms in clock gene expression in mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Jiffin K Paulose

    Full Text Available The appearance, progression, and potential role for circadian rhythms during early development have previously focused mainly on the suprachiasmatic nucleus (SCN and peri- and postnatal expression of canonical clock genes. More recently, gene expression studies in embryonic stem cells have shown that some clock genes are expressed in undifferentiated cells; however rhythmicity was only established when cells are directed toward a neural fate. These studies also concluded that a functional clock is not present in ESCs, based solely on their gene expression. The null hypothesis underlying the present study is that embryonic stem cells become rhythmic in both clock gene expression and glucose utilization only when allowed to spontaneously differentiate. Undifferentiated stem cells (ESCs, n = 6 cultures/timepoint for all experiments were either maintained in their pluripotent state or released into differentiation (dESCs, n = 6 cultures/timepoint for all experiments. Glucose utilization was assayed through 2-deoxyglucose uptake measurement, and clock gene and glucose transporter expression was assayed every 4 hours for 2 days in ESCs and dESCs by quantitative PCR (qPCR in the same cell lysates. Undifferentiated stem cells expressed a self-sustained rhythm in glucose uptake that was not coincident with rhythmic expression of clock genes. This physiological rhythm was paralleled by glucose transporter mRNA expression. Upon differentiation, circadian patterns of some but not all clock genes were expressed, and the amplitude of the glucose utilization rhythm was enhanced in dESCs. These data provide the earliest evidence of a functional circadian clock, in addition to further challenging the idea that rhythmic transcription of clock genes are necessary for rhythmic physiological output and suggest a role for a clock-controlled physiology in the earliest stages of development.

  3. Association of CLOCK gene variants with semen quality in idiopathic infertile Han-Chinese males.

    Science.gov (United States)

    Zhang, Jie; Ding, Xinliang; Li, Yingchun; Xia, Yankai; Nie, Jihua; Yi, Cao; Wang, Xinru; Tong, Jian

    2012-11-01

    Recent experimental animal studies suggested that the circadian locomotor output cycles kaput protein gene (CLOCK) may play an important role in male reproduction. So far, such data for humans are not available. This study used single-nucleotide polymorphisms (SNP) to examine the association between CLOCK and semen quality in a human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 men with idiopathic infertility by SNP genotyping assays and computer-aided sperm analysis. Subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume (P=CLOCK genetic variants and altered semen quality in a human population with idiopathic infertility. The gene encoding the circadian locomotor output cycles kaput protein (CLOCK) functions as an important positive enhancer of the circadian system. The observations reported in recent experimental animal studies suggested that CLOCK may play an important role in male reproduction. So far, such data for humans are not available. In this study, single-nucleotide polymorphisms (SNP) were used to examine the association between CLOCK and semen quality in human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 males with idiopathic infertility by SNP genotyping assays and computer-assisted semen analysis. The results showed that the subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume compared with the TT genotype. For subjects carrying the CC genotype, sperm number per ejaculate and sperm motility were significantly lower compared with TT genotype carriers. The rs1801260 TC genotype carriers also had significantly lower sperm motility compared with the TT genotype. For the rs3817444 genotypes, the CA and AA genotype carriers presented significantly lower semen volume compared with the CC genotype. The findings suggested, as far as is

  4. Effects of CLOCK gene variants and early stress on hopelessness and suicide in bipolar depression.

    Science.gov (United States)

    Benedetti, Francesco; Riccaboni, Roberta; Dallaspezia, Sara; Locatelli, Clara; Smeraldi, Enrico; Colombo, Cristina

    2015-01-01

    Patients with mood disorders show a high dependence of behavior on the molecular characteristics of the biological clock. CLOCK rs1801260 gene polymorphism influences circadian behavior in bipolar disorder (BD), with *C carriers showing a delayed sleep onset and worse insomnia. Sleep phase delay and insomnia associate with suicide in the general population. We investigated the effects of rs1801260, and of exposure to stressful life events, on current suicidal ideation and history of suicide attempts in 87 depressed patients with BD. rs1801260*C carriers currently showed worse Hamilton Depression Rating Scale scores for suicide and worse ratings for depressive cognitive distortions. Previous history of attempted suicide associated with exposure to higher stressful events in the early life, with rs1801260*C carriers showing a higher dependency of the modeled probability of attempting suicide on the severity of exposure to early stress. CLOCK rs1801260 modulated the relationship between early stress, adult history of attempted suicide and current suicide ideation. Factors affecting the biological clock can influence "non-clock" core psychopathological features of mood disorders.

  5. Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy.

    Science.gov (United States)

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M; Bennis, Mohamed; Dkhissi-Benyahya, Ouria

    2014-01-01

    There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges.

  6. Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy.

    Directory of Open Access Journals (Sweden)

    Hasna Lahouaoui

    Full Text Available There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs are altered in retinal pathologies. Using a streptozotocin-induced (STZ model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN. The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1 successive light/dark (LD cycle of decreasing or increasing light intensities during the light phase and 2 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges.

  7. The association of inherited variation in the CLOCK gene with breast cancer tumor grade

    Directory of Open Access Journals (Sweden)

    Neha Gupta

    2017-07-01

    Full Text Available Background: Sufficient sleep and maintenance of circadian rhythm are important to health. We have shown that short duration of sleep before diagnosis is associated with higher-grade tumors among breast cancer patients. Earlier studies suggest that genetic variation in the CLOCK gene is associated with risk of cancers, including breast cancer. Studies of the association of genetic variation, including in CLOCK, and tumor grade, a standard marker of tumor aggressiveness, are lacking. Methods: We investigated the relationship between single nucleotide polymorphisms (SNPs in the CLOCK gene and tumor grade and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status in 293 breast cancer patients. Nine SNPs were determined by standard TaqMan assays. Tumor grade, receptor status, and other clinical variables were abstracted from medical records. Results: Two SNPs were excluded because of poor genotyping performance. None of the remaining seven variants had a statistically significant association with breast cancer tumor grade or with receptor status. Conclusion: As with all novel studies, further work is needed to examine the association of CLOCK and other genes in the circadian rhythm pathway with breast cancer tumor grade in other populations.

  8. The circadian clock gene period extends healthspan in aging Drosophila melanogaster.

    Science.gov (United States)

    Krishnan, Natraj; Kretzschmar, Doris; Rakshit, Kuntol; Chow, Eileen; Giebultowicz, Jadwiga M

    2009-11-19

    There is increasing evidence that aging is affected by biological (circadian) clocks - the internal mechanisms that coordinate daily changes in gene expression, physiological functions and behavior with external day/night cycles. Recent data suggest that disruption of the mammalian circadian clock results in accelerated aging and increased age-related pathologies such as cancer; however, the links between loss of daily rhythms and aging are not understood. We sought to determine whether disruption of the circadian clock affects lifespan and healthspan in the model organism Drosophila melanogaster. We examined effects of a null mutation in the circadian clock gene period (per(01)) on the fly healthspan by challenging aging flies with short-term oxidative stress (24h hyperoxia) and investigating their response in terms of mortality hazard, levels of oxidative damage, and functional senescence. Exposure to 24h hyperoxia during middle age significantly shortened the life expectancy in per(01) but not in control flies. This homeostatic challenge also led to significantly higher accumulation of oxidative damage in per(01) flies compared to controls. In addition, aging per(01) flies showed accelerated functional decline, such as lower climbing ability and increased neuronal degeneration compared to age-matched controls. Together, these data suggest that impaired stress defense pathways may contribute to accelerated aging in the per mutant. In addition, we show that the expression of per gene declines in old wild type flies, suggesting that the circadian regulatory network becomes impaired with age.

  9. Clock Genes and Behavioral Responses to Light Are Altered in a Mouse Model of Diabetic Retinopathy

    Science.gov (United States)

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M.; Bennis, Mohamed; Dkhissi-Benyahya, Ouria

    2014-01-01

    There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1–2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges. PMID:25006976

  10. Placental genetic variations in circadian clock-related genes increase the risk of placental abruption

    OpenAIRE

    Chunfang, Qiu; GELAYE, Bizu; Denis, Marie; Tadesse, Mahlet G.; Enquobahrie, Daniel A.; Ananth, Cande V.; Pacora, Percy N; Salazar, Manuel; Sanchez, Sixto E.; Williams, Michelle A

    2016-01-01

    The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to e...

  11. CLOCK gene variants associate with sleep duration in two independent populations.

    Science.gov (United States)

    Allebrandt, Karla V; Teder-Laving, Maris; Akyol, Mahmut; Pichler, Irene; Müller-Myhsok, Bertram; Pramstaller, Peter; Merrow, Martha; Meitinger, Thomas; Metspalu, Andreas; Roenneberg, Till

    2010-06-01

    Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. Sleep duration was assessed in Central Europe, Estonia, and South Tyrol (n approximately 77,000) with the Munich ChronoType Questionnaire. It showed a Gaussian distribution in all investigated populations after averaging over a standard workweek and normalization according to age and gender. A follow-up, two-stage design, linkage disequilibrium-based association study was conducted with subjects from South Tyrol (discovery sample; n = 283) and with short ( 8.5 hours) sleepers from Estonia (confirmation sample; n = 1011). One hundred ninety-four single nucleotide polymorphism markers covering 19 candidate clock genes were genotyped in the discovery sample, and two of the best association signals (analyzed by a linear regression model) were investigated in the confirmation sample. Single and multi-marker associations were found within a CLOCK gene intronic region (rs12649507 and rs11932595). In a meta-analysis between South Tyrol and Estonia association signals, rs12649507 (p = .0087) remained significant. Significance persisted only for the multiple-marker association signal of the rs12649507/rs11932595 haplotype GGAA with long sleep (p = .0015). We report an association between variants of the human CLOCK gene and sleep duration in two independent populations. This adds another putative function for CLOCK besides its possible involvement in circadian timing, depression, obesity, and personality. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Monitoring cell-autonomous circadian clock rhythms of gene expression using luciferase bioluminescence reporters.

    Science.gov (United States)

    Ramanathan, Chidambaram; Khan, Sanjoy K; Kathale, Nimish D; Xu, Haiyan; Liu, Andrew C

    2012-09-27

    In mammals, many aspects of behavior and physiology such as sleep-wake cycles and liver metabolism are regulated by endogenous circadian clocks (reviewed). The circadian time-keeping system is a hierarchical multi-oscillator network, with the central clock located in the suprachiasmatic nucleus (SCN) synchronizing and coordinating extra-SCN and peripheral clocks elsewhere. Individual cells are the functional units for generation and maintenance of circadian rhythms, and these oscillators of different tissue types in the organism share a remarkably similar biochemical negative feedback mechanism. However, due to interactions at the neuronal network level in the SCN and through rhythmic, systemic cues at the organismal level, circadian rhythms at the organismal level are not necessarily cell-autonomous. Compared to traditional studies of locomotor activity in vivo and SCN explants ex vivo, cell-based in vitro assays allow for discovery of cell-autonomous circadian defects. Strategically, cell-based models are more experimentally tractable for phenotypic characterization and rapid discovery of basic clock mechanisms. Because circadian rhythms are dynamic, longitudinal measurements with high temporal resolution are needed to assess clock function. In recent years, real-time bioluminescence recording using firefly luciferase as a reporter has become a common technique for studying circadian rhythms in mammals, as it allows for examination of the persistence and dynamics of molecular rhythms. To monitor cell-autonomous circadian rhythms of gene expression, luciferase reporters can be introduced into cells via transient transfection or stable transduction. Here we describe a stable transduction protocol using lentivirus-mediated gene delivery. The lentiviral vector system is superior to traditional methods such as transient transfection and germline transmission because of its efficiency and versatility: it permits efficient delivery and stable integration into the host

  13. Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans.

    Science.gov (United States)

    Ackermann, Katrin; Plomp, Rosina; Lao, Oscar; Middleton, Benita; Revell, Victoria L; Skene, Debra J; Kayser, Manfred

    2013-08-01

    This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean±SD: 23±5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.

  14. Dissecting Daily and Circadian Expression Rhythms of Clock-Controlled Genes in Human Blood.

    Science.gov (United States)

    Lech, Karolina; Ackermann, Katrin; Revell, Victoria L; Lao, Oscar; Skene, Debra J; Kayser, Manfred

    2016-02-01

    The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings. © 2015 The Author(s).

  15. Genetic variation of clock genes and cancer risk: a field synopsis and meta-analysis.

    Science.gov (United States)

    Benna, Clara; Helfrich-Förster, Charlotte; Rajendran, Senthilkumar; Monticelli, Halenya; Pilati, Pierluigi; Nitti, Donato; Mocellin, Simone

    2017-04-04

    The number of studies on the association between clock genes' polymorphisms and cancer susceptibility has increased over the last years but the results are often conflicting and no comprehensive overview and quantitative summary of the evidence in this field is available. Literature search identified 27 eligible studies comprising 96756 subjects (cases: 38231) and investigating 687 polymorphisms involving 14 clock genes. Overall, 1025 primary and subgroup meta-analyses on 366 gene variants were performed. Study distribution by tumor was as follows: breast cancer (n=15), prostate cancer (n=3), pancreatic cancer (n=2), non-Hodgkin's lymphoma (n=2), glioma (n=1), chronic lymphocytic leukemia (n=1), colorectal cancer (n=1), non-small cell lung cancer (n=1) and ovarian cancer (n=1).We identified 10 single nucleotide polymorphisms (SNPs) significantly associated with cancer risk: NPAS2 rs10165970 (mixed and breast cancer shiftworkers), rs895520 (mixed), rs17024869 (breast) and rs7581886 (breast); CLOCK rs3749474 (breast) and rs11943456 (breast); RORA rs7164773 (breast and breast cancer postmenopausal), rs10519097 (breast); RORB rs7867494 (breast cancer postmenopausal), PER3 rs1012477 (breast cancer subgroups) and assessed the level of quality evidence to be intermediate. We also identified polymorphisms with lower quality statistically significant associations (n=30). Our work supports the hypothesis that genetic variation of clock genes might affect cancer risk. These findings also highlight the need for more efforts in this research field in order to fully establish the contribution of clock gene variants to the risk of developing cancer. We conducted a systematic review and meta-analysis of the evidence on the association between clock genes' germline variants and the risk of developing cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate

  16. Differential expression of circadian clock genes in two strains of beetles reveals candidates related to photoperiodic induction of summer diapause.

    Science.gov (United States)

    Zhu, Li; Liu, Wen; Tan, Qian-Qian; Lei, Chao-Liang; Wang, Xiao-Ping

    2017-03-01

    Diapause (also known as dormancy) is a state of arrested development induced by photoperiod or temperature that allows insects to survive adverse environmental conditions. By regulating diapause induction, the circadian clock is involved in short-day-induced winter diapause but whether this is also the case in long-day (LD)-induced summer diapause remains unknown. The cabbage beetle Colaphellus bowringi could enter summer diapause under LD conditions. However, a non-photoperiodic-diapause (NPD) strain of this species, which was developed in our laboratory by artificial selection, could not enter diapause under LD photoperiod. Therefore, we identified circadian clock genes in this species and measured differences in their expression between a high diapause (HD) strain and the NPD strain to investigate the potential relationship between circadian clock genes and summer diapause induction in C. bowringi. We successfully cloned eight circadian clock genes and obtained intact ORFs of four; cryptochrome2, double-time, shaggy and vrille. Phylogenetic trees and sequence alignment analyses indicated that these circadian clock genes were conserved across insect taxa. The quantitative real-time PCR indicated that clock, cycle, period, timeless, cryptochrome2, and vrille were differentially expressed between HD and NPD strains reared under LD photoperiod during the diapause induction phase. These findings suggest the potential relationship between circadian clock genes and LD-regulated summer diapause induction in C. bowringi. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure.

    Science.gov (United States)

    Drägert, Katja; Bhattacharya, Indranil; Pellegrini, Giovanni; Seebeck, Petra; Azzi, Abdelhalim; Brown, Steven A; Georgiopoulou, Stavroula; Held, Ulrike; Blyszczuk, Przemyslaw; Arras, Margarete; Humar, Rok; Hall, Michael N; Battegay, Edouard; Haas, Elvira

    2015-08-01

    The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (Rictor(aP2KO)) mice generated using adipocyte protein-2 gene promoter-driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in Rictor(aP2KO) mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of Rictor(aP2KO) mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity. © 2015 American Heart Association, Inc.

  18. Rhythmic expression of circadian clock genes in the preovulatory ovarian follicles of the laying hen.

    Directory of Open Access Journals (Sweden)

    Zhichao Zhang

    Full Text Available The circadian clock is reported to play a role in the ovaries in a variety of vertebrate species, including the domestic hen. However, the ovary is an organ that changes daily, and the laying hen maintains a strict follicular hierarchy. The aim of this study was to examine the spatial-temporal expression of several known canonical clock genes in the granulosa and theca layers of six hierarchy follicles. We demonstrated that the granulosa cells (GCs of the F1-F3 follicles harbored intrinsic oscillatory mechanisms in vivo. In addition, cultured granulosa cells (GCs from F1 follicles exposed to luteinizing hormone (LH synchronization displayed Per2 mRNA oscillations, whereas, the less mature GCs (F5 plus F6 displayed no circadian change in Per2 mRNA levels. Cultures containing follicle-stimulating hormone (FSH combined with LH expressed levels of Per2 mRNA that were 2.5-fold higher than those in cultures with LH or FSH alone. These results show that there is spatial specificity in the localization of clock cells in hen preovulatory follicles. In addition, our results support the hypothesis that gonadotropins provide a cue for the development of the functional cellular clock in immature GCs.

  19. Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature.

    Science.gov (United States)

    Riedel, Casper Schwartz; Georg, Birgitte; Jørgensen, Henrik L; Hannibal, Jens; Fahrenkrug, Jan

    2018-01-01

    Early growth response transcription factor 1 (EGR1) is expressed in the suprachiasmatic nucleus (SCN) after light stimulation. We used EGR1-deficient mice to address the role of EGR1 in the clock function and light-induced resetting of the clock. The diurnal rhythms of expression of the clock genes BMAL1 and PER1 in the SCN were evaluated by semi-quantitative in situ hybridization. We found no difference in the expression of PER1 mRNA between wildtype and EGR1-deficient mice; however, the daily rhythm of BMAL1 mRNA was completely abolished in the EGR1-deficient mice. In addition, we evaluated the circadian running wheel activity, telemetric locomotor activity, and core body temperature of the mice. Loss of EGR1 neither altered light-induced phase shifts at subjective night nor affected negative masking. Overall, circadian light entrainment was found in EGR1-deficient mice but they displayed a reduced locomotor activity and an altered temperature regulation compared to wild type mice. When placed in running wheels, a subpopulation of EGR1-deficient mice displayed a more disrupted activity rhythm with no measurable endogenous period length (tau). In conclusion, the present study provides the first evidence that the circadian clock in the SCN is disturbed in mice deficient of EGR1.

  20. Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans.

    OpenAIRE

    Ackermann, K; Plomp, R; Lao, O; Middleton, B; Revell, VL; Skene, DJ; Kayser, M

    2013-01-01

    This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean ± SD: 23 ± 5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g...

  1. Circadian clock genes: effects on dopamine, reward and addiction.

    Science.gov (United States)

    Parekh, Puja K; Ozburn, Angela R; McClung, Colleen A

    2015-06-01

    Addiction is a widespread public health issue with social and economic ramifications. Substance abuse disorders are often accompanied by disruptions in circadian rhythms including sleep/wake cycles, which can exacerbate symptoms of addiction and dependence. Additionally, genetic disturbance of circadian molecular mechanisms can predispose some individuals to substance abuse disorders. In this review, we will discuss how circadian genes can regulate midbrain dopaminergic activity and subsequently, drug intake and reward. We will also suggest future directions for research on circadian genes and drugs of abuse. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work.

    Science.gov (United States)

    James, Francine O; Cermakian, Nicolas; Boivin, Diane B

    2007-11-01

    The synchronization of peripheral circadian oscillators in humans living on atypical sleep/wake schedules is largely unknown. In this night shift work simulation, we evaluate clock gene expression in peripheral blood mononuclear cells (PBMCs) relative to reliable markers of the central circadian pacemaker. Participants were placed on a 10-hr delayed sleep/wake schedule simulating nighttime work followed by a daytime sleep episode. Baseline, intermediate and final circadian evaluations were performed in the temporal isolation laboratory. Five healthy candidates, 18-30 years. Polychromatic white light of (mean +/-SEM) 6,036 +/-326 lux (approximately 17,685 +/-955 W/m2) during night shifts; dim light exposure after each night shift; an 8-hr sleep/darkness episode beginning 2 hrs after the end of each night shift. Melatonin and cortisol in plasma; clock genes HPER1, HPER2 and HBMAL1 RNA in PBMCs. Following 9 days on the night schedule, hormonal rhythms were adapted to the shifted schedule. HPER1 and HPER2 expression in PBMCs displayed significant circadian rhythmicity, which was in a conventional relationship with the shifted sleep/wake schedule. Changes in the pattern of clock gene expression were apparent as of 3 days on the shifted sleep/wake schedule. This preliminary study is the first documentation of the effects of a shifted sleep/wake schedule on the circadian expression of both peripheral circadian oscillators in PBMCs and centrally-driven hormonal rhythms. In light of evidence associating clock gene expression with tissue function, the study of peripheral circadian oscillators has important implications for understanding medical disorders affecting night shift workers.

  3. Circadian clock gene Per2 is not necessary for the photoperiodic response in mice.

    Directory of Open Access Journals (Sweden)

    Keisuke Ikegami

    Full Text Available In mammals, light information received by the eyes is transmitted to the pineal gland via the circadian pacemaker, i.e., the suprachiasmatic nucleus (SCN. Melatonin secreted by the pineal gland at night decodes night length and regulates seasonal physiology and behavior. Melatonin regulates the expression of the β-subunit of thyroid-stimulating hormone (TSH; Tshb in the pars tuberalis (PT of the pituitary gland. Long day-induced PT TSH acts on ependymal cells in the mediobasal hypothalamus to induce the expression of type 2 deiodinase (Dio2 and reduce type 3 deiodinase (Dio3 that are thyroid hormone-activating and hormone-inactivating enzymes, respectively. The long day-activated thyroid hormone T3 regulates seasonal gonadotropin-releasing hormone secretion. It is well established that the circadian clock is involved in the regulation of photoperiodism. However, the involvement of the circadian clock gene in photoperiodism regulation remains unclear. Although mice are generally considered non-seasonal animals, it was recently demonstrated that mice are a good model for the study of photoperiodism. In the present study, therefore, we examined the effect of changing day length in Per2 deletion mutant mice that show shorter wheel-running rhythms under constant darkness followed by arhythmicity. Although the amplitude of clock gene (Per1, Cry1 expression was greatly attenuated in the SCN, the expression profile of arylalkylamine N-acetyltransferase, a rate-limiting melatonin synthesis enzyme, was unaffected in the pineal gland, and robust photoperiodic responses of the Tshb, Dio2, and Dio3 genes were observed. These results suggested that the Per2 clock gene is not necessary for the photoperiodic response in mice.

  4. Circadian clock-controlled genes isolated from Neurospora crassa are late night- to early morning-specific

    Science.gov (United States)

    Bell-Pedersen, Deborah; Shinohara, Mari L.; Loros, Jennifer J.; Dunlap, Jay C.

    1996-01-01

    An endogenous circadian biological clock controls the temporal aspects of life in most organisms, including rhythmic control of genes involved in clock output pathways. In the fungus Neurospora crassa, one pathway known to be under control of the clock is asexual spore (conidia) development. To understand more fully the processes that are regulated by the N. crassa circadian clock, systematic screens were carried out for genes that oscillate at the transcriptional level. Time-of-day-specific cDNA libraries were generated and used in differential screens to identify six new clock-controlled genes (ccgs). Transcripts specific for each of the ccgs preferentially accumulate during the late night to early morning, although they vary with respect to steady-state mRNA levels and amplitude of the rhythm. Sequencing of the ends of the new ccg cDNAs revealed that ccg-12 is identical to N. crassa cmt encoding copper metallothionein, providing the suggestion that not all clock-regulated genes in N. crassa are specifically involved in the development of conidia. This was supported by finding that half of the new ccgs, including cmt(ccg-12), are not transcriptionally induced by developmental or light signals. These data suggest a major role for the clock in the regulation of biological processes distinct from development. PMID:8917550

  5. Differential effect of fructose on fat metabolism and clock gene expression in hepatocytes vs. myotubes.

    Science.gov (United States)

    Chapnik, Nava; Rozenblit-Susan, Sigal; Genzer, Yoni; Froy, Oren

    2016-08-01

    In the liver, fructose bypasses the main rate-limiting step of glycolysis at the level of phosphofructokinase, allowing it to act as an unregulated substrate for de novo lipogenesis. It has been reported that consumption of large amounts of fructose increases de novo lipogenesis in the liver. However, the effect of fructose on ectopic deposition of muscle fat has been under dispute. Our aim was to study the effect of fructose on levels of genes and proteins involved in fatty acid oxidation and synthesis in hepatocytes vs. muscle cells. In addition, as fat accumulation leads to disruption of daily rhythms, we tested the effect of fructose treatment on clock gene expression. AML-12 hepatocytes and C2C12 myotubes were treated with fructose or glucose for 2 consecutive 24-h cycles and harvested every 6h. In contrast to glucose, fructose disrupted clock gene rhythms in hepatocytes, but in myotubes, it led to more robust rhythms. Fructose led to low levels of phosphorylated AMP-activated protein kinase (pAMPK) and high levels of LIPIN1 in hepatocytes compared with glucose. In contrast, fructose led to high pAMPK and low LIPIN1 and microsomal triacylglycerol transfer protein (MTTP) levels in myotubes compared with glucose. Analysis of fat content revealed that fructose led to less fat accumulation in myotubes compared to hepatocytes. In summary, fructose shifts metabolism towards fatty acid synthesis and clock disruption in hepatocytes, but not in myotubes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Modeling the zebrafish segmentation clock's gene regulatory network constrained by expression data suggests evolutionary transitions between oscillating and nonoscillating transcription.

    Science.gov (United States)

    Schwendinger-Schreck, Jamie; Kang, Yuan; Holley, Scott A

    2014-06-01

    During segmentation of vertebrate embryos, somites form in accordance with a periodic pattern established by the segmentation clock. In the zebrafish (Danio rerio), the segmentation clock includes six hairy/enhancer of split-related (her/hes) genes, five of which oscillate due to negative autofeedback. The nonoscillating gene hes6 forms the hub of a network of 10 Her/Hes protein dimers, which includes 7 DNA-binding dimers and 4 weak or non-DNA-binding dimers. The balance of dimer species is critical for segmentation clock function, and loss-of-function studies suggest that the her genes have both unique and redundant functions within the clock. However, the precise regulatory interactions underlying the negative feedback loop are unknown. Here, we combine quantitative experimental data, in silico modeling, and a global optimization algorithm to identify a gene regulatory network (GRN) designed to fit measured transcriptional responses to gene knockdown. Surprisingly, we find that hes6, the clock gene that does not oscillate, responds to negative feedback. Consistent with prior in silico analyses, we find that variation in transcription, translation, and degradation rates can mediate the gain and loss of oscillatory behavior for genes regulated by negative feedback. Extending our study, we found that transcription of the nonoscillating Fgf pathway gene sef responds to her/hes perturbation similarly to oscillating her genes. These observations suggest a more extensive underlying regulatory similarity between the zebrafish segmentation clock and the mouse and chick segmentation clocks, which exhibit oscillations of her/hes genes as well as numerous other Notch, Fgf, and Wnt pathway genes. Copyright © 2014 by the Genetics Society of America.

  7. Functional circadian clock genes are essential for the overwintering diapause of the Northern house mosquito, Culex pipiens.

    Science.gov (United States)

    Meuti, Megan E; Stone, Mary; Ikeno, Tomoko; Denlinger, David L

    2015-02-01

    The short day lengths of late summer are used to program the overwintering adult diapause (dormancy) of the Northern house mosquito, Culex pipiens. Here, we investigated the role of clock genes in initiating this diapause and asked whether the circadian cycling of clock gene expression persists during diapause. We provide evidence that the major circadian clock genes continue to cycle throughout diapause and after diapause has been terminated. RNA interference (RNAi) was used to knock down the core circadian clock genes and to then assess the impact of the various clock genes on the ability of females to enter diapause. RNAi directed against negative circadian regulators (period, timeless and cryptochrome2) caused females that were reared under diapause-inducing, short day conditions to avert diapause. In contrast, knocking down the circadian-associated gene pigment dispersing factor caused females that were reared under diapause-averting, long day conditions to enter a diapause-like state. Our results implicate the circadian clock in the initiation of diapause in C. pipiens. © 2015. Published by The Company of Biologists Ltd.

  8. Circadian expression of clock genes in purified hematopoietic stem cells is developmentally regulated in mouse bone marrow.

    Science.gov (United States)

    Tsinkalovsky, Oleg; Filipski, Elisabeth; Rosenlund, Benedikte; Sothern, Robert B; Eiken, Hans Geir; Wu, Ming Wei; Claustrat, Bruno; Bayer, Jan; Lévi, Francis; Laerum, Ole Didrik

    2006-09-01

    Clock genes are known to mediate circadian rhythms in the central nervous system and peripheral organs. Although they are expressed in mouse hematopoietic progenitor and stem cells, it is unknown if they are related to circadian rhythms in these cells. We therefore investigated the 24-hour patterns in the activity of several clock genes in the bone marrow (BM) side population (SP) primitive stem cells, and compared these 24-hour patterns to clock gene variations in the whole BM and liver. Cells were obtained from 84 B6D2F(1) mice in three replicate experiments on the second day after release into constant darkness from a standardizing light-dark schedule. mRNA expression of clock genes was measured with quantitative reverse transcriptase polymerase chain reaction. mPer2 displayed circadian rhythms in SP cells, whole BM, and liver cells. mPer1 and mRev-erb alpha showed a circadian rhythm in whole BM and liver, but not SP cells. mBmal1 was not expressed rhythmically in SP cells, nor in the whole BM, contrary to rhythms observed in the liver. With the exception of mPer2, most clock genes studied in primitive hematopoietic SP stem cells were not oscillating in a fully organized circadian manner, which is similar to immature cells in rapidly proliferating organs, such as the testis and thymus. These findings indicate that circadian clock gene expression variations in BM are developmentally regulated.

  9. Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

    Directory of Open Access Journals (Sweden)

    Wen-Kai Li

    2017-05-01

    Full Text Available Aim Atorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice. Methods Adult male mice were given atorvastatin (10, 30, and 100 mg/kg, po daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined. Results Repeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression. Conclusion Repeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

  10. Clock gene polymorphism, migratory behaviour and geographic distribution: a comparative study of trans-Saharan migratory birds.

    Science.gov (United States)

    Bazzi, Gaia; Cecere, Jacopo G; Caprioli, Manuela; Gatti, Emanuele; Gianfranceschi, Luca; Podofillini, Stefano; Possenti, Cristina D; Ambrosini, Roberto; Saino, Nicola; Spina, Fernando; Rubolini, Diego

    2016-12-01

    Migratory behaviour is controlled by endogenous circannual rhythms that are synchronized by external cues, such as photoperiod. Investigations on the genetic basis of circannual rhythmicity in vertebrates have highlighted that variation at candidate 'circadian clock' genes may play a major role in regulating photoperiodic responses and timing of life cycle events, such as reproduction and migration. In this comparative study of 23 trans-Saharan migratory bird species, we investigated the relationships between species-level genetic variation at two candidate genes, Clock and Adcyap1, and species' traits related to migration and geographic distribution, including timing of spring migration across the Mediterranean Sea, migration distance and breeding latitude. Consistently with previous evidence showing latitudinal clines in 'circadian clock' genotype frequencies, Clock allele size increased with breeding latitude across species. However, early- and late-migrating species had similar Clock allele size. Species migrating over longer distances, showing delayed spring migration and smaller phenotypic variance in spring migration timing, had significantly reduced Clock (but not Adcyap1) gene diversity. Phylogenetic confirmatory path analysis suggested that migration date and distance were the most important variables directly affecting Clock gene diversity. Hence, our study supports the hypothesis that Clock allele size increases poleward as a consequence of adaptation to the photoperiodic regime of the breeding areas. Moreover, we show that long-distance migration is associated with lower Clock diversity, coherently with strong stabilizing selection acting on timing of life cycle events in long-distance migratory species, likely resulting from the time constraints imposed by late spring migration. © 2016 John Wiley & Sons Ltd.

  11. Circadian Clock Genes Modulate Human Bone Marrow Mesenchymal Stem Cell Differentiation, Migration and Cell Cycle.

    Directory of Open Access Journals (Sweden)

    Helene Boucher

    Full Text Available Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties.

  12. Circadian Clock Genes Modulate Human Bone Marrow Mesenchymal Stem Cell Differentiation, Migration and Cell Cycle.

    Science.gov (United States)

    Boucher, Helene; Vanneaux, Valerie; Domet, Thomas; Parouchev, Alexandre; Larghero, Jerome

    2016-01-01

    Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties.

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

    Science.gov (United States)

    Nelson, D C; Lasswell, J; Rogg, L E; Cohen, M A; Bartel, B

    2000-04-28

    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.

  14. Are clock genes involved in altered circadian rhythms during space flight?

    Science.gov (United States)

    Egli, Marcel; Betram, Richard; Cogoli-Greuter, Marianne; Vadrucci, Sonia; Henggeler, Daniele

    2005-08-01

    Hormone secretion in mammals often displays circadian rhythms. These rhythms usually relay on internal "biological clocks", which adjusts to geophysical parameters like the light/dark cycle, temperature cycle, or gravity force, all functioning as time cues. In humans, synchronized external and internal rhythms are important for good performance. This study focuses on the effect of altered gravity on the rhythmic secretory pattern of prolactin (PRL), a hormone of the hypothalamic-pituitary system. Several studies have shown that space flight disturbs PRL secretion. Further, we will investigate the response of clock gene expression in the suprachiasmatic nucleus (SCN), the central circadian pacemaker implicated in the neural network for timed PRL secretion, under various gravitational fields. The results of this study will demonstrate the vulnerability of mammalian endocrine systems to changes in gravity and may help in the design of counter actions for stabilizing circadian rhythms during long-term manned space flight.

  15. Placental genetic variations in circadian clock-related genes increase the risk of placental abruption.

    Science.gov (United States)

    Qiu, Chunfang; Gelaye, Bizu; Denis, Marie; Tadesse, Mahlet G; Enquobahrie, Daniel A; Ananth, Cande V; Pacora, Percy N; Salazar, Manuel; Sanchez, Sixto E; Williams, Michelle A

    2016-01-01

    The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to estimate odds ratios (ORs). The combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score. We examined independent and joint associations of wGRS derived from placental and maternal genomes with PA. Seven SNPs in five genes (ARNTL2, CRY2, DEC1, PER3 and RORA), in the placental genome, were associated with PA risk. Each copy of the minor allele (G) of a SNP in the RORA gene (rs2899663) was associated with a 30% reduced odds of PA (95% CI 0.52-0.95). The odds of PA increased with increasing placental-wGRS (Ptrendcircadian clock-related genes are associated with PA risk; and the association persists after control of genetic variants in the maternal genome.

  16. Characterisation, analysis of expression and localisation of circadian clock genes from the perspective of photoperiodism in the aphid Acyrthosiphon pisum.

    Science.gov (United States)

    Barberà, Miquel; Collantes-Alegre, Jorge Mariano; Martínez-Torres, David

    2017-04-01

    Aphids are typical photoperiodic insects that switch from viviparous parthenogenetic reproduction typical of long day seasons to oviparous sexual reproduction triggered by the shortening of photoperiod in autumn yielding an overwintering egg in which an embryonic diapause takes place. While the involvement of the circadian clock genes in photoperiodism in mammals is well established, there is still some controversy on their participation in insects. The availability of the genome of the pea aphid Acyrthosiphon pisum places this species as an excellent model to investigate the involvement of the circadian system in the aphid seasonal response. In the present report, we have advanced in the characterisation of the circadian clock genes and showed that these genes display extensive alternative splicing. Moreover, the expression of circadian clock genes, analysed at different moments of the day, showed a robust cycling of central clock genes period and timeless. Furthermore, the rhythmic expression of these genes was shown to be rapidly dampened under DD (continuous darkness conditions), thus supporting the model of a seasonal response based on a heavily dampened circadian oscillator. Additionally, increased expression of some of the circadian clock genes under short-day conditions suggest their involvement in the induction of the aphid seasonal response. Finally, in situ localisation of transcripts of genes period and timeless in the aphid brain revealed the site of clock neurons for the first time in aphids. Two groups of clock cells were identified: the Dorsal Neurons (DN) and the Lateral Neurons (LN), both in the protocerebrum. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Circadian rhythm genes CLOCK and PER3 polymorphisms and morning gastric motility in humans.

    Directory of Open Access Journals (Sweden)

    Mitsue Yamaguchi

    Full Text Available Clock genes regulate circadian rhythm and are involved in various physiological processes, including digestion. We therefore investigated the association between the CLOCK 3111T/C single nucleotide polymorphism and the Period3 (PER3 variable-number tandem-repeat polymorphism (either 4 or 5 repeats 54 nt in length with morning gastric motility.Lifestyle questionnaires and anthropometric measurements were performed with 173 female volunteers (mean age, 19.4 years. Gastric motility, evaluated by electrogastrography (EGG, blood pressure, and heart rate levels were measured at 8:30 a.m. after an overnight fast. For gastric motility, the spectral powers (% normal power and dominant frequency (DF, peak of the power spectrum of the EGG were evaluated. The CLOCK and PER3 polymorphisms were determined by polymerase chain reaction (PCR restriction fragment length polymorphism analysis.Subjects with the CLOCK C allele (T/C or C/C genotypes: n = 59 showed a significantly lower DF (mean, 2.56 cpm than those with the T/T genotype (n = 114, 2.81 cpm, P < 0.05. Subjects with the longer PER3 allele (PER34/5 or PER35/5 genotypes: n = 65 also showed a significantly lower DF (2.55 cpm than those with the shorter PER34/4 genotype (n = 108, 2.83 cpm, P < 0.05. Furthermore, subjects with both the T/C or C/C and PER34/5 or PER35/5 genotypes showed a significantly lower DF (2.43 cpm, P < 0.05 than subjects with other combinations of the alleles (T/T and PER34/4 genotype, T/C or C/C and PER34/4 genotypes, and T/T and PER34/5 or PER35/5 genotypes.These results suggest that minor polymorphisms of the circadian rhythm genes CLOCK and PER3 may be associated with poor morning gastric motility, and may have a combinatorial effect. The present findings may offer a new viewpoint on the role of circadian rhythm genes on the peripheral circadian systems, including the time-keeping function of the gut.

  18. Circadian clock gene expression in brain regions of Alzheimer 's disease patients and control subjects.

    Science.gov (United States)

    Cermakian, Nicolas; Lamont, Elaine Waddington; Boudreau, Philippe; Boivin, Diane B

    2011-04-01

    Circadian oscillators have been observed throughout the rodent brain. In the human brain, rhythmic expression of clock genes has been reported only in the pineal gland, and little is known about their expression in other regions. The investigators sought to determine whether clock gene expression could be detected and whether it varies as a function of time of day in the bed nucleus of the stria terminalis (BNST) and cingulate cortex, areas known to be involved in decision making and motivated behaviors, as well as in the pineal gland, in the brains of Alzheimer's disease (AD) patients and aged controls. Relative expression levels of PERIOD1 (PER1 ), PERIOD2 (PER2), and Brain and muscle Arnt-like protein-1 (BMAL1) were detected by quantitative PCR in all 3 brain regions. A harmonic regression model revealed significant 24-h rhythms of PER1 in the BNST of AD subjects. A significant rhythm of PER2 was found in the cingulate cortex and BNST of control subjects and in all 3 regions of AD patients. In controls, BMAL1 did not show a diurnal rhythm in the cingulate cortex but significantly varied with time of death in the pineal and BNST and in all 3 regions for AD patients. Notable differences in the phase of clock gene rhythms and phase relationships between genes and regions were observed in the brains of AD compared to those of controls. These results indicate the presence of multiple circadian oscillators in the human brain and suggest altered synchronization among these oscillators in the brain of AD patients. © 2011 Sage Publications

  19. Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development

    NARCIS (Netherlands)

    Schachtschneider, Kyle M.; Liu, Yingkai; Rund, Laurie A.; Madsen, Ole; Johnson, Rodney W.; Groenen, Martien A.M.; Schook, Lawrence B.

    2016-01-01


    Background

    Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene

  20. The impact of nutrients on clock genes and metabolism: their role for the prevention and treatment of metabolic diseases

    OpenAIRE

    Castillo Figueroa, Ana Lucía

    2017-01-01

    [eng] A number of recent studies in animals and humans have linked energy regulation and the circadian clock at the molecular, physiological and behavioral levels, concluding that disruption of clock genes results in metabolic dysregulation. Obesity and type 2 diabetes are associated with disruption of circadian rhythms. Strategies to prevent disturbances in circadian rhythms are critical in order to find potential targets for new therapies development and treatment for metabolic diseases. ...

  1. The impact of nutrients on clock genes and metabolism: their role for the prevention and treatment of metabolic diseases

    OpenAIRE

    Castillo Figueroa, Ana Lucía

    2017-01-01

    A number of recent studies in animals and humans have linked energy regulation and the circadian clock at the molecular, physiological and behavioral levels, concluding that disruption of clock genes results in metabolic dysregulation. Obesity and type 2 diabetes are associated with disruption of circadian rhythms. Strategies to prevent disturbances in circadian rhythms are critical in order to find potential targets for new therapies development and treatment for metabolic diseases. Potentia...

  2. CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet.

    Science.gov (United States)

    Garaulet, M; Corbalán, M D; Madrid, J A; Morales, E; Baraza, J C; Lee, Y C; Ordovas, J M

    2010-03-01

    The success of obesity therapy is dependent on the genetic background of the patient. Circadian Locomotor Output Cycles Kaput (CLOCK), one of the transcription factors from the positive limb of the molecular clock, is involved in metabolic alterations. To investigate whether five candidate polymorphisms from CLOCK were associated with anthropometric, metabolic measures and weight loss in response to a behavioural weight reduction programme based on the Mediterranean diet. Five hundred overweight/obese subjects, aged 20-65 years, who attended outpatient clinics specializing in obesity, were studied. Anthropometric, biochemical and dietary intake variables were analysed. Effectiveness of the programme and weight loss progression during 28 weeks of treatment was assessed. Four of five CLOCK SNPs selected were significantly associated with obesity variables (PCLOCK was associated with obesity at baseline and also affected weight loss. Patients with the variant allele (G) lost significantly less weight i(P=0.008) compared with wild type. Repeated measures analysis showed that weight loss over time was significantly different between rs1801260 CLOCK variations (P=0.038). Carriers of the G allele displayed greater difficulty in losing weight than non-carriers. In this particular polymorphism, the frequency of short-time sleepers (CLOCK polymorphisms were also associated with significant differences in total plasma cholesterol at the completion of dietary treatment (PCLOCK gene polymorphisms and obesity. CLOCK rs1801260 SNP may predict the outcome of body weight reduction strategies based on low-energy diets.

  3. Circadian CLOCK gene polymorphisms in relation to sleep patterns and obesity in African Americans: findings from the Jackson heart study.

    Science.gov (United States)

    Riestra, Pia; Gebreab, Samson Y; Xu, Ruihua; Khan, Rumana J; Gaye, Amadou; Correa, Adolfo; Min, Nancy; Sims, Mario; Davis, Sharon K

    2017-06-23

    Circadian rhythms regulate key biological processes and the dysregulation of the intrinsic clock mechanism affects sleep patterns and obesity onset. The CLOCK (circadian locomotor output cycles protein kaput) gene encodes a core transcription factor of the molecular circadian clock influencing diverse metabolic pathways, including glucose and lipid homeostasis. The primary objective of this study was to evaluate the associations between CLOCK single nucleotide polymorphisms (SNPs) and body mass index (BMI). We also evaluated the association of SNPs with BMI related factors such as sleep duration and quality, adiponectin and leptin, in 2962 participants (1116 men and 1810 women) from the Jackson Heart Study. Genotype data for the selected 23 CLOCK gene SNPS was obtained by imputation with IMPUTE2 software and reference phase data from the 1000 genome project. Genetic analyses were conducted with PLINK RESULTS: We found a significant association between the CLOCK SNP rs2070062 and sleep duration, participants carriers of the T allele showed significantly shorter sleep duration compared to non-carriers after the adjustment for individual proportions of European ancestry (PEA), socio economic status (SES), body mass index (BMI), alcohol consumption and smoking status that reach the significance threshold after multiple testing correction. In addition, we found nominal associations of the CLOCK SNP rs6853192 with longer sleep duration and the rs6820823, rs3792603 and rs11726609 with BMI. However, these associations did not reach the significance threshold after correction for multiple testing. In this work, CLOCK gene variants were associated with sleep duration and BMI suggesting that the effects of these polymorphisms on circadian rhythmicity may affect sleep duration and body weight regulation in Africans Americans.

  4. Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver.

    Science.gov (United States)

    Wang, Danfeng; Chen, Siyu; Liu, Mei; Liu, Chang

    2015-06-01

    Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.

  5. The in vitro maintenance of clock genes expression within the rat pineal gland under standard and norepinephrine-synchronized stimulation.

    Science.gov (United States)

    Andrade-Silva, Jéssica; Cipolla-Neto, José; Peliciari-Garcia, Rodrigo A

    2014-01-01

    Although the norepinephrine (NE) synchronization protocol was proved to be an important procedure for further modulating in vitro pineal melatonin synthesis, the maintenance of clock genes under the same conditions remained to be investigated. The aim of this study was to investigate the maintenance of the clock genes expression in pineal gland cultures under standard and NE-synchronized stimulation. The glands were separated into three experimental groups: Control, Standard (acute NE-stimulation), and NE-synchronized. The expression of Bmal1, Per2, Cry2, Rev-erbα, the clock controlled gene Dbp and Arylalkylamine-N-acetyltransferase were investigated, as well as melatonin content. No oscillations were observed in the expression of the investigated genes from the control group. Under Standard NE stimulation, the clock genes did not exhibit a rhythmic pattern of expression. However, in the NE-synchronized condition, a rhythmic expression pattern was observed in all cases. An enhancement in pineal gland responsiveness to NE stimulation, reflected in an advanced synthesis of melatonin was also observed. Our results reinforce our previous hypothesis that NE synchronization of pineal gland culture mimics the natural rhythmic release of NE in the gland, increasing melatonin synthesis and keeping the pineal circadian clock synchronized, ensuring the fine adjustments that are relied in the clockwork machinery. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  6. Clock genes and their genomic distributions in three species of salmonid fishes: Associations with genes regulating sexual maturation and cell cycling

    Directory of Open Access Journals (Sweden)

    Ferguson Moira M

    2010-07-01

    Full Text Available Abstract Background Clock family genes encode transcription factors that regulate clock-controlled genes and thus regulate many physiological mechanisms/processes in a circadian fashion. Clock1 duplicates and copies of Clock3 and NPAS2-like genes were partially characterized (genomic sequencing and mapped using family-based indels/SNPs in rainbow trout (RT(Oncorhynchus mykiss, Arctic charr (AC(Salvelinus alpinus, and Atlantic salmon (AS(Salmo salar mapping panels. Results Clock1 duplicates mapped to linkage groups RT-8/-24, AC-16/-13 and AS-2/-18. Clock3/NPAS2-like genes mapped to RT-9/-20, AC-20/-43, and AS-5. Most of these linkage group regions containing the Clock gene duplicates were derived from the most recent 4R whole genome duplication event specific to the salmonids. These linkage groups contain quantitative trait loci (QTL for life history and growth traits (i.e., reproduction and cell cycling. Comparative synteny analyses with other model teleost species reveal a high degree of conservation for genes in these chromosomal regions suggesting that functionally related or co-regulated genes are clustered in syntenic blocks. For example, anti-müllerian hormone (amh, regulating sexual maturation, and ornithine decarboxylase antizymes (oaz1 and oaz2, regulating cell cycling, are contained within these syntenic blocks. Conclusions Synteny analyses indicate that regions homologous to major life-history QTL regions in salmonids contain many candidate genes that are likely to influence reproduction and cell cycling. The order of these genes is highly conserved across the vertebrate species examined, and as such, these genes may make up a functional cluster of genes that are likely co-regulated. CLOCK, as a transcription factor, is found within this block and therefore has the potential to cis-regulate the processes influenced by these genes. Additionally, clock-controlled genes (CCGs are located in other life-history QTL regions within

  7. The possible interplay of synaptic and clock genes in autism spectrum disorders.

    Science.gov (United States)

    Bourgeron, T

    2007-01-01

    Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by deficits in social communication, absence or delay in language, and stereotyped and repetitive behaviors. Results from genetic studies reveal one pathway associated with susceptibility to ASD, which includes the synaptic cell adhesion molecules NLGN3, NLGN4, and NRXN1 and a postsynaptic scaffolding protein SHANK3. This protein complex is crucial for the maintenance of functional synapses as well as the adequate balance between neuronal excitation and inhibition. Among the factors that could modulate this pathway are the genes controlling circadian rhythms. Indeed, sleep disorders and low melatonin levels are frequently observed in ASD. In this context, an alteration of both this synaptic pathway and the setting of the clock would greatly increase the risk of ASD. In this chapter, I report genetic and neurobiological findings that highlight the major role of synaptic and clock genes in the susceptibility to ASD. On the basis of these lines of evidence, I propose that future studies of ASD should investigate the circadian modulation of synaptic function as a focus for functional analyses and the development of new therapeutic strategies.

  8. The role of circadian clock genes in the photoperiodic timer of the linden bug Pyrrhocoris apterus during the nymphal stage

    Czech Academy of Sciences Publication Activity Database

    Kotwica-Rolinska, Joanna; Pivarčiová, Lenka; Vaněčková, Hana; Doležel, David

    2017-01-01

    Roč. 42, č. 3 (2017), s. 266-273 ISSN 0307-6962 R&D Projects: GA ČR GA15-23681S; GA MŠk(CZ) EE2.3.30.0032 EU Projects: European Commission(XE) 316790 - INsecTIME Institutional support: RVO:60077344 Keywords : activity of nympha * circadian clock gene * Clock gene Subject RIV: ED - Physiology OBOR OECD: Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology Impact factor: 1.364, year: 2016 http://onlinelibrary.wiley.com/doi/10.1111/phen.12197/abstract

  9. Defining the robust behaviour of the plant clock gene circuit with absolute RNA timeseries and open infrastructure.

    Science.gov (United States)

    Flis, Anna; Fernández, Aurora Piñas; Zielinski, Tomasz; Mengin, Virginie; Sulpice, Ronan; Stratford, Kevin; Hume, Alastair; Pokhilko, Alexandra; Southern, Megan M; Seaton, Daniel D; McWatters, Harriet G; Stitt, Mark; Halliday, Karen J; Millar, Andrew J

    2015-10-01

    Our understanding of the complex, transcriptional feedback loops in the circadian clock mechanism has depended upon quantitative, timeseries data from disparate sources. We measure clock gene RNA profiles in Arabidopsis thaliana seedlings, grown with or without exogenous sucrose, or in soil-grown plants and in wild-type and mutant backgrounds. The RNA profiles were strikingly robust across the experimental conditions, so current mathematical models are likely to be broadly applicable in leaf tissue. In addition to providing reference data, unexpected behaviours included co-expression of PRR9 and ELF4, and regulation of PRR5 by GI. Absolute RNA quantification revealed low levels of PRR9 transcripts (peak approx. 50 copies cell(-1)) compared with other clock genes, and threefold higher levels of LHY RNA (more than 1500 copies cell(-1)) than of its close relative CCA1. The data are disseminated from BioDare, an online repository for focused timeseries data, which is expected to benefit mechanistic modelling. One data subset successfully constrained clock gene expression in a complex model, using publicly available software on parallel computers, without expert tuning or programming. We outline the empirical and mathematical justification for data aggregation in understanding highly interconnected, dynamic networks such as the clock, and the observed design constraints on the resources required to make this approach widely accessible. © 2015 The Authors.

  10. Interaction of growth hormone overexpression and nutritional status on pituitary gland clock gene expression in coho salmon, Oncorhynchus kisutch.

    Science.gov (United States)

    Kim, Jin-Hyoung; White, Samantha L; Devlin, Robert H

    2015-02-01

    Clock genes are involved in generating a circadian rhythm that is integrated with the metabolic state of an organism and information from the environment. Growth hormone (GH) transgenic coho salmon, Oncorhynchus kisutch, show a large increase in growth rate, but also attenuated seasonal growth modulations, modified timing of physiological transformations (e.g. smoltification) and disruptions in pituitary gene expression compared with wild-type salmon. In several fishes, circadian rhythm gene expression has been found to oscillate in the suprachiasmatic nucleus of the hypothalamus, as well as in multiple peripheral tissues, but this control system has not been examined in the pituitary gland nor has the effect of transgenic growth modification been examined. Thus, the daily expression of 10 core clock genes has been examined in pituitary glands of GH transgenic (T) and wild-type coho salmon (NT) entrained on a regular photocycle (12L: 12D) and provided either with scheduled feeding or had food withheld for 60 h. Most clock genes in both genotypes showed oscillating patterns of mRNA levels with light and dark cycles. However, T showed different amplitudes and patterns of expression compared with wild salmon, both in fed and starved conditions. The results from this study indicate that constitutive expression of GH is associated with changes in clock gene regulation, which may play a role in the disrupted behavioural and physiological phenotypes observed in growth-modified transgenic strains.

  11. Barley (Hordeum vulgare) circadian clock genes can respond rapidly to temperature in an EARLY FLOWERING 3-dependent manner.

    Science.gov (United States)

    Ford, Brett; Deng, Weiwei; Clausen, Jenni; Oliver, Sandra; Boden, Scott; Hemming, Megan; Trevaskis, Ben

    2016-10-01

    An increase in global temperatures will impact future crop yields. In the cereal crops wheat and barley, high temperatures accelerate reproductive development, reducing the number of grains per plant and final grain yield. Despite this relationship between temperature and cereal yield, it is not clear what genes and molecular pathways mediate the developmental response to increased temperatures. The plant circadian clock can respond to changes in temperature and is important for photoperiod-dependent flowering, and so is a potential mechanism controlling temperature responses in cereal crops. This study examines the relationship between temperature, the circadian clock, and the expression of flowering-time genes in barley (Hordeum vulgare), a crop model for temperate cereals. Transcript levels of barley core circadian clock genes were assayed over a range of temperatures. Transcript levels of core clock genes CCA1, GI, PRR59, PRR73, PRR95, and LUX are increased at higher temperatures. CCA1 and PRR73 respond rapidly to a decrease in temperature whereas GI and PRR59 respond rapidly to an increase in temperature. The response of GI and the PRR genes to changes in temperature is lost in the elf3 mutant indicating that their response to temperature may be dependent on a functional ELF3 gene. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  12. Differential gene expression in dentate granule cells in mesial temporal lobe epilepsy with and without hippocampal sclerosis.

    Science.gov (United States)

    Griffin, Nicole G; Wang, Yu; Hulette, Christine M; Halvorsen, Matt; Cronin, Kenneth D; Walley, Nicole M; Haglund, Michael M; Radtke, Rodney A; Skene, J H Pate; Sinha, Saurabh R; Heinzen, Erin L

    2016-03-01

    Hippocampal sclerosis is the most common neuropathologic finding in cases of medically intractable mesial temporal lobe epilepsy. In this study, we analyzed the gene expression profiles of dentate granule cells of patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis to show that next-generation sequencing methods can produce interpretable genomic data from RNA collected from small homogenous cell populations, and to shed light on the transcriptional changes associated with hippocampal sclerosis. RNA was extracted, and complementary DNA (cDNA) was prepared and amplified from dentate granule cells that had been harvested by laser capture microdissection from surgically resected hippocampi from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis. Sequencing libraries were sequenced, and the resulting sequencing reads were aligned to the reference genome. Differential expression analysis was used to ascertain expression differences between patients with and without hippocampal sclerosis. Greater than 90% of the RNA-Seq reads aligned to the reference. There was high concordance between transcriptional profiles obtained for duplicate samples. Principal component analysis revealed that the presence or absence of hippocampal sclerosis was the main determinant of the variance within the data. Among the genes up-regulated in the hippocampal sclerosis samples, there was significant enrichment for genes involved in oxidative phosphorylation. By analyzing the gene expression profiles of dentate granule cells from surgically resected hippocampal specimens from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis, we have demonstrated the utility of next-generation sequencing methods for producing biologically relevant results from small populations of homogeneous cells, and have provided insight on the transcriptional changes associated with this pathology. Wiley Periodicals, Inc. © 2016

  13. Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda Eyestalk.

    Directory of Open Access Journals (Sweden)

    Valerio Sbragaglia

    Full Text Available The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12-12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50 was equal to 1796 (light and 2055 (darkness. We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79% and Macrobrachium rosenbergii (clock: 100%. We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster.

  14. Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda) Eyestalk.

    Science.gov (United States)

    Sbragaglia, Valerio; Lamanna, Francesco; M Mat, Audrey; Rotllant, Guiomar; Joly, Silvia; Ketmaier, Valerio; de la Iglesia, Horacio O; Aguzzi, Jacopo

    2015-01-01

    The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h) governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12-12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions) obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50) was equal to 1796 (light) and 2055 (darkness). We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI) with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79%) and Macrobrachium rosenbergii (clock: 100%). We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster.

  15. Inducible and reversible Clock gene expression in brain using the tTA system for the study of circadian behavior.

    Directory of Open Access Journals (Sweden)

    Hee-Kyung Hong

    2007-02-01

    Full Text Available The mechanism of circadian oscillations in mammals is cell autonomous and is generated by a set of genes that form a transcriptional autoregulatory feedback loop. While these "clock genes" are well conserved among animals, their specific functions remain to be fully understood and their roles in central versus peripheral circadian oscillators remain to be defined. We utilized the in vivo inducible tetracycline-controlled transactivator (tTA system to regulate Clock gene expression conditionally in a tissue-specific and temporally controlled manner. Through the use of Secretogranin II to drive tTA expression, suprachiasmatic nucleus- and brain-directed expression of a tetO::Clock(Delta19 dominant-negative transgene lengthened the period of circadian locomotor rhythms in mice, whereas overexpression of a tetO::Clock(wt wild-type transgene shortened the period. Low doses (10 mug/ml of doxycycline (Dox in the drinking water efficiently inactivated the tTA protein to silence the tetO transgenes and caused the circadian periodicity to return to a wild-type state. Importantly, low, but not high, doses of Dox were completely reversible and led to a rapid reactivation of the tetO transgenes. The rapid time course of tTA-regulated transgene expression demonstrates that the CLOCK protein is an excellent indicator for the kinetics of Dox-dependent induction/repression in the brain. Interestingly, the daily readout of circadian period in this system provides a real-time readout of the tTA transactivation state in vivo. In summary, the tTA system can manipulate circadian clock gene expression in a tissue-specific, conditional, and reversible manner in the central nervous system. The specific methods developed here should have general applicability for the study of brain and behavior in the mouse.

  16. Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene × environment analysis.

    Science.gov (United States)

    Little, Keriann; Olsson, Craig A; Youssef, George J; Whittle, Sarah; Simmons, Julian G; Yücel, Murat; Sheeber, Lisa B; Foley, Debra L; Allen, Nicholas B

    2015-11-01

    A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of parental aggression or lower levels of positive parenting. The previously reported finding of S-allele carriers' increased risk of depression in adverse environments may, therefore, be partly because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. (c) 2015 APA, all rights reserved).

  17. The clockwork orange Drosophila protein functions as both an activator and a repressor of clock gene expression.

    Science.gov (United States)

    Richier, Benjamin; Michard-Vanhée, Christine; Lamouroux, Annie; Papin, Christian; Rouyer, François

    2008-04-01

    The Drosophila clock relies on transcriptional feedback loops that generate daily oscillations of the clock gene expression at mRNA and protein levels. In the evening, the CLOCK (CLK) and CYCLE (CYC) basic helix-loop-helix (bHLH) PAS-domain transcription factors activate the expression of the period (per) and timeless (tim) genes. Posttranslational modifications delay the accumulation of PER and TIM, which inhibit CLK/CYC activity in the late night. We show here that a null mutant of the clockwork orange (cwo) gene encoding a bHLH orange-domain putative transcription factor displays long-period activity rhythms. cwo loss of function increases cwo mRNA levels but reduces mRNA peak levels of the 4 described CLK/CYC targets, inducing an almost complete loss of their cycling. In addition, the absence of CWO induces alterations of PER and CLK phosphorylation cycles. Our results indicate that, in vivo, CWO modulates clock gene expression through both repressor and activator transcriptional functions.

  18. There Is No Association Between the Circadian Clock Gene HPER3 and Cognitive Dysfunction After Noncardiac Surgery

    DEFF Research Database (Denmark)

    Voigt Hansen, Melissa; Simon Rasmussen, Lars; Jespersgaard, Cathrine

    2012-01-01

    The specific clock-gene PERIOD3 is important with regard to circadian rhythmicity, sleep homeostasis, and cognitive function. The allele PER3(5/5) has been associated with worse cognitive performance in response to sleep deprivation. We hypothesized that patients with the PER3(5/5) genotype would...

  19. Gene-gene interaction between serotonin transporter (SLC6A4) and CLOCK modulates the risk of metabolic syndrome in rotating shiftworkers.

    Science.gov (United States)

    Sookoian, Silvia; Gianotti, Tomas Fernandez; Burgueño, Adriana; Pirola, Carlos Jose

    2010-07-01

    Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variants of the gene CLOCK on the genetic risk underlying MS of shift-workers. To test this hypothesis, 856 men were studied; 518 dayworkers were compared with 338 rotating shiftworkers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviors, and biochemical determinations were obtained from every participant. 5-HTTLPR genotypes were determined using polymerase chain reaction followed by gel electrophoresis. Six tag single-nucleotide polymorphisms (SNPs) in the CLOCK gene with a minor allele frequency >10 % (rs1554483 C/G, rs11932595 A/G, rs4580704 C/G, rs6843722 A/C, rs6850524 C/G, and rs4864548 A/G), encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r(2) > .8), were genotyped. A significant interaction between the 5-HTTLPR variant and the haplotype rs1554483-rs4864548 of the CLOCK gene was detected for diastolic (p = .0058) and systolic blood pressure (p = .0014), arterial hypertension (p = .033), plasma triglycerides levels (p = .033), and number of MS components (p = .01). In all these cases, the higher values were observed in rotating shiftworkers homozygous for the SLC6A4 S allele and carrying the haplotype composed by the CLOCK rs1554483 G and rs4864548 A variants. In conclusion, these data suggest a potential interaction (epistatic effect) of serotonin transporter and CLOCK gene variation on the genetic susceptibility to develop MS by rotating shiftworkers.

  20. The mammalian adult neurogenesis gene ontology (MANGO provides a structural framework for published information on genes regulating adult hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Rupert W Overall

    Full Text Available BACKGROUND: Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies, is essential in any field for comprehensive interpretation of existing knowledge but, until now, such a structure has been lacking for adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We have created a resource with three components 1. A structured ontology describing the key stages in the development of adult hippocampal neural stem cells into functional granule cell neurons. 2. A comprehensive survey of the literature to annotate the results of all published reports on gene function in adult hippocampal neurogenesis (257 manuscripts covering 228 genes to the appropriate terms in our ontology. 3. An easy-to-use searchable interface to the resulting database made freely available online. The manuscript presents an overview of the database highlighting global trends such as the current bias towards research on early proliferative stages, and an example gene set enrichment analysis. A limitation of the resource is the current scope of the literature which, however, is growing by around 100 publications per year. With the ontology and database in place, new findings can be rapidly annotated and regular updates of the database will be made publicly available. CONCLUSIONS/SIGNIFICANCE: The resource we present allows relevant interpretation of gene expression screens in terms of defined stages of postnatal neuronal development. Annotation of genes by hand from the adult neurogenesis literature ensures the data are directly applicable to the system under study. We believe this approach could also serve as an example to other fields in a 'bottom-up' community effort complementing the already

  1. Effects of Stress and MDMA on Hippocampal Gene Expression

    Directory of Open Access Journals (Sweden)

    Georg F. Weber

    2014-01-01

    Full Text Available MDMA (3,4-methylenedioxymethamphetamine is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD. On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature.

  2. Effect of monochromatic light on circadian rhythmic expression of clock genes and arylalkylamine N-acetyltransferase in chick retina.

    Science.gov (United States)

    Cao, Jing; Bian, Jiang; Wang, Zixu; Dong, Yulan; Chen, Yaoxing

    2017-01-01

    Birds have more developed visual function. They not only have the ability to detect light and darkness but also have the color vision. Previous study showed that monochromatic light influenced avian physiological processes, which were controlled by clock genes. Therefore, bird's eye is a good model to studying the impact of color of light on circadian rhythms. Avian retina is one of the most important central oscillations. The study was designed to investigate the effect of color of light on the expression of clock genes and arylalkylamine N-acetyltransferase (Aanat) mRNA expression in chick retina. A total of 240 post-hatching day (P) 0 broiler chickens were exposed to blue (BL), green (GL), red (RL) and white light (WL) from a LED system under a light-dark cycle 12L:12D for 14 d. The results show that the significant daily variations existed in the gene expression of cBmal1, cBmal2, cCry1, cCry2, cPer2 and cPer3, but not for cClock under four light treatments. The genes cBmal1, cCry1, cPer2 and cPer3 presented circadian rhythmic expression under the various monochromatic lights. When compared with WL, GL elevated the expression of positive regulators of cellular clock (cBmal1, cBmal2 and cClock) and cAanat mRNA level, whereas RL increased the mRNA levels of negative regulators of cellular clock (cCry1, cCry2, cPer2 and cPer3) and decreased the cAanat mRNA expression in the retina. These results demonstrated that monochromatic light affect the periodic expression levels of the biological clock mRNA by positive and negative feedback loop interactions, GL activated the transcription of cAanat; while RL suppressed the transcription of cAanat. Thereby, color of light regulates ocular cAanat expression by affecting on expression of cellular clock regulators.

  3. Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

    Science.gov (United States)

    Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

    2016-07-15

    A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Clock gene expression in human and mouse hepatic models shows similar periodicity but different dynamics of variation.

    Science.gov (United States)

    Mazzoccoli, Gianluigi; Rubino, Rosa; Tiberio, Cristiana; Giuliani, Francesco; Vinciguerra, Manlio; Oben, Jude; De Cata, Angelo; Tarquini, Roberto; De Cosmo, Salvatore; Liu, Shu; Cai, Yanning

    2016-01-01

    The biological hard-wiring of 24-hour rhythmicity relies on the circadian clock circuitry, made of peripheral oscillators operated by molecular clockworks and synchronized through humoral and neural outputs by central oscillators located in the hypothalamic suprachiasmatic nuclei. Metabolically active tissues, such as the liver, are entrained also by local cues represented by metabolic flux related to feeding. The mechanics of the molecular clockwork have been explored by studies using cell lines and wild type or genetically engineered mouse models. There is a compelling need to reduce the use of animals in experimental settings. The aim of our study was to evaluate the periodicity and dynamics of functioning of the hepatic clock gene machinery in human and mouse hepatic models. We compared the results obtained in human hepatoma cells (HepG2 cells) and in mouse liver, and a significant 24-hour rhythmic component was found for five clock genes in the HepG2 cells (Bmal1, Cry1, Per1, Per2, NR1D1) and for six clock genes in the mouse liver (Bmal1, Clock, Cry1, Per1, Per2, NR1D1). The amplitude of oscillation rendered by the cosine curve and the dynamics of expression rendered by the rate of change (the derivative of gene expression level with respect to time) were greater in the mouse liver than in the HepG2 cells for Bmal1, Per1, Per2 and NR1D1, and the cosine curve phase was different for many of them. In conclusion, the periodicity of expression of the clock genes showed similar patterns when the two experimental models were compared, whereas the dynamics of transcription in human hepatoma cells cultured in vitro were less vigorous and phased in a different way when compared to mouse hepatic tissue. The results support the reliability of the human hepatic in vitro model as an alternative to animal models only to study the periodicity of function of the molecular clockwork, but not to evaluate the dynamics of clock gene expression.

  5. α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

    Directory of Open Access Journals (Sweden)

    Takao Hirai

    2015-11-01

    Full Text Available Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG, was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1 and Bmal1 (Bmal1, also known as Arntl, which are components of the core loop of the circadian clock in osteoblasts.

  6. Geography of the circadian gene clock and photoperiodic response in western North American populations of the threespine stickleback Gasterosteus aculeatus

    Science.gov (United States)

    O’Brien, C.; Unruh, L.; Zimmerman, C.; Bradshaw, W. E.; Holzapfel, C. M.; Cresko, W. A.

    2014-01-01

    The gene clock is a core component of the daily circadian oscillator in flies and mammals. This gene gained renewed interest over a decade ago when the C-terminus of the Clock protein was found to include polyglutamine repeat domains (PolyQ). Since that time, several studies have used variation in PolyQ as a proxy for variation in circadian function. Furthermore, conjectures were made about the possible role of this variation in photoperiodic control of seasonal timing in birds and fishes, generally with questionable results. Herein, we use controlled laboratory experiments to show that Oregon and Alaskan threespine stickleback, collected from populations that differ by 18° of latitude, show no significant variation in length of the polyglutamine domain of clock, or in photoperiodic response within or between latitudes despite the fact that male and female sticklebacks are photoperiodic at both latitudes. Hence, we urge caution when interpreting variation in the PolyQ domain of the clock gene in the context of seasonal activities or in relationship to photoperiodism along geographical gradients. PMID:23464546

  7. The Clock Gene Rev-Erbα Regulates Methamphetamine Actions on Circadian Timekeeping in the Mouse Brain.

    Science.gov (United States)

    Salaberry, Nora L; Mateo, Maria; Mendoza, Jorge

    2017-09-01

    Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction.

  8. Clock gene variation is associated with breeding phenology and maybe under directional selection in the migratory barn swallow.

    Directory of Open Access Journals (Sweden)

    Manuela Caprioli

    Full Text Available BACKGROUND: In diverse taxa, photoperiodic responses that cause seasonal physiological and behavioural shifts are controlled by genes, including the vertebrate Clock orthologues, that encode for circadian oscillator mechanisms. While the genetic network behind circadian rhythms is well described, relatively few reports exist of the phenological consequences of and selection on Clock genes in the wild. Here, we investigated variation in breeding phenology in relation to Clock genetic diversity in a long-distance migratory bird, the barn swallow (Hirundo rustica. METHODOLOGY/PRINCIPAL FINDINGS: In a sample of 922 adult barn swallows from a single population breeding in Italy we found one very common (Q(7 and three rare (Q(5, Q(6, Q(8 length variants of a functionally significant polyglutamine repeat. Rare (2.9% Q(7/Q(8 heterozygous females, but not males, bred significantly later than common (91.5% Q(7/Q(7 females, consistent with the expectation that 'long' alleles cause late breeding, as observed in a resident population of another bird species. Because breeding date depends on arrival date from migration, present results suggest that the association between breeding date and Clock might be mediated by migration phenology. In addition, fecundity selection appears to be operating against Q(7/Q(8 because late migrating/breeding swallows have fewer clutches per season, and late breeding has additional negative selection effects via reduced offspring longevity. Genotype frequencies varied marginally non-significantly with age, as Q(7/Q(8 frequency showed a 4-fold reduction in old individuals. This result suggests negative viability selection against Q(7/Q(8, possibly mediated by costs of late breeding. CONCLUSIONS/SIGNIFICANCE: This is the first study of migratory birds showing an association between breeding phenology and Clock genotype and suggesting that negative selection occurs on a phenologically deviant genotype. Low polymorphism at Clock may

  9. The clock gene PER2 and sleep problems: association with alcohol consumption among Swedish adolescents.

    Science.gov (United States)

    Comasco, Erika; Nordquist, Niklas; Göktürk, Camilla; Aslund, Cecilia; Hallman, Jarmila; Oreland, Lars; Nilsson, Kent W

    2010-02-01

    Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents. The Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17-18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females. We found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females. These results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.

  10. Association between Circadian Clock Genes and Diapause Incidence in Drosophila triauraria

    OpenAIRE

    Yamada, Hirokazu; Yamamoto, Masa-Toshi

    2011-01-01

    Diapause is an adaptive response triggered by seasonal photoperiodicity to overcome unfavorable seasons. The photoperiodic clock is a system that controls seasonal physiological processes, but our knowledge about its physiological mechanisms and genetic architecture remains incomplete. The circadian clock is another system that controls daily rhythmic physiological phenomena. It has been argued that there is a connection between the two clocks. To examine the genetic connection between them, ...

  11. Photoperiodic Modulation of Circadian Clock and Reproductive Axis Gene Expression in the Pre-Pubertal European Sea Bass Brain

    Science.gov (United States)

    Martins, Rute S. T.; Gomez, Ana; Zanuy, Silvia; Carrillo, Manuel; Canário, Adelino V. M.

    2015-01-01

    The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG) axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL) alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP) accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis. PMID:26641263

  12. Photoperiodic Modulation of Circadian Clock and Reproductive Axis Gene Expression in the Pre-Pubertal European Sea Bass Brain.

    Directory of Open Access Journals (Sweden)

    Rute S T Martins

    Full Text Available The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis.

  13. The association of CLOCK gene T3111C polymorphism and hPER3 gene 54-nucleotide repeat polymorphism with Chinese Han people schizophrenics.

    Science.gov (United States)

    Zhang, Jing; Liao, Ga; Liu, Chang; Sun, Lei; Liu, Yanyou; Wang, Yuhui; Jiang, Zhou; Wang, Zhengrong

    2011-01-01

    Many reports have shown that the biologic rhythm could be altered due to mutations of circadian gene hClock or hPeriod, and the mutations of circadian genes have some relationship with psychosis according to recent studies. A preliminary study has been conducted to examine wether the T3111C single nucleotide polymorphism of the hClock gene or the length polymorphism of the hPer3 gene is associated with the development of schizophrenia. The samples from schizophrenics (n=148, male: 57.4%, female: 42.6%) and normal controls (n=199, male: 59.3%, female: 40.7%) were examined. Allele frequencies of T3111C SNP of hClock were significantly different between schizophrenics and controls (χ2=19.738, P0.05). Our results suggest that the T3111C (RS1801260) polymorphism of hClock gene is associated with schizophrenia, but it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. It is important to address of the relationship between circadian gene polymorphisms and dopamine functions in further study.

  14. Biomarkers of hippocampal gene expression in a mouse restraint chronic stress model.

    Science.gov (United States)

    Ubaldi, Massimo; Ricciardelli, Eugenia; Pasqualini, Lorenza; Sannino, Giuseppina; Soverchia, Laura; Ruggeri, Barbara; Falcinelli, Silvia; Renzi, Alessandra; Ludka, Colleen; Ciccocioppo, Roberto; Hardiman, Gary

    2015-01-01

    Acute stress provides many beneficial effects whereas chronic stress contributes to a variety of human health issues including anxiety, depression, gastrointestinal problems, cardiac disease, sleep disorders and obesity. The goal of this work was to identify, using a rodent model, hippocampal gene signatures associated with prolonged chronic stress representing candidate biomarkers and therapeutic targets for early diagnosis and pharmacological intervention for stress induced disease. Mice underwent 'restraint stress' over 7 consecutive days and hippocampal gene-expression changes were analyzed at 3, 12 and 24 h following the final restraint treatment. Data indicated that mice exposed to chronic restraint stress exhibit a differential gene-expression profile compared with non-stressed controls. The greatest differences were observed 12 and 24 h following the final stress test. Our study indicated that Gpr88, Ttr, Gh and Tac1 mRNAs were modulated in mice exposed to chronic restraint stress. These transcripts represent a panel of biomarkers and druggable targets for further analysis in the context of chronic stress associated disease in humans.

  15. Expression of the clock genes Per1 and Bmal1 during follicle development in the rat ovary. Effects of gonadotropin stimulation and hypophysectomy

    DEFF Research Database (Denmark)

    Gräs, Søren; Georg, Birgitte; Jørgensen, Henrik L

    2012-01-01

    Daily oscillations of clock genes have recently been demonstrated in the ovaries of several species. Clock gene knockout or mutant mice demonstrate a variety of reproductive defects. Accumulating evidence suggests that these rhythms act to synchronise the expression of specific ovarian genes...... examined the ovaries of prepubertal rats, of prepubertal rats stimulated with equine chorionic gonadotropin (eCG)/human chorionic gonadotropin (hCG) and of hypophysectomised adult animals. Using quantitative reverse transcription with the polymerase chain reaction, in situ hybridisation histochemistry...

  16. Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia.

    Science.gov (United States)

    Lippert, Julian; Halfter, Hartmut; Heidbreder, Anna; Röhr, Dominik; Gess, Burkhard; Boentert, Mathias; Osada, Nani; Young, Peter

    2014-01-01

    From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.

  17. Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia.

    Directory of Open Access Journals (Sweden)

    Julian Lippert

    Full Text Available From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH in comparison to those of healthy controls (HC. Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG and Multiple Sleep Latency Test (MSLT. Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.

  18. Physical activity and sex modulate obesity risk linked to 3111T/C gene variant of the CLOCK gene in an elderly population: the SUN Project.

    Science.gov (United States)

    Galbete, Cecilia; Contreras, Rafael; Martínez, J Alfredo; Martínez-González, Miguel Ángel; Guillén-Grima, Francisco; Marti, Amelia

    2012-12-01

    Genetic factors may interact with physical activity levels to modify obesity risk. Our aim was to explore the influence of rs1801260 single-nucleotide polymorphism (SNP) (3111T/C) of CLOCK gene on obesity risk, and to examine its potential interaction with lifestyle factors in an elderly population within the SUN ("Seguimiento Universidad de Navarra") Project. Subjects (n = 903, aged 69 ± 6 yrs) were recruited from the SUN Project. DNA was obtained from saliva, whereas lifestyle and dietary data were collected by validated self-report questionnaires. Genotype was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) plus allele discrimination. A significant interaction was observed between the 3111T/C SNP of CLOCK gene and sex for overweight/obesity risk (p for sex × CLOCK interaction the SUN Project.

  19. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes.

    Science.gov (United States)

    Jahanban-Esfahlan, Rana; Mehrzadi, Saeed; Reiter, Russel J; Seidi, Khaled; Majidinia, Maryam; Baghi, Hossein Bannazadeh; Khatami, Nasrin; Yousefi, Bahman; Sadeghpour, Alireza

    2017-06-05

    Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most prevalent joint diseases. A such, they are important causes of pain and disability in a substantial proportion of the human population. A common characteristic of these diseases is the erosion of articular cartilage and consequently joint dysfunction. Melatonin has been proposed as a link between circadian rhythms and joint diseases including RA and OA. This hormone exerts a diversity of regulatory actions through binding to specific receptors and intracellular targets as well as having receptor-independent actions as a free radical scavenger. Cytoprotective effects of melatonin involve a myriad of prominent receptor-mediated pathways/molecules associated with inflammation, of which the role of omnipresent NF-κB signalling is crucial. Likewise, disturbance of circadian timekeeping is closely involved in the aetiology of inflammatory arthritis. Melatonin is shown to stimulate cartilage destruction/regeneration through direct/indirect modulation of the expression of the main circadian clock genes, such as BMAL, CRY and/or DEC2. In the current article, we review the effects of melatonin on RA and OA, focusing on its ability to regulate inflammatory pathways and circadian rhythms. We also review the possible protective effects of melatonin on RA and OA pathogenesis. © 2017 The British Pharmacological Society.

  20. A novel role of the soybean clock gene LUX ARRHYTHMO in male reproductive development.

    Science.gov (United States)

    Liew, Lim Chee; Singh, Mohan B; Bhalla, Prem L

    2017-09-06

    The evening complex of ELF4-ELF3-LUX proteins is an integral component of a plant circadian clock. LUX ARRHYTHMO (LUX) is one of the key components of the evening complex, and that play a key role in circadian rhythms and flowering. Here, we report that diverged soybean LUX has the additional role in male reproductive development. We studied diurnal and circadian rhythms of soybean LUX (GmLUXa, GmLUXb, and GmLUXc) using qRT-PCR, and show its nuclear localisation by particle bombardment. Yeast-two hybrid (Y2H) studies indicate that both GmLUXb and GmLUXc form an evening complex with GmELF4b and GmELF3a, respectively. Ectopic expression of GmLUXb in Arabidopsis lux mutants can complement functions of AtLUX, whereas GmLUXc generates novel phenotypes of serrated leaves, stunted plants, shortened anther filament, and low seed set. Overall, our results suggest that the LUX gene has diverged in soybean where GmLUXb and GmLUXc share the role to control flowering time, but GmLUXc has evolved to regulate anther filament growth and seed set by regulating the Gibberellin hormone biosynthesis pathway.

  1. ROLE OF CLOCK GENES IN THE INHIBITION BY MELATONIN OF THE ADRENAL GLAND CORTISOL RESPONSE TO ACTH

    OpenAIRE

    VALENZUELA MELGAREJO, FRANCISCO JAVIER

    2012-01-01

    Cortisol production is regulated by the orchestrated action of a circadian rhythm of ACTH, adrenal innervation, the neurohormone melatonin and the circadian clock gene expression in the adrenal cortex. In several especies melatonin acting directly at the adrenal cortex level inhibits the cortisol response to ACTH. We investigated the hypothesis "lnhibition by melatonin of the adrenal cortisol response to ACTH is mediated by changes in the temporal pattern of expression of cl...

  2. Differentiation of PC12 Cells Results in Enhanced VIP Expression and Prolonged Rhythmic Expression of Clock Genes

    DEFF Research Database (Denmark)

    Pretzmann, C.P.; Fahrenkrug, J.; Georg, B.

    2008-01-01

    To examine for circadian rhythmicity, the messenger RNA (mRNA) amount of the clock genes Per1 and Per2 was measured in undifferentiated and nerve-growth-factor-differentiated PC12 cells harvested every fourth hour. Serum shock was needed to induce circadian oscillations, which in undifferentiated......, PC12 cells seem more useful for studying mechanisms behind acquirement of rhythmicity of cell cultures than for resetting of circadian rhythm Udgivelsesdato: 2008/11...

  3. Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice.

    Science.gov (United States)

    Murakami, Yuichi; Higashi, Yuko; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2008-11-01

    P-glycoprotein, the product of the multidrug resistance (mdr) gene, functions as a xenobiotic transporter contributing to the intestinal barrier. Although intestinal expression of the mdr1a gene and its efflux pump function has been shown to exhibit 24-hour variation, the mechanism of the variations remains poorly understood. Here, we demonstrated that the molecular components of the circadian clock act as regulators to control 24-hour variation in the expression of the mdr1a gene. Luciferase reporter assay and gel mobility shift assay were used to study the mechanism of transcriptional regulation of the mdr1a gene by clock gene products. The messenger RNA levels and protein abundances in colon 26 cells and mouse intestine were measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. Hepatic leukemia factor (HLF) and E4 promoter binding protein-4 (E4BP4) regulated transcription of the mdr1a gene by competing with each other for the same DNA binding site. Molecular and biochemical analyses of HLF- and E4BP4-down-regulated colon 26 cells and the intestinal tract of Clock mutant mice suggested that these 2 proteins consisted of a reciprocating mechanism in which HLF activated the transcription of the mdr1a gene, whereas E4BP4 periodically suppressed transcription at the time of day when E4BP4 was abundant. The intestinal expression of the mdr1a gene is influenced by the circadian organization of molecular clockwork. Our present findings provide a link between the circadian timekeeping system and xenobiotic detoxification.

  4. Transcriptome Profiling of the Lungs Reveals Molecular Clock Genes Expression Changes after Chronic Exposure to Ambient Air Particles

    Directory of Open Access Journals (Sweden)

    Pengcheng Song

    2017-01-01

    Full Text Available The symptoms of asthma, breathlessness, insomnia, etc. all have relevance to pulmonary rhythmic disturbances. Epidemiology and toxicology studies have demonstrated that exposure to ambient air particles can result in pulmonary dysfunction. However, there are no data directly supporting a link between air pollution and circadian rhythm disorder. In the present study, we found that breathing highly polluted air resulted in changes of the molecular clock genes expression in lung by transcriptome profiling analyses in a rodent model. Compared to those exposed to filtered air, in both pregnant and offspring rats in the unfiltered group, key clock genes (Per1, Per2, Per3, Rev-erbα and Dbp expression level decreased and Bmal1 expression level increased. In both rat dams and their offspring, after continuous exposure to unfiltered air, we observed significant histologic evidence for both perivascular and peribronchial inflammation, increased tissue and systemic oxidative stress in the lungs. Our results suggest that chronic exposure to particulate matter can induce alterations of clock genes expression, which could be another important pathway for explaining the feedbacks of ambient particle exposure in addition to oxidative stress and inflammation.

  5. Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development.

    Science.gov (United States)

    Schachtschneider, Kyle M; Liu, Yingkai; Rund, Laurie A; Madsen, Ole; Johnson, Rodney W; Groenen, Martien A M; Schook, Lawrence B

    2016-11-03

    Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency. In total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function. Neonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive

  6. Brain clocks for morning and evening behaviour

    Indian Academy of Sciences (India)

    Unknown

    228 taneously synthesized transcripts of a clock gene, mPer1, in one of the two lobes, and transcripts of another clock gene,. Bmal1, in the other, suggesting antiphasic nature of the two bilaterally symmetric SCN lobes. Further, it was ... resolution of clock cell targeting. The authors developed. Figure 1. Clock neurons in the ...

  7. Potential hippocampal genes and pathways involved in Alzheimer's disease: a bioinformatic analysis.

    Science.gov (United States)

    Zhang, L; Guo, X Q; Chu, J F; Zhang, X; Yan, Z R; Li, Y Z

    2015-06-29

    Alzheimer's disease (AD) is a neurodegenerative disor-der and the most common cause of dementia in elderly people. Nu-merous studies have focused on the dysregulated genes in AD, but the pathogenesis is still unknown. In this study, we explored critical hippocampal genes and pathways that might potentially be involved in the pathogenesis of AD. Four transcriptome datasets for the hip-pocampus of patients with AD were downloaded from ArrayExpress, and the gene signature was identified by integrated analysis of mul-tiple transcriptomes using novel genome-wide relative significance and genome-wide global significance models. A protein-protein interaction network was constructed, and five clusters were selected. The biologi-cal functions and pathways were identified by Gene Ontology and Kyo-to Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A total of 6994 genes were screened, and the top 300 genes were subjected to further analysis. Four significant KEGG pathways were identified, including oxidative phosphorylation and Parkinson's disease, Huntington's disease, and Alzheimer's disease pathways. The hub network of cluster 1 with the highest average rank value was de-fined. The genes (NDUFB3, NDUFA9, NDUFV1, NDUFV2, NDUFS3, NDUFA10, COX7B, and UQCR1) were considered critical with high degree in cluster 1 as well as being shared by the four significant path-ways. The oxidative phosphorylation process was also involved in the other three pathways and is considered to be relevant to energy-related AD pathology in the hippocampus. This research provides a perspec-tive from which to explore critical genes and pathways for potential AD therapies.

  8. Association study between a polymorphism at the 3'-untranslated region of CLOCK gene and attention deficit hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Xu Xiaohui

    2010-08-01

    Full Text Available Abstract Background The circadian locomotor output cycles kaput (CLOCK gene encodes protein regulation circadian rhythm and also plays some roles in neural transmitter systems including the dopamine system. Several lines of evidence implicate a relationship between attention-deficit hyperactivity disorder (ADHD, circadian rythmicity and sleeping disturbances. A recent study has reported that a polymorphism (rs1801260 at the 3'-untranslated region of the CLOCK gene is associated with adult ADHD. Methods To investigate the association between the polymorphism (rs1801260 in ADHD, two samples of ADHD probands from the United Kingdom (n = 180 and Taiwan (n = 212 were genotyped and analysed using within-family transmission disequilibrium test (TDT. Bonferroni correction procedures were used to just for multiple comparisons. Results We found evidence of increased transmission of the T allele of the rs1801260 polymorphism in Taiwanese samples (P = 0.010. There was also evidence of preferential transmission of the T allele of the rs1801260 polymorphism in combined samples from the Taiwan and UK (P = 0.008. Conclusion This study provides evidence for the possible involvement of CLOCK in susceptibility to ADHD.

  9. Alzheimer's disease susceptibility genes APOE and TOMM40, and hippocampal volumes in the Lothian birth cohort 1936.

    Directory of Open Access Journals (Sweden)

    Donald M Lyall

    Full Text Available The APOE ε and TOMM40 rs10524523 ('523' variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer's disease (AD related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 '523' genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 '523' poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636. No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1 their specific techniques in adjusting for brain size; 2 assessing more detailed sub-divisions of the hippocampal formation; and 3 testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.

  10. The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

    Directory of Open Access Journals (Sweden)

    Onkar B. Sawant

    2017-10-01

    Full Text Available Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone (TH-activating enzyme type 2 iodothyronine deiodinase (Dio2 and thus regulates the expression of Dio2. TH treatment resulted in a partial rescue of the phenotype caused by the loss of Bmal1, thus revealing a functional relationship between Bmal1 and Dio2 in establishing cone photoreceptor identity. Furthermore, Bmal1 and Dio2 are required to maintain cone photoreceptor functional integrity. Overall, our results suggest a mechanism by which circadian proteins can locally regulate the availability of TH and influence tissue development and function.

  11. Adenosinergic regulation of striatal clock gene expression and ethanol intake during constant light.

    Science.gov (United States)

    Ruby, Christina L; Vadnie, Chelsea A; Hinton, David J; Abulseoud, Osama A; Walker, Denise L; O'Connor, Katheryn M; Noterman, Maria F; Choi, Doo-Sup

    2014-09-01

    Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the co-occurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption.

  12. Light modulation of human sleep depends on a polymorphism in the clock gene Period3.

    Science.gov (United States)

    Chellappa, Sarah L; Viola, Antoine U; Schmidt, Christina; Bachmann, Valérie; Gabel, Virginie; Maire, Micheline; Reichert, Carolin F; Valomon, Amandine; Landolt, Hans-Peter; Cajochen, Christian

    2014-09-01

    Non-image-forming (NIF) responses to light powerfully modulate human physiology. However, it remains scarcely understood how NIF responses to light modulate human sleep and its EEG hallmarks, and if there are differences across individuals. Here we investigated NIF responses to light on sleep in individuals genotyped for the PERIOD3 (PER3) variable-number tandem-repeat (VNTR) polymorphism. Eighteen healthy young men (20-28 years; mean ± SEM: 25.9 ± 1.2) homozygous for the PER3 polymorphism were matched by age, body-mass index, and ethnicity. The study protocol comprised a balanced cross-over design during the winter, during which participants were exposed to either light of 40 lx at 6,500 K (blue-enriched) or light at 2,500 K (non-blue enriched), during 2h in the evening. Compared to light at 2,500 K, light at 6,500 K induced a significant increase in all-night NREM sleep slow-wave activity (SWA: 1.0-4.5 Hz) in the occipital cortex for PER3(5/5) individuals, but not for PER3(4/4) volunteers. Dynamics of SWA across sleep cycles revealed increased occipital NREM sleep SWA for virtually all sleep episode only for PER3(5/5) individuals. Furthermore, they experienced light at 6,500 K as significantly brighter. Intriguingly, this subjective perception of brightness significantly predicted their increased occipital SWA throughout the sleep episode. Our data indicate that humans homozygous for the PER3(5/5) allele are more sensitive to NIF light effects, as indexed by specific changes in sleep EEG activity. Ultimately, individual differences in NIF light responses on sleep may depend on a clock gene polymorphism involved in sleep-wake regulation. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP

    DEFF Research Database (Denmark)

    Sørensen, Andreas T; Nikitidou, Litsa; Ledri, Marco

    2009-01-01

    gene therapy. Here we report how rAAV vector-mediated overexpression of NPY in the hippocampus affects rapid kindling, and subsequently explore how synaptic plasticity and transmission is affected by kindling and NPY overexpression by field recordings in CA1 stratum radiatum of brain slices. In animals...... injected with rAAV-NPY, we show that rapid kindling-induced hippocampal seizures in vivo are effectively suppressed as compared to rAAV-empty injected (control) rats. Six to nine weeks later, basal synaptic transmission and short-term synaptic plasticity are unchanged after rapid kindling, while LTP...... is significantly attenuated in vitro. Importantly, transgene NPY overexpression has no effect on short-term synaptic plasticity, and does not further compromise LTP in kindled animals. These data suggest that epileptic seizure-induced impairment of memory function in the hippocampus may not be further affected...

  14. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05 and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001. High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05. AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01 and glucagon release (p<0.05. These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.

  15. Time-place learning and memory persist in mice lacking functional Per1 and Per2 clock genes.

    Science.gov (United States)

    Mulder, C; Van Der Zee, E A; Hut, R A; Gerkema, M P

    2013-12-01

    With time-place learning, animals link a stimulus with the location and the time of day. This ability may optimize resource localization and predator avoidance in daily changing environments. Time-place learning is a suitable task to study the interaction of the circadian system and memory. Previously, we showed that time-place learning in mice depends on the circadian system and Cry1 and/or Cry2 clock genes. We questioned whether time-place learning is Cry specific or also depends on other core molecular clock genes. Here, we show that Per1/Per2 double mutant mice, despite their arrhythmic phenotype, acquire time-place learning similar to wild-type mice. As well as an established role in circadian rhythms, Per genes have also been implicated in the formation and storage of memory. We found no deficiencies in short-term spatial working memory in Per mutant mice compared to wild-type mice. Moreover, both Per mutant and wild-type mice showed similar long-term memory for contextual features of a paradigm (a mild foot shock), measured in trained mice after a 2-month nontesting interval. In contrast, time-place associations were lost in both wild-type and mutant mice after these 2 months, suggesting a lack of maintained long-term memory storage for this type of information. Taken together, Cry-dependent time-place learning does not require Per genes, and Per mutant mice showed no PER-specific short-term or long-term memory deficiencies. These results limit the functional role of Per clock genes in the circadian regulation of time-place learning and memory.

  16. Influence of menopause on adipose tissue clock gene genotype and its relationship with metabolic syndrome in morbidly obese women.

    Science.gov (United States)

    Hernandez-Morante, Juan José; Gomez-Santos, Cecilia; Margareto, Javier; Formiguera, Xavier; Martínez, Carlos Manuel; González, Raquel; Martínez-Augustín, Olga; Madrid, Juan Antonio; Ordovas, Jose María; Garaulet, Marta

    2012-12-01

    Menopausal women exhibit a loss of circadian coordination, a process that runs parallel with a redistribution of adipose tissue. However, the specific genetic mechanisms underlying these alterations have not been studied. Thus, the aim of the present study was to determine whether the development of menopause induces an alteration of the genes that control biological rhythms in human subcutaneous (SAT) and visceral (VAT) adipose tissue, and whether changes in clock gene expression are involved in the increased risk of developing metabolic syndrome (MetS), which is frequently associated with menopause. To this end, VAT and SAT biopsies were taken in pre- (n = 7) and postmenopausal (n = 7) women at similar hours in the morning. RNA was extracted, and a microarray analysis was made. Data were confirmed by quantitative real-time polymerase chain reaction. Western blot and immunohistochemical analysis were also performed. When clock gene expression was compared between both groups of women, data in SAT showed that expression of the core clock gene period3 was significantly higher in postmenopausal women, while casein kinase-1δ, E1A-binding protein and cAMP-responsive element were preferentially expressed in the premenopausal group. In VAT, period2 (PER2) and v-myc myelocytomatosis viral oncogene expressions were significantly higher in the postmenopausal group. Western blot analysis indicated that PER2 and PER3 protein expression was also increased in postmenopausal women. In addition, several genes, including PER2, were differentially expressed depending on whether or not the patient met the MetS criteria. We conclude that menopause transition induces several changes in the genotype of the adipose tissue chronobiological machinery related to an increased risk of developing MetS.

  17. Diurnal expression of clock genes in pineal gland and brain and plasma levels of melatonin and cortisol in Atlantic salmon parr and smolts.

    Science.gov (United States)

    Huang, Tien-sheng; Ruoff, Peter; Fjelldal, Per G

    2010-10-01

    In Atlantic salmon, the preadaptation to a marine life, i.e., parr-smolt transformation, and melatonin production in the pineal gland are regulated by the photoperiod. However, the clock genes have never been studied in the pineal gland of this species. The aim of the present study was to describe the diurnal expression of clock genes (Per1-like, Cry2, and Clock) in the pineal gland and brain of Atlantic salmon parr and smolts in freshwater, as well as plasma levels of melatonin and cortisol. By employing an out-of-season smolt production model, the parr-smolt transformation was induced by subjecting triplicate groups of parr to 6 wks (wks 0 to 6) under a 12 h:12 h light-dark (LD) regime followed by 6 wks (wks 6 to 12) of continuous light (LL). The measured clock genes in both pineal gland and brain and the plasma levels of melatonin and cortisol showed significant daily variations in parr under LD in wk 6, whereas these rhythms were abolished in smolts under LL in wk 12. In parr, the pineal Per1-like and Cry2 expression peaked in the dark phase, whereas the pineal Clock expression was elevated during the light phase. Although this study presents novel findings on the clock gene system in the teleost pineal gland, the role of this system in the regulation of smoltification needs to be studied in more detail.

  18. Diurnal rhythmicity of the canonical clock genes Per1, per2 and Bmal1 in the rat adrenal gland is unaltered after hypophysectomy

    DEFF Research Database (Denmark)

    Fahrenkrug, J.; Hannibal, J.; Georg, B.

    2008-01-01

    the existence of a core oscillator in the individual adrenal gland cells. Our findings support the existence of a circadian core oscillator in cells of the rat adrenal cortex and indicate that the activity of the oscillator is independent of SCN signalling via the pituitary gland. The adrenal cortical clock......Circadian rhythms are generated by endogenous clocks in the central brain oscillator, the suprachiasmatic nucleus (SCN), and peripheral tissues. The molecular basis for the circadian clock consists of a number of genes and proteins that form transcriptional/translational feedback loops. Rhythmic...... by real-time reverse transcription-polymerase chain reaction during a 24-h-cycle in normal and hypophysectomised rats. The mRNAs for all the three clock genes disclosed rhythmic oscillations with a period of 24 h and the phase did not differ between the hypophysectomised and intact rats. The expression...

  19. Effect of cadmium on 24-hour pattern in expression of redox enzyme and clock genes in rat medial basal hypothalamus.

    Science.gov (United States)

    Jiménez-Ortega, Vanesa; Cardinali, Daniel P; Fernández-Mateos, María P; Ríos-Lugo, María J; Scacchi, Pablo A; Esquifino, Ana I

    2010-04-01

    The effect of cadmium (Cd) in the brain has been attributed to an increase in reactive oxygen species in cells, particularly when high amounts of the metal are given. In this study we examined the effect of a low dose of Cd (7.5 microg/day) on 24-h changes in expression of redox pathway enzyme and circadian genes in rat medial basal hypothalamus (MBH). Rats receiving CdCl(2) (5 ppm in drinking water) or tap water for 1 month were killed at six different time intervals throughout a 24 h cycle. MBH mRNA levels were measured by real-time PCR analysis. In CdCl(2) treated rats a disruption of 24-h pattern of hypothalamic gene expression of nitric oxide synthase (NOS)-1 and -2, heme oxygenase (HO)-1 and -2, Mn- superoxide dismutase (SOD), catalase, glutathione peroxidase and glutathione reductase was detectable. Mean levels of MBH mRNA for HO-2, Mn-SOD and catalase augmented after Cd intake, whereas those of NOS-2 decreased. After CdCl(2) intake rats the 24-h pattern of clock gene expression in MBH seen in controls was significantly suppressed (Bmal1) or changed in phase (Per1, Per2, Cry2) while in the case of Clock significant 24-h variations were induced. The results are compatible with the view that a low amount of Cd given in tap water brought about significant changes in circadian expression of redox enzyme and clock genes in rat MBH.

  20. Origin of the Animal Circadian Clock: Diurnal and Light-Entrained Gene Expression in the Sponge Amphimedon queenslandica

    Directory of Open Access Journals (Sweden)

    Katia Jindrich

    2017-10-01

    Full Text Available The circadian clock is a molecular network that coordinates organismal behavior and physiology with daily environmental changes in the day-night cycle. In eumetazoans (bilaterians + cnidarians, this network appears to be largely conserved, yet different from other known eukaryotic circadian networks. To determine if the eumetazoan circadian network has an older origin, we ask here whether orthologs comprising this network are expressed in a manner consistent with a role in regulating circadian patterns in a representative of an earlier-branching animal lineage, the sponge Amphimedon queenslandica. The A. queenslandica genome encodes orthologs of many eumetazoan circadian genes, including two cryptochrome genes that encode flavoproteins, three Timeout genes, and two PAR-bZIP and seven bHLH-PAS transcription factor genes. There is no apparent Cycle ortholog, although we can identify three closely related ARNT genes. Of the putative circadian genes, only AqPARa and AqCry2 have a consistent oscillating diurnal expression profile, and the rhythmic expression of both these genes is partially lost when the animals are exposed to constant light or darkness. Expression of the other putative circadian genes, in particular AqClock, is neither diurnally-oscillating nor light-dependent. AqPARa and AqCry2 are also temporally and spatially co-expressed throughout embryonic and larval development. Transcripts of these genes are enriched first in cells comprising the larval posterior pigment ring, which is a simple photosensory organ that is responsible for the negative phototactic behavior displayed by larvae, and subsequently in the larval epithelial and subepithelial layers. The combined findings of no clear Cycle ortholog and of PAR-bZIP and cryptochrome being the only orthologs expressed in a pattern consistent with a circadian role suggests that either (i the ancestral metazoan circadian network was simpler than the eumetazoan network, or (ii that this

  1. Effects of Photoperiod Extension on Clock Gene and Neuropeptide RNA Expression in the SCN of the Soay Sheep.

    Directory of Open Access Journals (Sweden)

    Hugues Dardente

    Full Text Available In mammals, changing daylength (photoperiod is the main synchronizer of seasonal functions. The photoperiodic information is transmitted through the retino-hypothalamic tract to the suprachiasmatic nuclei (SCN, site of the master circadian clock. To investigate effects of day length change on the sheep SCN, we used in-situ hybridization to assess the daily temporal organization of expression of circadian clock genes (Per1, Per2, Bmal1 and Fbxl21 and neuropeptides (Vip, Grp and Avp in animals acclimated to a short photoperiod (SP; 8h of light and at 3 or 15 days following transfer to a long photoperiod (LP3, LP15, respectively; 16h of light, achieved by an acute 8-h delay of lights off. We found that waveforms of SCN gene expression conformed to those previously seen in LP acclimated animals within 3 days of transfer to LP. Mean levels of expression for Per1-2 and Fbxl21 were nearly 2-fold higher in the LP15 than in the SP group. The expression of Vip was arrhythmic and unaffected by photoperiod, while, in contrast to rodents, Grp expression was not detectable within the sheep SCN. Expression of the circadian output gene Avp cycled robustly in all photoperiod groups with no detectable change in phasing. Overall these data suggest that synchronizing effects of light on SCN circadian organisation proceed similarly in ungulates and in rodents, despite differences in neuropeptide gene expression.

  2. Association between the CLOCK gene 3111 T > C polymorphism and an irregular menstrual cycle in Korean adolescents.

    Science.gov (United States)

    Kim, Kye-Hyun; Kim, Yunsin; Ha, Juwon; Shin, Dong-Won; Shin, Young-Chul; Oh, Kang-Seob; Woo, Hee-Yeon; Lim, Se-Won

    2015-01-01

    The menstrual cycle is an example of a human infradian rhythm, but an altered sleep-wake cycle or a disrupted circadian rhythm can change the regularity of the menstrual cycle. In this study, we investigated whether an irregular menstrual cycle is associated with polymorphisms in the CLOCK (3111T > C) and/or PER3 (variable number tandem repeat, VNTR) genes, which are known to have an impact on the circadian rhythm. One hundred ninety-seven postmenarchal, adolescent girls from two girls' high schools in Seoul, Korea, were studied. All participants were requested to complete the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) to assess the emotional distress that might cause menstrual irregularity. Every participant donated a blood sample from which DNA was extracted and genotyped for the CLOCK 3111T > C and PER3 VNTR polymorphisms. A significant association was found between the CLOCK 3111T > C genotype and irregular menstrual cycles. Subjects with the 3111T > C genotype had a high risk of an irregular menstrual cycle compared with 3111T/T homozygous subjects (odds ratio [OR] = 2.88; 95% confidence interval [CI]: 1.26-6.55). When multivariate logistic regression analysis was performed to adjust for age, PSS, STAI, BDI and BMI, subjects with the 3111T > C polymorphism showed a significantly increased OR for irregular menstrual cycles (OR = 3.09; 95% CI: 1.32-7.21). There was no significant association between the PER3 VNTR polymorphism and the irregularity of the menstrual cycle (p > 0.05). The results of this study suggest that the CLOCK 3111T > C polymorphism could be an independent risk factor for irregular menstrual cycles, irrespective of psychological distress and endocrine or metabolic conditions, and could be used as a molecular marker for gynecological studies on this aspect.

  3. The Choline Acetyltransferase (CHAT) Gene is Associated with Parahippocampal and Hippocampal Structure and Short-term Memory Span.

    Science.gov (United States)

    Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K; Dong, Qi; Lin, Chongde

    2018-01-15

    The CHAT gene encodes choline acetyltransferase, which is an enzyme responsible for the biosynthesis of the neurotransmitter acetylcholine in the brain. This study collected structural MRI, genetic, and behavioral data from 324 healthy Chinese adults, and examined the associations between CHAT genetic variants, parahippocampal and hippocampal structure, and short-term memory span. After controlling for intracranial volume, sex, and age, CHAT SNP rs12246528 had the strongest association with parahippocampal structure, with the A allele being linked to smaller volume, surface area, and thickness. SNP rs1917814 had the strongest association with hippocampal volume, with the T allele being linked to larger hippocampal volume. After controlling for sex and age, CHAT rs3729496 had the strongest association with memory span, with the T allele being associated with a greater memory span. Finally, the left parahippocampal gyrus surface area was positively associated with memory span. This study provides the first evidence for the involvement of the CHAT gene in parahippocampal and hippocampal structures and memory span in healthy Chinese adults. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

    National Research Council Canada - National Science Library

    Ben-Moshe Livne, Zohar; Alon, Shahar; Vallone, Daniela; Bayleyen, Yared; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C; Burgess, Harold A; Foulkes, Nicholas S; Gothilf, Yoav

    2016-01-01

    ... its synchronization with the solar day [2]. At the heart of the molecular clock in vertebrates are daily oscillations in the expression and function of evolutionarily conserved clock genes and their protein products, including CLOCK and BMAL, which form heterodimers that activate the transcription of clock and clock-controlled genes (CCGs) via E-box enhan...

  5. 24-hour oscillation of mouse methionine aminopeptidase2, a regulator of tumor progression, is regulated by clock gene proteins.

    Science.gov (United States)

    Nakagawa, Hiroo; Koyanagi, Satoru; Takiguchi, Takako; Kuramoto, Yukako; Soeda, Shinji; Shimeno, Hiroshi; Higuchi, Shun; Ohdo, Shigehiro

    2004-11-15

    Methionine aminopeptidase2 (MetAP2) plays an important role in the growth of endothelial cells during the tumor angiogenesis stage. Recently, we have clarified that mouse methionine aminopeptidases (mMetAPs) show a 24-hour rhythm in implanted tumor masses. In the present study, we investigated the mechanism underlying the 24-hour rhythm of mMetAP2 activity in tumor-bearing mice under a light-dark (lights on from 7 a.m. to 7 p.m.) cycle. The 5' flanking region of mMetAP2 included eight E-boxes. The transcription of the mMetAP2 promoter was enhanced by the mCLOCK:mBMAL1 heterodimer, and its activation was inhibited by mPER2 or mCRY1. Deletion and mutation of the E-boxes in the region indicated that the E-box nearest to the initiation start site played an important role in the transcriptional regulation by clock genes. In sarcoma180-bearing mice, the pattern of binding of mCLOCK and mBMAL1 to the E-box and transcription of the mMetAP2 promoter showed a 24-hour rhythm with higher levels from the mid-light to early dark phase. The pattern of mMetAP2 transcription was closely associated with that of mMetAP2 mRNA expression in three types of tumor-bearing mice. mMetAP2 protein expression varied with higher levels from the late-dark to early light phase. The rhythmicity of the protein expression was synchronous with that of the activity of mMetAPs but out of phase with that of the mMetAP2 mRNA expression. These results suggest that the 24-hour rhythm of mMetAP2 activity is regulated by the transcription of clock genes within the clock feedback loops.

  6. Inferring bi-directional interactions between circadian clock genes and metabolism with model ensembles

    NARCIS (Netherlands)

    Grzegorczyk, Marco; Aderhold, Andrej; Husmeier, Dirk

    There has been much interest in reconstructing bi-directional regulatory networks linking the circadian clock to metabolism in plants. A variety of reverse engineering methods from machine learning and computational statistics have been proposed and evaluated. The emphasis of the present paper is on

  7. Entrainment Dissociates Transcription and Translation of a Circadian Clock Gene in Neurospora

    NARCIS (Netherlands)

    Tan, Ying; Dragovic, Zdravko; Roenneberg, Till; Merrow, Martha

    2004-01-01

    Circadian systems coordinate the daily sequence of events in cells, tissues, and organisms. In constant conditions, the biological clock oscillates with its endogenous period, whereas it is synchronized to the 24 hr light:dark cycle in nature. Here, we investigate light entrainment of Neurospora

  8. CIRCADIAN AND ACAMPROSATE MODULATION OF ELEVATED ETHANOL DRINKING IN mPer2 CLOCK GENE MUTANT MICE

    OpenAIRE

    Brager, Allison J.; Prosser, Rebecca A.; Glass, J. David

    2011-01-01

    The Per2 clock gene modulates ethanol consumption, such that mutant mice not expressing functional mPer2 have altered circadian behavior that promotes higher ethanol intake and preference. Experiments were undertaken to characterize circadian-related behavioral effects of mPer2 deletion on ethanol intake and to explore how acamprosate (used to reduce alcohol dependence) alters diurnal patterns of ethanol intake. Male mPer2 mutant and WT (wild-type) mice were entrained to a 12L:12D photocycle ...

  9. Comparative study of pineal clock gene and AANAT2 expression in relation to melatonin synthesis in Atlantic salmon (Salmo salar) and European seabass (Dicentrarchus labrax).

    Science.gov (United States)

    McStay, Elsbeth; Migaud, Herve; Vera, Luisa Maria; Sánchez-Vázquez, Francisco Javier; Davie, Andrew

    2014-03-01

    The photoreceptive teleost pineal is considered to be essential to the generation, synchronisation and maintenance of biological rhythms, primarily via melatonin release. The role of internal (circadian clock) and external (light) signals controlling melatonin production in the fish pineal differs between species, yet the reasons underpinning this remain largely unknown. Whilst in salmonids, pineal melatonin is apparently regulated directly by light, in all other studied teleosts, rhythmic melatonin production persists endogenously under the regulation of clock gene expression. To better understand the role of clocks in teleost pineals, this study aimed to characterise the expression of selected clock genes in vitro under different photoperiodic conditions in comparison to in vivo in both Atlantic salmon (Salmo salar) and in European seabass (Dicentrarchus labrax) (in vitro 12L:12D), a species known to display endogenous rhythmic melatonin synthesis. Results revealed no rhythmic clock gene (Clock, Period 1 &2) expression in Atlantic salmon or European seabass (Clock and Period 1) pineal in vitro. However rhythmic expression of Cryptochrome 2 and Period 1 in the Atlantic salmon pineal was observed in vivo, which infers extra-pineal regulation of clocks in this species. No rhythmic arylalkylamine N-acetyltransferase 2 (Aanat2) expression was observed in the Atlantic salmon yet in the European seabass, circadian Aanat2 expression was observed. Subsequent in silico analysis of available Aanat2 genomic sequences reveals that Atlantic salmon Aanat2 promoter sequences do not contain similar regulatory architecture as present in European seabass, and previously described in other teleosts which alludes to a loss in functional connection in the pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.

    Science.gov (United States)

    Corella, Dolores; Asensio, Eva M; Coltell, Oscar; Sorlí, José V; Estruch, Ramón; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Castañer, Olga; Arós, Fernando; Lapetra, José; Serra-Majem, Lluís; Gómez-Gracia, Enrique; Ortega-Azorín, Carolina; Fiol, Miquel; Espino, Javier Díez; Díaz-López, Andrés; Fitó, Montserrat; Ros, Emilio; Ordovás, José M

    2016-01-07

    Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43-0.78; P CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model. In agreement with our previous results showing a

  11. Clock genes and diurnal transcriptome dynamics in summer and winter in the gymnosperm Japanese cedar (Cryptomeria japonica (L.f.) D.Don).

    Science.gov (United States)

    Nose, Mine; Watanabe, Atsushi

    2014-11-18

    The circadian clock and diurnal dynamics of the transcriptome are presumed to play important roles in the regulation of physiological, biological and developmental processes synchronized with diurnal and annual cycles of plant environments. However, little is known about the circadian clock and its regulation in gymnosperms, including conifers. Here we present the diurnal transcriptome dynamics of Japanese cedar (Cryptomeria japonica (L.f.) D.Don) in both active (summer) and dormant (winter) periods. Microarray analysis revealed significant differences in transcripts between summer and winter, and diurnal transcriptome dynamics only in the summer. About 7.7% of unique genes (556 out of 7,254) on the microarray were periodically expressed in summer. Expression patterns of some genes, especially light-related genes, did not show significant oscillation in Japanese cedar, thus differing from those reported in angiosperms. Gene network analysis of the microarray data revealed a network associated with the putative core clock genes (CjLHYa, CjLHYb, CjTOC1, CjGI and CjZTL), which were also isolated, indicating their importance in the diurnal regulation of the transcriptome. This study revealed the existence of core clock genes and diurnal rhythms of the transcriptome in summer in Japanese cedar. Dampening of diurnal rhythms in winter indicated seasonal change in the rhythms according to environmental conditions. The data also revealed genes that showed different expression patterns compared to angiosperms, suggesting a unique gene regulatory network in conifers. This study provides fundamental data to understand transcriptional regulatory mechanisms in conifers.

  12. Effect of continuous light on daily levels of plasma melatonin and cortisol and expression of clock genes in pineal gland, brain, and liver in atlantic salmon postsmolts.

    Science.gov (United States)

    Huang, Tien-Sheng; Ruoff, Peter; Fjelldal, Per G

    2010-10-01

    Continuous light is a common practice in salmon farming, where it is used to enhance growth, induce smoltification, and regulate puberty. However, knowledge about how different tissues receive information about daylength is limited. The aim of the present study was to evaluate the daily expression of clock (Per1-like, Cry2, and Clock), the nuclear transcription factor (peroxisome proliferator-activated receptor, PPAR; CCAAT/enhancer binding protein, C/EBP), and the endoplasmic reticulum (ER) stress (protein disulfide isomerase associated 3, PDIA3) genes in the pineal gland, brain, and liver of Atlantic salmon postsmolts reared under 12-h light:12-h dark (LD) regimes or under continuous light (LL) for 6 wks following transfer to seawater. All measured clock mRNAs displayed daily variations in one or more organs under LD, as well as plasma levels of melatonin. Similar variations were noted in the liver c/ebpα, pineal c/ebpδ, and pdia3 mRNAs. Under LL, the clock and nuclear transcription factor mRNAs did not show any daily variation in the studied organs, with the exception of pineal pdia3. Furthermore, LL had the opposite effect on the levels of melatonin and cortisol, as observed by the increase in pineal Clock, Per2, pparα, and c/ebpα and c/ebpδ mRNAs and decrease in liver Clock, Per2, and pparα mRNAs compared to those under LD. The present findings show that the expression of clock genes is affected by the light across organs and that there is a relation between PPAR, C/EBP, and clock mRNAs; however, the functional role of the individual nuclear transcription factors related to this observation remains to be established in the pineal gland and liver. (Author correspondence: Tihu@nifes.no ).

  13. Altered expression of circadian clock gene, mPer1, in mouse brain and kidney under morphine dependence and withdrawal

    Directory of Open Access Journals (Sweden)

    Wang Yuhui

    2006-08-01

    Full Text Available Abstract Every physiological function in the human body exhibits some form of circadian rhythmicity. Under pathological conditions, however, circadian rhythmicity may be dusrupted. Patients infected with HIV or addicted to drugs of abuse often suffer from sleep disorders and altered circadian rhythms. Early studies in Drosophila suggested that drug seeking behavior might be related to the expression of certain circadian clock genes. Our previous research showed that conditioned place preference with morphine treatment was altered in mice lacking the Period-1 (mPer1 circadian clock gene. Thus, we sought to investigate whether morphine treatment could alter the expression of mPer1, especially in brain regions outside the SCN and in peripheral tissues. Our results using Western blot analysis showed that the mPER1 immunoreactivity exhibited a strong circadian rhythm in the brains of the control (Con, morphine-dependent (MD, and morphine-withdrawal (MW mice. However, the phase of the circadian rhythm of mPER1 expression in the brains of MD mice significantly differed from that of the Con mice (p mPer1 may vary among different organs, resulting in desynchronization of circadian function between the SCN and peripheral organs.

  14. The SEMA5A gene is associated with hippocampal volume, and their interaction is associated with performance on Raven's Progressive Matrices.

    Science.gov (United States)

    Zhu, Bi; Chen, Chuansheng; Xue, Gui; Moyzis, Robert K; Dong, Qi; Chen, Chunhui; Li, Jin; He, Qinghua; Lei, Xuemei; Wang, Yunxin; Lin, Chongde

    2014-03-01

    The Allen Brain Atlas shows that the semaphorin 5A (SEMA5A) gene, which encodes an important protein for neurogenesis and neuronal apoptosis, is predominantly expressed in the human hippocampus. Structural and functional neuroimaging studies have further shown that the hippocampus plays an important role in the performance on Raven's Progressive Matrices (RPM), a measure of reasoning ability and general fluid intelligence. Thus far, however, no study has examined the relationships between the SEMA5A gene polymorphism, hippocampal volume, and RPM performance. The current study collected both structural MRI, genetic, and behavioral data in 329 healthy Chinese adults, and examined associations between SEMA5A variants, hippocampal volume, and performance on RAPM (the advanced form of RPM). After controlling for intracranial volume (ICV), sex, and age, SEMA5A genetic polymorphism at the SNP rs42352 had the strongest association with hippocampal volume (p=0.00000552 and 0.000103 for right and left hippocampal volumes, respectively), with TT homozygotes having higher hippocampal volume than the other genotypes. Furthermore, there was a high correlation between right hippocampal volume and RAPM performance (r=0.42, p=0.0000509) for SEMA5A rs42352 TT homozygotes. This study provides the first evidence for the involvement of the SEMA5A gene in hippocampal structure and their interaction on RAPM performance. Future studies of the hippocampus-RPM associations should consider genetic factors as potential moderators. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells

    Energy Technology Data Exchange (ETDEWEB)

    Nakabayashi, Hiroko; Ohta, Yasuharu, E-mail: yohta@yamaguchi-u.ac.jp; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio, E-mail: tanizawa@yamaguchi-u.ac.jp

    2013-05-03

    Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1{sup −/−} A{sup y}/a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the

  16. Chronic Ethanol Consumption Disrupts the Core Molecular Clock and Diurnal Rhythms of Metabolic Genes in the Liver without Affecting the Suprachiasmatic Nucleus

    Science.gov (United States)

    Filiano, Ashley N.; Millender-Swain, Telisha; Johnson, Russell; Young, Martin E.; Gamble, Karen L.; Bailey, Shannon M.

    2013-01-01

    Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease). However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef) were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN). These results were confirmed in Per2Luciferase knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to cause steatosis

  17. Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell-autonomous fashion.

    Science.gov (United States)

    Völkening, Bianca; Schönig, Kai; Kronenberg, Golo; Bartsch, Dusan; Weber, Tillmann

    2017-05-01

    Ca(2+) is a universal signal transducer which fulfills essential functions in cell development and differentiation. CACNA1C, the gene encoding the alpha-1C subunit (i.e., Cav 1.2) of the voltage-dependent l-type calcium channel (LTCC), has been implicated as a risk gene in a variety of neuropsychiatric disorders. To parse the role of Cav 1.2 channels located on astrocyte-like stem cells and their descendants in the development of new granule neurons, we created Tg(GLAST-CreERT2) /Cacna1c(fl/fl) /RCE:loxP mice, a transgenic tool that allows cell-type-specific inducible deletion of Cacna1c. The EGFP reporter was used to trace the progeny of recombined type-1 cells. FACS-sorted Cacna1c-deficient neural precursor cells from the dentate gyrus showed reduced proliferative activity in neurosphere cultures. Moreover, under differentiation conditions, Cacna1c-deficient NPCs gave rise to fewer neurons and more astroglia. Similarly, under basal conditions in vivo, Cacna1c gene deletion in type-1 cells decreased type-1 cell proliferation and reduced the neuronal fate-choice decision of newly born cells, resulting in reduced net hippocampal neurogenesis. Unexpectedly, electroconvulsive seizures completely compensated for the proliferation deficit of Cacna1c deficient type-1 cells, indicating that there must be Cav 1.2-independent mechanisms of controlling proliferation related to excitation. In the aggregate, this is the first report demonstrating the presence of functional L-type 1.2 channels on type-1 cells. Cav 1.2 channels promote type-1 cell proliferation and push the glia-to-neuron ratio in the direction of a neuronal fate choice and subsequent neuronal differentiation. Cav 1.2 channels expressed on NPCs and their progeny possess the ability to shape neurogenesis in a cell-autonomous fashion. © 2017 Wiley Periodicals, Inc.

  18. Chronic intermittent ethanol regulates hippocampal GABA(A receptor delta subunit gene expression

    Directory of Open Access Journals (Sweden)

    Paolo eFollesa

    2015-11-01

    Full Text Available Chronic ethanol consumption causes structural and functional reorganization in the hippocampus and induces alterations in the gene expression of gamma-aminobutyric acid type A receptors (GABAARs. Distinct forced intermittent exposure models have been used previously to investigate changes in GABAAR expression, with contrasting results. Here, we used repeated cycles of a Chronic Intermittent Ethanol paradigm to examine the relationship between voluntary, dependence-associated ethanol consumption and GABAAR gene expression in mouse hippocampus. Adult male C57BL/6J mice were exposed to four 16-h ethanol vapor (or air cycles in inhalation chambers alternated with limited-access two-bottle choice between ethanol (15% and water consumption. The mice exposed to ethanol vapor showed significant increases in ethanol consumption compared to their air-matched controls. GABAAR alpha4 and delta subunit gene expression were measured by qRT-PCR at different stages. There were significant changes in GABAAR delta subunit transcript levels at different time points in ethanol-vapor exposed mice, while the alpha4 subunit levels remained unchanged. Correlated concurrent blood ethanol concentrations suggested that GABAAR delta subunit mRNA levels fluctuate depending on ethanol intoxication, dependence, and withdrawal state. Using a vapor-based Chronic Intermittent Ethanol procedure with combined two-bottle choice consumption, we corroborated previous evidences showing that discontinuous ethanol exposure affects GABAAR delta subunit expression but we did not observe changes in alpha4 subunit. These findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a Chronic Intermittent Ethanol paradigm associated with voluntary intake, in response to ethanol-mediated disturbance of GABAergic neurotransmission.

  19. Biological clocks in theory and experiments

    OpenAIRE

    Millar Andrew J

    2005-01-01

    Eukaryotes and some prokaryotes have adapted to the 24 h day/night cycle by evolving circadian clocks. The circadian clock now controls 24-hour rhythms in very many aspects of metabolism, physiology and behaviour. Day-length (photoperiod) measurement depends on the circadian clock, so the 24 h clock mechanism also governs seasonal rhythms, such as reproduction. In the model plant species, Arabidopsis thaliana, the clock controls the expression of about 10% of genes, and this proportion is sim...

  20. Distinct epigenetic and gene expression changes in rat hippocampal neurons after Morris water maze training

    Directory of Open Access Journals (Sweden)

    Sylvia D. eCarter

    2015-06-01

    Full Text Available Gene transcription and translation in the hippocampus is of critical importance in hippocampus-dependent memory formation, including during Morris water maze (MWM learning. Previous work using gene deletion models has shown that the immediate-early genes (IEGs c-Fos, Egr-1 and Arc are crucial for such learning. Recently, we reported that induction of IEGs in sparse dentate gyrus neurons requires ERK MAPK signaling and downstream formation of a distinct epigenetic histone mark (i.e. phospho-acetylated histone H3. Until now, this signaling, epigenetic and gene transcriptional pathway has not been comprehensively studied in the MWM model. Therefore, we conducted a detailed study of the phosphorylation of ERK1/2 and serine10 in histone H3 (H3S10p and induction of IEGs in the hippocampus of MWM trained rats and matched controls. MWM training evoked consecutive waves of ERK1/2 phosphorylation and H3S10 phosphorylation, as well as c-Fos, Egr-1 and Arc induction in sparse hippocampal neurons. The observed effects were most pronounced in the dentate gyrus. A positive correlation was found between the average latency to find the platform and the number of H3S10p-positive dentate gyrus neurons. Furthermore, chromatin immuno-precipitation (ChIP revealed a significantly increased association of phospho-acetylated histone H3 (H3K9ac-S10p with the gene promoters of c-Fos and Egr-1, but not Arc, after MWM exposure compared with controls. Surprisingly, however, we found very little difference between IEG responses (regarding both protein and mRNA in MWM-trained rats compared with matched swim controls. We conclude that exposure to the water maze evokes ERK MAPK activation, distinct epigenetic changes and IEG induction predominantly in sparse dentate gyrus neurons. It appears, however, that a specific role for IEGs in the learning aspect of MWM training may become apparent in downstream AP-1- and Egr-1-regulated (second wave genes and Arc-dependent effector

  1. Expression patterns of a circadian clock gene are associated with age-related polyethism in harvester ants, Pogonomyrmex occidentalis

    Directory of Open Access Journals (Sweden)

    Ingram Krista K

    2009-04-01

    Full Text Available Abstract Background Recent advances in sociogenomics allow for comparative analyses of molecular mechanisms regulating the development of social behavior. In eusocial insects, one key aspect of their sociality, the division of labor, has received the most attention. Age-related polyethism, a derived form of division of labor in ants and bees where colony tasks are allocated among distinct behavioral phenotypes, has traditionally been assumed to be a product of convergent evolution. Previous work has shown that the circadian clock is associated with the development of behavior and division of labor in honeybee societies. We cloned the ortholog of the clock gene, period, from a harvester ant (Pogonomyrmex occidentalis and examined circadian rhythms and daily activity patterns in a species that represents an evolutionary origin of eusociality independent of the honeybee. Results Using real time qPCR analyses, we determined that harvester ants have a daily cyclic expression of period and this rhythm is endogenous (free-running under dark-dark conditions. Cyclic expression of period is task-specific; foragers have strong daily fluctuations but nest workers inside the nest do not. These patterns correspond to differences in behavior as activity levels of foragers show a diurnal pattern while nest workers tend to exhibit continuous locomotor activity at lower levels. In addition, we found that foragers collected in the early fall (relative warm, long days exhibit a delay in the nightly peak of period expression relative to foragers collected in the early spring (relative cold, short days. Conclusion The association of period mRNA expression levels with harvester ant task behaviors suggests that the development of circadian rhythms is associated with the behavioral development of ants. Thus, the circadian clock pathway may represent a conserved 'genetic toolkit' that has facilitated the parallel evolution of age-related polyethism and task allocation in

  2. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.

    Science.gov (United States)

    Nelson, Peter T; Estus, Steven; Abner, Erin L; Parikh, Ishita; Malik, Manasi; Neltner, Janna H; Ighodaro, Eseosa; Wang, Wang-Xia; Wilfred, Bernard R; Wang, Li-San; Kukull, Walter A; Nandakumar, Kannabiran; Farman, Mark L; Poon, Wayne W; Corrada, Maria M; Kawas, Claudia H; Cribbs, David H; Bennett, David A; Schneider, Julie A; Larson, Eric B; Crane, Paul K; Valladares, Otto; Schmitt, Frederick A; Kryscio, Richard J; Jicha, Gregory A; Smith, Charles D; Scheff, Stephen W; Sonnen, Joshua A; Haines, Jonathan L; Pericak-Vance, Margaret A; Mayeux, Richard; Farrer, Lindsay A; Van Eldik, Linda J; Horbinski, Craig; Green, Robert C; Gearing, Marla; Poon, Leonard W; Kramer, Patricia L; Woltjer, Randall L; Montine, Thomas J; Partch, Amanda B; Rajic, Alexander J; Richmire, KatieRose; Monsell, Sarah E; Schellenberg, Gerard D; Fardo, David W

    2014-01-01

    Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was

  3. Ontogeny of clock and KiSS-1 metastasis-suppressor (Kiss1) gene expression in the prepubertal mouse hypothalamus.

    Science.gov (United States)

    Yap, Cassandra C; Mark, Peter J; Waddell, Brendan J; Smith, Jeremy T

    2017-09-01

    Kisspeptin is crucial for the generation of the circadian-gated preovulatory gonadotrophin-releasing hormone (GnRH)-LH surge in female rodents, with expression in the anteroventral periventricular nucleus (AVPV) peaking in the late afternoon of pro-oestrus. Given kisspeptin expression is established before puberty, the aim of the present study was to investigate kisspeptin and clock gene rhythms during the neonatal period. Anterior and posterior hypothalami were collected from C57BL/6J mice on Postnatal Days (P) 5, 15 and 25, at six time points across 24h, for analysis of gene expression by reverse transcription-quantitative polymerase chain reaction. Expression of aryl hydrocarbon receptor nuclear translocator-like gene (Bmal1) and nuclear receptor subfamily 1, group D, member 2 (Rev-erbα) in the anterior hypothalamus (containing the suprachiasmatic nucleus) was not rhythmic at P5 or P15, but Bmal1 expression exhibited rhythmicity in P25 females, whereas Rev-erbα expression was rhythmic in P25 males. KiSS-1 metastasis-suppressor (Kiss1) expression did not exhibit time-of-day variation in the anterior (containing the AVPV) or posterior (containing the arcuate nucleus) hypothalami in female and male mice at P5, P15 or P25. The data indicate that the kisspeptin circadian peak in expression observed in the AVPV of pro-oestrous females does not manifest at P5, P15 or P25, likely due to inadequate oestrogenic stimuli, as well as incomplete development of clock gene rhythmicity before puberty.

  4. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence.

    Science.gov (United States)

    Yan, Han; Mitschelen, Matthew; Bixler, Georgina V; Brucklacher, Robert M; Farley, Julie A; Han, Song; Freeman, Willard M; Sonntag, William E

    2011-10-01

    GH and its anabolic mediator, IGF1, are important not only in somatic growth but also in the regulation of brain function. Even though GH treatment has been used clinically to improve body composition and exercise capacity in adults, its influence on central nervous system function has only recently been recognized. This is also the case for children with childhood-onset GH deficiency (GHD) where GH has been used to stimulate bone growth and enhance final adult height. Circulating IGF1 is transported across the blood-brain barrier and IGF1 and its receptors are also synthesized in the brain by neurons and glial and endothelial cells. Nevertheless, the relationship between circulating IGF1 and brain IGF1 remains unclear. This study, using a GH-deficient dwarf rat model and peripheral GH replacement, investigated the effects of circulating IGF1 during adolescence on IGF1 levels in the brain. Our results demonstrated that hippocampal IGF1 protein concentrations during adolescence are highly regulated by circulating IGF1, which were reduced by GHD and restored by systematic GH replacement. Importantly, IGF1 levels in the cerebrospinal fluid were decreased by GHD but not restored by GH replacement. Furthermore, analysis of gene expression using microarrays and RT-PCR indicated that circulating IGF1 levels did not modify the transcription of Igf1 or its receptor in the hippocampus but did regulate genes that are involved in microvascular structure and function, brain development, and synaptic plasticity, which potentially support brain structures involved in cognitive function during this important developmental period.

  5. Circadian clocks: Not your grandfather's clock.

    Science.gov (United States)

    Turek, Fred W

    2016-11-25

    The last 20 years have seen the rapid evolution of our understanding of the molecular genes and networks that enable almost all forms of life to generate 24-hour-or circadian-rhythms. One finding has been particularly exciting: that the molecular circadian clock resides in almost all of the cells of the body and that the clock regulates the timing of many cellular and signaling pathways associated with multiple disease states. Such advances represent a new frontier for medicine: circadian medicine. Copyright © 2016, American Association for the Advancement of Science.

  6. The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function.

    Science.gov (United States)

    Sawant, Onkar B; Horton, Amanda M; Zucaro, Olivia F; Chan, Ricky; Bonilha, Vera L; Samuels, Ivy S; Rao, Sujata

    2017-10-17

    Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone (TH)-activating enzyme type 2 iodothyronine deiodinase (Dio2) and thus regulates the expression of Dio2. TH treatment resulted in a partial rescue of the phenotype caused by the loss of Bmal1, thus revealing a functional relationship between Bmal1 and Dio2 in establishing cone photoreceptor identity. Furthermore, Bmal1 and Dio2 are required to maintain cone photoreceptor functional integrity. Overall, our results suggest a mechanism by which circadian proteins can locally regulate the availability of TH and influence tissue development and function. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Clock, Circadian Rhythms, and Breast Cancer

    National Research Council Canada - National Science Library

    Hill, Steven M

    2004-01-01

    .... Work involving circadian clock genes and cell cycle components suggests not only an association between the two time-keeping systems, but also regulation of the cell cycle by the circadian clock...

  8. The effect of high fat diet on daily rhythm of the core clock genes and muscle functional genes in the skeletal muscle of Chinese soft-shelled turtle (Trionyx sinensis).

    Science.gov (United States)

    Liu, Li; Jiang, Guomin; Peng, Zhitao; Li, Yulong; Li, Jinlong; Zou, Li; He, Zhigang; Wang, Xiaoqing; Chu, Wuying

    2017-11-01

    In the present study, we sought to investigate the influence of high fat diet on the core clock genes and the muscle functional genes daily expression in the skeletal muscle of Chinese soft-shelled turtle. The turtles were fed by two diets including a control fat diet (the CON treatment, 7.98% lipid) and a high fat diet (the HFD treatment, 13.86% lipid) for six weeks and administrated by the photophase regimen of 24h light/dark (12L:12D) cycle. After the feeding trial experiment, we measured the daily expression levels of 17 core clock genes (Clock, Bmal1/2, NPAS2, Tim, Cry1/2, Per1/2, DBP, AANAT, NIFL3, BHLHE40, NR1D2, RORA, RORB, RORC) and 12 muscle functional genes (FBXO32, MBNL1, MSTN, Myf5, Myf6, MyoD, MyoG, MyoM1, PPARa, PDK4, Trim63, UCP3) in the skeletal muscle of the two treatments. The results showed that except for Bmal1, NPAS2, Per2 and RORB, the expression of the other 13 core clock genes exhibited circadian oscillation in the CON treatment. Among the 12 muscle functional genes, MBNL1, PDK4 and MyoM1 did not exhibit circadian oscillation in the CON treatment. In the HFD treatment, the circadian rhythms expressional patterns of the 8 core clock genes (Clock, Bmal2, Cry2, Per1, DBP, NFIL3, BHLHE40 and RORA) and 6 muscle functional genes (MSTN, Myf5, MyoD, MyoG, PPARa and Trim63) were disrupted. In addition, compared with the CON treatment, the circadian expression of the 5 core clock genes (Tim, Cry1, AANAT, NR1D2, RORC) and the 3 muscle functional genes (FBXO32, Myf6, UCP3) showed the advanced or delayed expression peaks in the HFD treatment. In CON treatment, the circadian expression of the MyoG, MyoD, Myf6, FBXO32 and PPARa showed positive or negative correlation with the transcription pattern of Clock, Bmal2, Cry1/2, Per1/2. However, only the FBXO32 and Myf6 presented positive or negative correlation with the circadian expression of Cry1, RORB, AANAT and Tim in HFD treatment. In summary, these results demonstrate that the disruption of the circadian

  9. Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin: identification of cardiac clock-controlled genes using open access bioinformatics data.

    Directory of Open Access Journals (Sweden)

    Peter S Podobed

    Full Text Available Circadian rhythms are important for healthy cardiovascular physiology and are regulated at the molecular level by a circadian clock mechanism. We and others previously demonstrated that 9-13% of the cardiac transcriptome is rhythmic over 24 h daily cycles; the heart is genetically a different organ day versus night. However, which rhythmic mRNAs are regulated by the circadian mechanism is not known. Here, we used open access bioinformatics databases to identify 94 transcripts with expression profiles characteristic of CLOCK and BMAL1 targeted genes, using the CircaDB website and JTK_Cycle. Moreover, 22 were highly expressed in the heart as determined by the BioGPS website. Furthermore, 5 heart-enriched genes had human/mouse conserved CLOCK:BMAL1 promoter binding sites (E-boxes, as determined by UCSC table browser, circadian mammalian promoter/enhancer database PEDB, and the European Bioinformatics Institute alignment tool (EMBOSS. Lastly, we validated findings by demonstrating that Titin cap (Tcap, telethonin was targeted by transcriptional activators CLOCK and BMAL1 by showing 1 Tcap mRNA and TCAP protein had a diurnal rhythm in murine heart; 2 cardiac Tcap mRNA was rhythmic in animals kept in constant darkness; 3 Tcap and control Per2 mRNA expression and cyclic amplitude were blunted in Clock(Δ19/Δ19 hearts; 4 BMAL1 bound to the Tcap promoter by ChIP assay; 5 BMAL1 bound to Tcap promoter E-boxes by biotinylated oligonucleotide assay; and 6 CLOCK and BMAL1 induced tcap expression by luciferase reporter assay. Thus this study identifies circadian regulated genes in silico, with validation of Tcap, a critical regulator of cardiac Z-disc sarcomeric structure and function.

  10. Geography of the circadian gene clock and photoperiodic response in western North American populations of the three-spined stickleback Gasterosteus aculeatus.

    Science.gov (United States)

    O'Brien, C; Unruh, L; Zimmerman, C; Bradshaw, W E; Holzapfel, C M; Cresko, W A

    2013-03-01

    Controlled laboratory experiments were used to show that Oregon and Alaskan three-spined stickleback Gasterosteus aculeatus, collected from locations differing by 18° of latitude, exhibited no significant variation in length of the polyglutamine domain of the clock protein or in photoperiodic response within or between latitudes despite the fact that male and female G. aculeatus are photoperiodic at both latitudes. Hence, caution is urged when interpreting variation in the polyglutamine repeat (PolyQ) domain of the gene clock in the context of seasonal activities or in relationship to photoperiodism along geographical gradients. © 2013 The Authors. Journal of Fish Biology © 2013 The Fisheries Society of the British Isles.

  11. Genes associated with honey bee behavioral maturation affect clock-dependent and -independent aspects of daily rhythmic activity in fruit flies.

    Science.gov (United States)

    Fu, Chen; Whitfield, Charles W

    2012-01-01

    In the honey bee, the age-related and socially regulated transition of workers from in-hive task performance (e.g., caring for young) to foraging (provisioning the hive) is associated with changes in many behaviors including the 24-hour pattern of rhythmic activity. We have previously shown that the hive-bee to forager transition is associated with extensive changes in brain gene expression. In this study, we test the possible function of a subset of these genes in daily rhythmic activity pattern using neural-targeted RNA interference (RNAi) of an orthologous gene set in Drosophila melanogaster. Of 10 genes tested, knockdown of six affected some aspect of locomotor activity under a 12 h:h light:dark regime (LD). Inos affected anticipatory activity preceding lights-off, suggesting a possible clock-dependent function. BM-40-SPARC, U2af50 and fax affected peak activity at dawn without affecting anticipation or overall inactivity (proportion of 15-min intervals without activity), suggesting that these effects may depend on the day-night light cycle. CAH1 affected overall inactivity. The remaining gene, abl, affected peak activity levels but was not clearly time-of-day-specific. No gene tested affected length of period or strength of rhythmicity in constant dark (DD), suggesting that these genes do not act in the core clock. Taking advantage of Drosophila molecular genetic tools, our study provides an important step in understanding the large set of gene expression changes that occur in the honey bee transition from hive bee to forager. We show that orthologs of many of these genes influence locomotor activity in Drosophila, possibly through both clock-dependent and -independent pathways. Our results support the importance of both circadian clock and direct environmental stimuli (apart from entrainment) in shaping the bee's 24-hour pattern of activity. Our study also outlines a new approach to dissecting complex behavior in a social animal.

  12. Genes associated with honey bee behavioral maturation affect clock-dependent and -independent aspects of daily rhythmic activity in fruit flies.

    Directory of Open Access Journals (Sweden)

    Chen Fu

    Full Text Available BACKGROUND: In the honey bee, the age-related and socially regulated transition of workers from in-hive task performance (e.g., caring for young to foraging (provisioning the hive is associated with changes in many behaviors including the 24-hour pattern of rhythmic activity. We have previously shown that the hive-bee to forager transition is associated with extensive changes in brain gene expression. In this study, we test the possible function of a subset of these genes in daily rhythmic activity pattern using neural-targeted RNA interference (RNAi of an orthologous gene set in Drosophila melanogaster. PRINCIPAL FINDINGS: Of 10 genes tested, knockdown of six affected some aspect of locomotor activity under a 12 h:h light:dark regime (LD. Inos affected anticipatory activity preceding lights-off, suggesting a possible clock-dependent function. BM-40-SPARC, U2af50 and fax affected peak activity at dawn without affecting anticipation or overall inactivity (proportion of 15-min intervals without activity, suggesting that these effects may depend on the day-night light cycle. CAH1 affected overall inactivity. The remaining gene, abl, affected peak activity levels but was not clearly time-of-day-specific. No gene tested affected length of period or strength of rhythmicity in constant dark (DD, suggesting that these genes do not act in the core clock. SIGNIFICANCE: Taking advantage of Drosophila molecular genetic tools, our study provides an important step in understanding the large set of gene expression changes that occur in the honey bee transition from hive bee to forager. We show that orthologs of many of these genes influence locomotor activity in Drosophila, possibly through both clock-dependent and -independent pathways. Our results support the importance of both circadian clock and direct environmental stimuli (apart from entrainment in shaping the bee's 24-hour pattern of activity. Our study also outlines a new approach to dissecting complex

  13. Human CLOCK gene-associated attention deficit hyperactivity disorder-related features in healthy adults: quantitative association study using Wender Utah Rating Scale.

    Science.gov (United States)

    Jeong, Seong Hoon; Yu, Je-Chun; Lee, Chang Hwa; Choi, Kyeong-Sook; Choi, Jung-Eun; Kim, Se Hyun; Joo, Eun-Jeong

    2014-02-01

    Circadian rhythm disturbance is highly prevalent in attention deficit hyperactivity disorder (ADHD). Recently, the association between the CLOCK gene and ADHD has been demonstrated in clinical samples, and the CLOCK gene's role was thought to be mediated by rhythm dysregulation. Meanwhile, ADHD has been suggested as the extreme end of a continuously distributed trait that can be found in the general population. Therefore, we examined two possibilities: (1) an ADHD-related continuous trait may be associated with the CLOCK gene, and (2) this association may be mediated by the degree of individuals' evening preference. To explore these possibilities, we performed a quantitative trait locus association study with a sample of 1,289 healthy adults. The Wender Utah Rating Scale (WURS) and the Composite Scale of Morningness (CSM) were utilized to measure the quantitative traits. Quantitative association analysis was performed using PLINK software. We found that rs1801260 (=T3111C) was associated with WURS scores in both allele-wise (p = 0.018) and haplotype-wise analyses (range of p values: 0.0155-0.0171) in male participants only. After controlling for the CSM total score as a covariate, the strength of the association did not change at all, suggesting that the association was not mediated by evening preference. Despite the very weak association signal, our results provide evidence that the CLOCK gene's association with ADHD in clinical samples may be generalizable to traits measured in the normal population. However, as our results failed to show a mediating role of evening preference, ongoing efforts are needed to identify the mechanisms by which the CLOCK gene determines ADHD-related traits.

  14. Effects of continuous white light and 12h white-12h blue light-cycles on the expression of clock genes in diencephalon, liver, and skeletal muscle in chicks.

    Science.gov (United States)

    Honda, Kazuhisa; Kondo, Makoto; Hiramoto, Daichi; Saneyasu, Takaoki; Kamisoyama, Hiroshi

    2017-05-01

    The core circadian clock mechanism relies on a feedback loop comprised of clock genes, such as the brain and muscle Arnt-like 1 (Bmal1), chriptochrome 1 (Cry1), and period 3 (Per3). Exposure to the light-dark cycle synchronizes the master circadian clock in the brain, and which then synchronizes circadian clocks in peripheral tissues. Birds have long been used as a model for the investigation of circadian rhythm in human neurobiology. In the present study, we examined the effects of continuous light and the combination of white and blue light on the expression of clock genes (Bmal1, Cry1, and Per3) in the central and peripheral tissues in chicks. Seventy two day-old male chicks were weighed, allocated to three groups and maintained under three light schedules: 12h white light-12h dark-cycles group (control); 24h white light group (WW group); 12h white light-12h blue light-cycles group (WB group). The mRNA levels of clock genes in the diencephalon were significantly different between the control and WW groups. On the other hand, the alteration in the mRNA levels of clock genes was similar between the control and WB groups. Similar phenomena were observed in the liver and skeletal muscle (biceps femoris). These results suggest that 12h white-12h blue light-cycles did not disrupt the circadian rhythm of clock gene expression in chicks. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Circadian clock gene aryl hydrocarbon receptor nuclear translocator-like polymorphisms are associated with seasonal affective disorder: An Indian family study

    OpenAIRE

    Rajendran, Bhagya; Janakarajan, Veeramahali Natarajan

    2016-01-01

    Background and Aim: Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms. Materials and Methods: In this study, 30 members of close-knit family with SAD, 30 age- and sex-matched controls of the same ca...

  16. Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy.

    Science.gov (United States)

    Miller-Delaney, Suzanne F C; Bryan, Kenneth; Das, Sudipto; McKiernan, Ross C; Bray, Isabella M; Reynolds, James P; Gwinn, Ryder; Stallings, Raymond L; Henshall, David C

    2015-03-01

    Temporal lobe epilepsy is associated with large-scale, wide-ranging changes in gene expression in the hippocampus. Epigenetic changes to DNA are attractive mechanisms to explain the sustained hyperexcitability of chronic epilepsy. Here, through methylation analysis of all annotated C-phosphate-G islands and promoter regions in the human genome, we report a pilot study of the methylation profiles of temporal lobe epilepsy with or without hippocampal sclerosis. Furthermore, by comparative analysis of expression and promoter methylation, we identify methylation sensitive non-coding RNA in human temporal lobe epilepsy. A total of 146 protein-coding genes exhibited altered DNA methylation in temporal lobe epilepsy hippocampus (n = 9) when compared to control (n = 5), with 81.5% of the promoters of these genes displaying hypermethylation. Unique methylation profiles were evident in temporal lobe epilepsy with or without hippocampal sclerosis, in addition to a common methylation profile regardless of pathology grade. Gene ontology terms associated with development, neuron remodelling and neuron maturation were over-represented in the methylation profile of Watson Grade 1 samples (mild hippocampal sclerosis). In addition to genes associated with neuronal, neurotransmitter/synaptic transmission and cell death functions, differential hypermethylation of genes associated with transcriptional regulation was evident in temporal lobe epilepsy, but overall few genes previously associated with epilepsy were among the differentially methylated. Finally, a panel of 13, methylation-sensitive microRNA were identified in temporal lobe epilepsy including MIR27A, miR-193a-5p (MIR193A) and miR-876-3p (MIR876), and the differential methylation of long non-coding RNA documented for the first time. The present study therefore reports select, genome-wide DNA methylation changes in human temporal lobe epilepsy that may contribute to the molecular architecture of the epileptic brain. © The

  17. Mapping-by-Sequencing Identifies HvPHYTOCHROME C as a Candidate Gene for the early maturity 5 Locus Modulating the Circadian Clock and Photoperiodic Flowering in Barley

    Science.gov (United States)

    Pankin, Artem; Campoli, Chiara; Dong, Xue; Kilian, Benjamin; Sharma, Rajiv; Himmelbach, Axel; Saini, Reena; Davis, Seth J; Stein, Nils; Schneeberger, Korbinian; von Korff, Maria

    2014-01-01

    Phytochromes play an important role in light signaling and photoperiodic control of flowering time in plants. Here we propose that the red/far-red light photoreceptor HvPHYTOCHROME C (HvPHYC), carrying a mutation in a conserved region of the GAF domain, is a candidate underlying the early maturity 5 locus in barley (Hordeum vulgare L.). We fine mapped the gene using a mapping-by-sequencing approach applied on the whole-exome capture data from bulked early flowering segregants derived from a backcross of the Bowman(eam5) introgression line. We demonstrate that eam5 disrupts circadian expression of clock genes. Moreover, it interacts with the major photoperiod response gene Ppd-H1 to accelerate flowering under noninductive short days. Our results suggest that HvPHYC participates in transmission of light signals to the circadian clock and thus modulates light-dependent processes such as photoperiodic regulation of flowering. PMID:24996910

  18. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Michael Verwey

    2016-08-01

    Full Text Available Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN, the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease. For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson’s disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms.

  19. CBF gene expression in peach leaf and bark tissues is gated by a circadian clock

    Science.gov (United States)

    CBF transcription factors are part of the AP2/ERF domain family of DNA-binding proteins that recognize a C-repeat response cis-acting element that regulates a number of cold-responsive genes (CBF-regulon). In peach (Prunus persica), five CBF genes are situated in tandem on scaffold (Linkage Group) ...

  20. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism.

    Science.gov (United States)

    Shiraki, Ayako; Saito, Fumiyo; Akane, Hirotoshi; Akahori, Yumi; Imatanaka, Nobuya; Itahashi, Megu; Yoshida, Toshinori; Shibutani, Makoto

    2016-01-01

    We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. Copyright © 2015 John Wiley & Sons, Ltd.

  1. CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet

    Science.gov (United States)

    Introduction: The success of obesity therapy is dependent on the genetic background of the patient. Circadian Locomotor Output Cycles Kaput (CLOCK), one of the transcription factors from the positive limb of the molecular clock, is involved in metabolic alterations. Objective: To investigate whethe...

  2. Effects of circadian clock genes and health-related behavior on metabolic syndrome in a Taiwanese population: Evidence from association and interaction analysis.

    Directory of Open Access Journals (Sweden)

    Eugene Lin

    Full Text Available Increased risk of developing metabolic syndrome (MetS has been associated with the circadian clock genes. In this study, we assessed whether 29 circadian clock-related genes (including ADCYAP1, ARNTL, ARNTL2, BHLHE40, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, GSK3B, HCRTR2, KLF10, NFIL3, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, REV1, RORA, RORB, RORC, SENP3, SERPINE1, TIMELESS, TIPIN, VIP, and VIPR2 are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with several single nucleotide polymorphisms (SNPs in five key circadian clock genes including ARNTL, GSK3B, PER3, RORA, and RORB; but none of these SNPs persisted significantly after performing Bonferroni correction. Moreover, we identified the effect of GSK3B rs2199503 on high fasting glucose (P = 0.0002. Additionally, we found interactions among the ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, RORA rs8034880, and RORB rs972902 SNPs influenced MetS (P < 0.001 ~ P = 0.002. Finally, we investigated the influence of interactions between ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, and RORB rs972902 with environmental factors such as alcohol consumption, smoking status, and physical activity on MetS and its individual components (P < 0.001 ~ P = 0.002. Our study indicates that circadian clock genes such as ARNTL, GSK3B, PER3, RORA, and RORB genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.

  3. The modern molecular clock.

    Science.gov (United States)

    Bromham, Lindell; Penny, David

    2003-03-01

    The discovery of the molecular clock--a relatively constant rate of molecular evolution--provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology. The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral. Theory predicts several sources of variation in the rate of molecular evolution. However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.

  4. Clock Genes Explain a Large Proportion of Phenotypic Variance in Systolic Blood Pressure and This Control Is Not Modified by Environmental Temperature.

    Science.gov (United States)

    Dashti, Hassan S; Aslibekyan, Stella; Scheer, Frank A J L; Smith, Caren E; Lamon-Fava, Stefania; Jacques, Paul; Lai, Chao-Qiang; Tucker, Katherine L; Arnett, Donna K; Ordovás, José M

    2016-01-01

    Diurnal variation in blood pressure (BP) is regulated, in part, by an endogenous circadian clock; however, few human studies have identified associations between clock genes and BP. Accounting for environmental temperature may be necessary to correct for seasonal bias. We examined whether environmental temperature on the day of participants' assessment was associated with BP, using adjusted linear regression models in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) (n = 819) and the Boston Puerto Rican Health Study (BPRHS) (n = 1,248) cohorts. We estimated phenotypic variance in BP by 18 clock genes and examined individual single-nucleotide polymorphism (SNP) associations with BP using an additive genetic model, with further consideration of environmental temperature. In GOLDN, each additional 1 °C increase in environmental temperature was associated with 0.18 mm Hg lower systolic BP [SBP; β ± SE = -0.18 ± 0.05 mm Hg; P = 0.0001] and 0.10mm Hg lower diastolic BP [DBP; -0.10 ± 0.03 mm Hg; P = 0.001]. Similar results were seen in the BPRHS for SBP only. Clock genes explained a statistically significant proportion of the variance in SBP [V G/V P ± SE = 0.071 ± 0.03; P = 0.001] in GOLDN, but not in the BPRHS, and we did not observe associations between individual SNPs and BP. Environmental temperature did not influence the identified genetic associations. We identified clock genes that explained a statistically significant proportion of the phenotypic variance in SBP, supporting the importance of the circadian pathway underlying cardiac physiology. Although temperature was associated with BP, it did not affect results with genetic markers in either study. Therefore, it does not appear that temperature measures are necessary for interpreting associations between clock genes and BP. Trials related to this study were registered at clinicaltrials.gov as NCT00083369 (Genetic and Environmental Determinants of Triglycerides) and NCT01231958 (Boston Puerto

  5. Molecular cloning, characterization, and temporal expression of the clock genes period and timeless in the oriental river prawn Macrobrachium nipponense during female reproductive development.

    Science.gov (United States)

    Chen, SuHua; Qiao, Hui; Fu, HongTuo; Sun, Shengming; Zhang, WenYi; Jin, ShuBo; Gong, Yongsheng; Jiang, Sufei; Xiong, Weiyi; YanWu

    2017-05-01

    The circadian clock is crucial for sustaining rhythmic biochemical, physiological, and behavioral processes in living creatures. In this study, we isolated and characterized two circadian clock genes in Macrobrachium nipponense, period (Mnper) and timeless (Mntim). The complete Mnper cDNA measures 4283bp in length with an open reading frame encoding 1292 amino acids, including functional domains such as PER-ARNT-SIM (PAS), cytoplasmic localization domain (CLD), TIM interaction site (TIS), and nuclear localization signal (NLS). The deduced Mntim protein comprises1540 amino acids with functional domains such as PER interaction site (PIS), NLS, and CLD. Tissue distribution analyses showed that the two genes were highly expressed in the eyestalk and brain in both males and females, as well as being expressed in the ovary. The expression profiles of Mnper and Mntim were determined in the eyestalk, brain, and ovary under simulated breeding season and non-breeding season conditions. The expression profiles of both Mnper and Mntim appeared to be unaffected in the eyestalk. However, the expression of both genes exhibited significant seasonal variations in the brain, and thus we assumed the brain to be their functional location. The expression profiles under different simulated seasons and the variations during different ovarian stages indicate that both genes might be involved with female reproduction. Especially the mRNA levels in the brain varied greatly during these stages indicating that the clock function in the brain is closely related to ovarian development and female reproduction. And the reproductive roles of clock genes need to be elucidated. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Zbtb20 Defines a Hippocampal Neuronal Identity Through Direct Repression of Genes That Control Projection Neuron Development in the Isocortex

    DEFF Research Database (Denmark)

    Nielsen, Jakob V; Thomassen, Mads; Møllgård, Kjeld

    2014-01-01

    Hippocampal pyramidal neurons are important for encoding and retrieval of spatial maps and episodic memories. While previous work has shown that Zbtb20 is a cell fate determinant for CA1 pyramidal neurons, the regulatory mechanisms governing this process are not known. In this study, we demonstrate...... that Zbtb20 binds to genes that control neuronal subtype specification in the developing isocortex, including Cux1, Cux2, Fezf2, Foxp2, Mef2c, Rorb, Satb2, Sox5, Tbr1, Tle4, and Zfpm2. We show that Zbtb20 represses these genes during ectopic CA1 pyramidal neuron development in transgenic mice. These data...... reveal a novel regulatory mechanism by which Zbtb20 suppresses the acquisition of an isocortical fate during archicortical neurogenesis to ensure commitment to a CA1 pyramidal neuron fate. We further show that the expression pattern of Zbtb20 is evolutionary conserved in the fetal human hippocampus...

  7. Chronic consumption of a low-fat diet improves cardiometabolic risk factors according to the CLOCK gene in patients with coronary heart disease.

    Science.gov (United States)

    Gomez-Delgado, Francisco; Garcia-Rios, Antonio; Alcala-Diaz, Juan Francisco; Rangel-Zuñiga, Oriol; Delgado-Lista, Javier; Yubero-Serrano, Elena M; Lopez-Moreno, Javier; Tinahones, Francisco Jose; Ordovas, Jose M; Garaulet, Marta; Lopez-Miranda, Jose; Perez-Martinez, Pablo

    2015-12-01

    Single nucleotide polymorphisms (SNPs) of the circadian locomotor output cycles kaput (CLOCK) gene have been associated with cardiometabolic conditions such as obesity and dyslipidemia. Our aim was to examine whether the chronic consumption of two healthy diets interacts with SNPs of the CLOCK gene in order to improve lipid metabolism and inflammation status in patients with coronary heart disease (CHD). The diets were low-fat (LF) diet and Mediterranean diet (MedDiet). CLOCK SNPs (rs1801260, rs3749474, rs4580704) and the study procedures were performed in 897 patients from the CORDIOPREV clinical trial. After 12 months of intervention, we found significant gene-diet interactions between rs4580704 SNP and the LF diet. Specifically, major allele carriers C/C displayed a greater decrease in high sensitivity C-reactive protein (p diet interactions were observed in this research. These results suggest that rs4580704 SNP interacts with the LF diet improving inflammation status and dyslipidemia related with CHD. The shift toward "personalized nutrition" based on gene-nutrient interactions may be suitable for promoting cardiovascular health in patients with CHD. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Genetic Association of the PERIOD3 (Per3) Clock Gene with Bipolar Disorder.

    Science.gov (United States)

    Brasil Rocha, Paulo Marcos; Campos, Simone Becho; Neves, Fernando Silva; da Silva Filho, Humberto Corrêa

    2017-09-01

    Circadian rhythms have been linked to psychiatric disorders such as Depression and Bipolar Disorder (BD). Given previous evidences of sleep/circadian disturbances as well as the genetic susceptibility for BD, we decided to investigate the possible link between the PERIOD3 (Per3) circadian gene and BD. This is a genetic association case (BD) vs. control study of the Per3 gene. We further subdivided our BD sample into "good sleepers" (PSQI ≤5) and "poor sleepers" (PSQI>5) according to the Pittsburgh Sleep Quality Index (PSQI) global score, and then we assessed genetic association of the Per3 gene with sleep quality in the BD group. There were 209 cases and 213 controls in our sample. The GT genotype of the SNP rs707467 significantly associated with BD (χ2=8.80; p-value=0.01; adjusted residual=±2.6). We also found significant association of the SNP rs10462020 allele T with BD (χ2=5.81; p-value=0.01) as well as the genotype TT (χ2= 6.01; p-value=0.04; adjusted residual=±2.4). In this study we demonstrated evidences of genetic association between the Per3 gene and BD. The results of association between the Per3 gene and BD in our sample may bring additional evidence to the former findings of association between the Per3 gene and BD.

  9. Developmental hypothyroidism abolishes bilateral differences in sonic hedgehog gene control in the rat hippocampal dentate gyrus.

    Science.gov (United States)

    Tanaka, Takeshi; Wang, Liyun; Kimura, Masayuki; Abe, Hajime; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2015-03-01

    Both developmental and adult-stage hypothyroidism disrupt rat hippocampal neurogenesis. We previously showed that exposing mouse offspring to manganese permanently disrupts hippocampal neurogenesis and abolishes the asymmetric distribution of cells expressing Mid1, a molecule regulated by sonic hedgehog (Shh) signaling. The present study examined the involvement of Shh signaling on the disruption of hippocampal neurogenesis in rats with hypothyroidism. Pregnant rats were treated with methimazole (MMI) at 0 or 200 ppm in the drinking water from gestation day 10-21 days after delivery (developmental hypothyroidism). Adult male rats were treated with MMI in the same manner from postnatal day (PND) 46 to PND 77 (adult-stage hypothyroidism). Developmental hypothyroidism reduced the number of Mid1(+) cells within the subgranular zone of the dentate gyrus of offspring on PND 21, and consequently abolished the normal asymmetric predominance of Mid1(+) cells on the right side through the adult stage. In control animals, Shh was expressed in a subpopulation of hilar neurons, showing asymmetric distribution with left side predominance on PND 21; however, this asymmetry did not continue through the adult stage. Developmental hypothyroidism increased Shh(+) neurons bilaterally and abolished the asymmetric distribution pattern on PND 21. Adult hypothyroidism also disrupted the asymmetric distribution of Mid1(+) cells but did not affect the distribution of Shh(+) hilar neurons. The results suggest that the hippocampal neurogenesis disruption seen in hypothyroidism involves changes in asymmetric Shh(+) neuron distribution in developmental hypothyroidism and altered Mid1 expression in both developmental and adult-stage hypothyroidism. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Melatonin adjusts the expression pattern of clock genes in the suprachiasmatic nucleus and induces antidepressant-like effect in a mouse model of seasonal affective disorder.

    Science.gov (United States)

    Nagy, Andras David; Iwamoto, Ayaka; Kawai, Misato; Goda, Ryosei; Matsuo, Haruka; Otsuka, Tsuyoshi; Nagasawa, Mao; Furuse, Mitsuhiro; Yasuo, Shinobu

    2015-05-01

    Recently, we have shown that C57BL/6J mice exhibit depression-like behavior under short photoperiod and suggested them as an animal model for investigating seasonal affective disorder (SAD). In this study, we tested if manipulations of the circadian clock with melatonin treatment could effectively modify depression-like and anxiety-like behaviors and brain serotonergic system in C57BL/6J mice. Under short photoperiods (8-h light/16-h dark), daily melatonin treatments 2 h before light offset have significantly altered the 24-h patterns of mRNA expression of circadian clock genes (per1, per2, bmal1 and clock) within the suprachiasmatic nuclei (SCN) mostly by increasing amplitude in their expressional rhythms without inducing robust phase shifts in them. Melatonin treatments altered the expression of genes of serotonergic neurotransmission in the dorsal raphe (tph2, sert, vmat2 and 5ht1a) and serotonin contents in the amygdala. Importantly, melatonin treatment reduced the immobility in forced swim test, a depression-like behavior. As a key mechanism of melatonin-induced antidepressant-like effect, the previously proposed phase-advance hypothesis of the circadian clock could not be confirmed under conditions of our experiment. However, our findings of modest adjustments in both the amplitude and phase of the transcriptional oscillators in the SCN as a result of melatonin treatments may be sufficient to associate with the effects seen in the brain serotonergic system and with the improvement in depression-like behavior. Our study confirmed a predictive validity of C57BL/6J mice as a useful model for the molecular analysis of links between the clock and brain serotonergic system, which could greatly accelerate our understanding of the pathogenesis of SAD, as well as the search for new treatments.

  11. Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.

    LENUS (Irish Health Repository)

    Frodl, T

    2012-01-01

    Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and\\/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

  12. Circadian and acamprosate modulation of elevated ethanol drinking in mPer2 clock gene mutant mice.

    Science.gov (United States)

    Brager, Allison J; Prosser, Rebecca A; Glass, J David

    2011-10-01

    The PER2 clock gene modulates ethanol consumption, such that mutant mice not expressing functional mPer2 have altered circadian behavior that promotes higher ethanol intake and preference. Experiments were undertaken to characterize circadian-related behavioral effects of mPer2 deletion on ethanol intake and to explore how acamprosate (used to reduce alcohol dependence) alters diurnal patterns of ethanol intake. Male mPer2 mutant and WT (wild-type) mice were entrained to a 12:12 h light-dark (12L:12D) photocycle, and their locomotor and drinking activities were recorded. Circadian locomotor measurements confirmed that mPer2 mutants had an advanced onset of nocturnal activity of about 2 h relative to WTs, and an increased duration of nocturnal activity (p drinking episodes vs. WTs. Measurements of systemic ethanol using subcutaneous microdialysis confirmed the advanced rise in ethanol intake in the mPer2 mutants, with 24-h averages being ∼60 vs. ∼25 mM for WTs (p drinking in the mPer2 mutants, but reduced the overall amplitude of drinking and preference (both p drinking activity. The suppressive action of acamprosate on ethanol intake is not due to an altered diurnal pattern of drinking, but rather a decrease in the number of daily drinking bouts and amount of drinking per bout.

  13. Investigation of 3111T/C polymorphism of the CLOCK gene in obese individuals with or without binge eating disorder: association with higher body mass index.

    Science.gov (United States)

    Monteleone, Palmiero; Tortorella, Alfonso; Docimo, Ludovico; Maldonato, Mauro N; Canestrelli, Benedetta; De Luca, Luca; Maj, Mario

    2008-04-11

    Loss of circadian patterning of metabolism-related functions seems to play a role in the pathogenesis of obesity; therefore, it is reasonable to hypothesize that the functional 3111T/C single nucleotide polymorphism (SNP) of the (Circadian locomotor output cycles kaput) CLOCK gene may have a part in the genetic susceptibility to obesity. The aim of this study was to assess the frequencies of 3111T/C CLOCK gene SNP in overweight/obese subjects with or without binge eating disorder (BED) as compared to normal weight healthy controls. A total of 284 Caucasian subjects, including 92 normal weight healthy subjects and 192 overweight/obese patients (107 with BED) participated into the study. Genotype and allele frequencies did not significantly differ between normal weight controls and overweight/obese patients with and/or without BED. However, overweight/obese patients carrying the CC genotype had significantly higher values of body mass index (BMI) as compared to those carrying the CT and/or TT genotypes. Moreover, obese class III individuals had a significantly higher frequency of both the CC genotype and the C allele as compared to individuals with BMISNP of the CLOCK gene is not associated to human obesity and/or BED, but it seems to predispose obese individuals to a higher BMI.

  14. Daily rhythm variations of the clock gene PER1 and cancer-related genes during various stages of carcinogenesis in a golden hamster model of buccal mucosa carcinoma.

    Science.gov (United States)

    Ye, Hua; Yang, Kai; Tan, Xue-Mei; Fu, Xiao-Juan; Li, Han-Xue

    2015-01-01

    Recent studies have demonstrated that the clock gene PER1 regulates various tumor-related genes. Abnormal expressions and circadian rhythm alterations of PER1 are closely related to carcinogenesis. However, the dynamic circadian variations of PER1 and tumor-related genes at different stages of carcinogenesis remain unknown. This study was conducted to investigate the daily rhythm variation of PER1 and expression of tumor-related genes VEGF, KI67, C-MYC, and P53 in different stages of carcinogenesis. Dimethylbenzanthracene was used to establish a golden hamster model of buccal mucosa carcinogenesis. Hamsters with normal buccal mucosa, precancerous lesion, and cancerous lesion were sacrificed at six different time points during a 24-hour period of a day. Pathological examination was conducted using routine hematoxylin and eosin staining. PER1, VEGF, KI67, C-MYC, and P53 mRNAs were detected by real-time reverse transcriptase polymerase chain reaction, and a cosinor analysis was applied to analyze the daily rhythm. PER1, VEGF, C-MYC, and P53 mRNA exhibited daily rhythmic expression in three carcinogenesis stages, and KI67 mRNA exhibited daily rhythmic expression in the normal and precancerous stages. The daily rhythmic expression of KI67 was not observed in cancerous stages. The mesor and amplitude of PER1 and P53 mRNA expression decreased upon the development of cancer (Pclock gene PER1 and tumor-related genes VEGF, KI67, C-MYC, and P53 correlate with the development of cancer. Additional studies might provide new insights and methods to explore carcinogenic mechanisms and cancer treatment.

  15. Circadian clock components in the rat neocortex

    DEFF Research Database (Denmark)

    Rath, Martin Fredensborg; Rohde, Kristian; Fahrenkrug, Jan

    2013-01-01

    The circadian master clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the clock of the SCN is driven by a transcriptional/posttranslational autoregulatory network with clock gene products as core elements. Recent investigations...... in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene...... expression in the neocortex is dependent on the SCN. In situ hybridization and immunohistochemistry showed that products of the canonical clock gene Per2 are located in perikarya throughout all areas of the neocortex. These findings show that local circadian oscillators driven by the SCN reside within...

  16. Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish

    Directory of Open Access Journals (Sweden)

    Lasse Dahl Jensen

    2012-08-01

    Full Text Available Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.

  17. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome.

    Science.gov (United States)

    Garcia-Rios, Antonio; Gomez-Delgado, Francisco Jesus; Garaulet, Marta; Alcala-Diaz, Juan Francisco; Delgado-Lista, Francisco Javier; Marin, Carmen; Rangel-Zuñiga, Oriol Alberto; Rodriguez-Cantalejo, Fernando; Gomez-Luna, Purificacion; Ordovas, Jose Maria; Perez-Jimenez, Francisco; Lopez-Miranda, Jose; Perez-Martinez, Pablo

    2014-04-01

    Genetic variation at the Circadian Locomotor Output Cycles Kaput (CLOCK) locus has been associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular diseases. In fact, it has been suggested that the disruption of the circadian system may play a causal role in manifestations of MetS. The aim of this research was to find out whether habitual consumption of a low-fat diet, compared with a Mediterranean diet enriched with olive oil, modulates the associations between common CLOCK single nucleotide polymorphisms (SNPs) (rs1801260, rs3749474 and rs4580704) and lipid and glucose-related traits among MetS patients. Plasma lipid and insulin concentrations, indexes related with insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)) and CLOCK SNPs were determined in 475 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% monounsaturated fatty acids (MUFA)) versus low-fat diet (28% fat, 12% MUFA)). We found significant gene-diet interactions between rs1801260 SNP and the dietary pattern for insulin concentrations (p = 0.009), HOMA-IR (p = 0.014) and QUICKI (p = 0.028). Specifically, after 12 months of low-fat intervention, subjects who were homozygous for the major allele (TT) displayed lower plasma insulin concentrations (p = 0.032), lower insulin resistance (HOMA-IR; p = 0.027) and higher insulin sensitivity (QUICKI; p = 0.024) compared with carriers of the minor allele C (TC + CC). In contrast, in the Mediterranean intervention group a different trend was observed although no significant differences were found between CLOCK genotypes after 12 months of treatment. Our data support the notion that a chronic consumption of a healthy diet may play a contributing role in triggering glucose metabolism by interacting with

  18. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Steven G Potkin

    Full Text Available BACKGROUND: With the exception of APOE epsilon4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD are unknown. METHODS AND FINDINGS: We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/. Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40, at a genome-wide significance level of < or =10(-6 (10(-11 for a haplotype. TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value < or =10(-6, which can be considered potential "new" candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication. CONCLUSIONS: Using

  19. Gender effects of single nucleotide polymorphisms and miRNAs targeting clock-genes in metastatic colorectal cancer patients (mCRC).

    Science.gov (United States)

    Garufi, Carlo; Giacomini, Elisa; Torsello, Angela; Sperduti, Isabella; Melucci, Elisa; Mottolese, Marcella; Zeuli, Massimo; Ettorre, Giuseppe Maria; Ricciardi, Teresa; Cognetti, Francesco; Magnani, Mauro; Ruzzo, Annamaria

    2016-09-26

    The circadian system is composed of a set of clock-genes including PERIOD, CLOCK, BMAL1 and CRY. Disrupting this system promotes cancer development and progression. The expression levels of miR-206, miR-219, miR-192, miR-194 and miR-132 regulating clock-genes and three functional polymorphisms rs11133373 C/G, rs1801260 T/C, rs11133391 T/C in CLOCK sequence were associated with the survival of 83 mCRC patients (50 males and 33 females). Longer overall survival (OS) was observed in women compared to men, 50 versus 31 months. This difference was associated with rs11133373 C/C genotype (p = 0.01), rs1801260 T/C+C/C genotype (p = 0.06) and rs11133391 T/T genotype (p = 0.06). Moreover women expressing high levels (H) of miR-192 (p = 0.03), miR-206 (p = 0.003), miR-194 (p = 0.02) and miR-219 (p = 0.002) had a longer OS compared to men. In women longer OS was reinforced by the simultaneous presence of two or more H-miR, 58 months versus 15 months (p = 0.0008); in this group of women an OS of 87 months was reached with the additional presence of rs11133391T/T genotype (p = 0.02). In this study we identified a subgroup of female patients who seems to have a better prognosis. Personalized medicine should prospectively take into account both genetic and gender differences.

  20. Human melatonin and alerting response to blue-enriched light depend on a polymorphism in the clock gene PER3.

    Science.gov (United States)

    Chellappa, Sarah L; Viola, Antoine U; Schmidt, Christina; Bachmann, Valérie; Gabel, Virginie; Maire, Micheline; Reichert, Carolin F; Valomon, Amandine; Götz, Thomas; Landolt, Hans-Peter; Cajochen, Christian

    2012-03-01

    Light exposure, particularly at the short-wavelength range, triggers several nonvisual responses in humans. However, the extent to which the melatonin-suppressing and alerting effect of light differs among individuals remains unknown. Here we investigated whether blue-enriched polychromatic light impacts differentially on melatonin and subjective and objective alertness in healthy participants genotyped for the PERIOD3 (PER3) variable-number, tandem-repeat polymorphism. Eighteen healthy young men homozygous for the PER3 polymorphism (PER3(5/5)and PER3(4/4)) underwent a balanced crossover design during the winter season, with light exposure to compact fluorescent lamps of 40 lux at 6500 K and at 2500 K during 2 h in the evening. In comparison to light at 2500 K, blue-enriched light at 6500 K induced a significant suppression of the evening rise in endogenous melatonin levels in PER3(5/5) individuals but not in PER3(4/4). Likewise, PER3(5/5) individuals exhibited a more pronounced alerting response to light at 6500 K than PER3(4/4) volunteers. Waking electroencephalographic activity in the theta range (5-7 Hz), a putative correlate of sleepiness, was drastically attenuated during light exposure at 6500 K in PER3(5/5) individuals as compared with PER3(4/4). We provide first evidence that humans homozygous for the PER3 5/5 allele are particularly sensitive to blue-enriched light, as indexed by the suppression of endogenous melatonin and waking theta activity. Light sensitivity in humans may be modulated by a clock gene polymorphism implicated in the sleep-wake regulation.

  1. Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.

    Science.gov (United States)

    Soria, Virginia; Martínez-Amorós, Erika; Escaramís, Geòrgia; Valero, Joaquín; Pérez-Egea, Rosario; García, Cecilia; Gutiérrez-Zotes, Alfonso; Puigdemont, Dolors; Bayés, Mònica; Crespo, José M; Martorell, Lourdes; Vilella, Elisabet; Labad, Antonio; Vallejo, Julio; Pérez, Víctor; Menchón, José M; Estivill, Xavier; Gratacòs, Mònica; Urretavizcaya, Mikel

    2010-05-01

    Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3' near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

  2. Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder

    Science.gov (United States)

    Soria, Virginia; Martínez-Amorós, Èrika; Escaramís, Geòrgia; Valero, Joaquín; Pérez-Egea, Rosario; García, Cecilia; Gutiérrez-Zotes, Alfonso; Puigdemont, Dolors; Bayés, Mònica; Crespo, José M; Martorell, Lourdes; Vilella, Elisabet; Labad, Antonio; Vallejo, Julio; Pérez, Víctor; Menchón, José M; Estivill, Xavier; Gratacòs, Mònica; Urretavizcaya, Mikel

    2010-01-01

    Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3′ near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity. PMID:20072116

  3. Cadmium-induced disruption in 24-h expression of clock and redox enzyme genes in rat medial basal hypothalamus. Prevention by melatonin.

    Directory of Open Access Journals (Sweden)

    Vanesa eJiménez Ortega

    2011-03-01

    Full Text Available In a previous study we reported that a low daily p.o. dose of cadmium (Cd disrupted the circadian expression of clock and redox enzyme genes in rat medial basal hypothalamus (MBH. To assess whether melatonin could counteract Cd activity, male Wistar rats (45 days of age received CdCl2 (5 ppm and melatonin (3 μg/mL or vehicle (0.015 % ethanol in drinking water. Groups of animals receiving melatonin or vehicle alone were also included. After 1 month, MBH mRNA levels were measured by real-time PCR analysis at 6 time intervals in a 24-h cycle. In control MBH Bmal1 expression peaked at early scotophase, Per1 expression at late afternoon and Per2 and Cry2 expression at mid-scotophase, whereas neither Clock nor Cry1 expression showed significant 24-h variations. This pattern was significantly disrupted (Clock, Bmal1 or changed in phase (Per1, Per2, Cry2 by CdCl2 while melatonin counteracted the changes brought about by Cd on Per1 expression only. In animals receiving melatonin alone the 24-h pattern of MBH Per2 and Cry2 expression was disrupted. CdCl2 disrupted the 24-h rhythmicity of Cu/Zn- and Mn-superoxide dismutase (SOD, nitric oxide synthase (NOS-1, NOS-2, heme oxygenase (HO-1 and HO-2 gene expression, most of the effects being counteracted by melatonin. In particular, the co-administration of melatonin and CdCl2 increased Cu/Zn-SOD gene expression and decreased that of glutathione peroxidase (GPx, glutathione reductase (GSR and HO-2. In animals receiving melatonin alone, significant increases in mean Cu/Zn and Mn-SOD gene expression, and decreases in that of GPx, GSR, NOS-1, NOS-2, HO-1 and HO-2, were found. The results indicate that the interfering effect of melatonin on the activity of a low dose of CdCl2 on MBH clock and redox enzyme genes is mainly exerted at the level of redox enzyme gene expression.

  4. Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice

    DEFF Research Database (Denmark)

    Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens

    2012-01-01

    RNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor......The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular......) the adrenal Star mRNA and (3) the serum corticosterone concentration both during a light/dark (L/D) cycle and at constant darkness in wild type (WT) and VPAC2 receptor-deficient mice (VPAC2-KO). We also examined if PER1 and StAR were co-localised in the adrenal steroidogenic cells. Per1 and Bmal1 mRNA showed...

  5. Circadian clock genes Per1 and Per2 regulate the response of metabolism-associated transcripts to sleep disruption.

    Directory of Open Access Journals (Sweden)

    Jana Husse

    Full Text Available Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction--TSR. We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects

  6. Circadian clock, cell cycle and cancer

    Directory of Open Access Journals (Sweden)

    Cansu Özbayer

    2011-12-01

    Full Text Available There are a few rhythms of our daily lives that we are under the influence. One of them is characterized by predictable changes over a 24-hour timescale called circadian clock. This cellular clock is coordinated by the suprachiasmatic nucleus in the anterior hypothalamus. The clock consist of an autoregulatory transcription-translation feedback loop compose of four genes/proteins; BMAL1, Clock, Cyrptochrome, and Period. BMAL 1 and Clock are transcriptional factors and Period and Cyrptochrome are their targets. Period and Cyrptochrome dimerize in the cytoplasm to enter the nucleus where they inhibit Clock/BMAL activity.It has been demonstrate that circadian clock plays an important role cellular proliferation, DNA damage and repair mechanisms, checkpoints, apoptosis and cancer.

  7. Sumoylation Contributes to Timekeeping and Temperature Compensation of the Plant Circadian Clock

    NARCIS (Netherlands)

    Hansen, L.L; van den Burg, H.A.; van Ooijen, G.

    2017-01-01

    The transcriptional circadian clock network is tuned into a 24-h oscillator by numerous posttranslational modifications on the proteins encoded by clock genes, differentially influencing their subcellular localization or activity. Clock proteins in any circadian organism are subject to

  8. HvLUX1 is a candidate gene underlying the early maturity 10 locus in barley: phylogeny, diversity, and interactions with the circadian clock and photoperiodic pathways

    Science.gov (United States)

    Campoli, Chiara; Pankin, Artem; Drosse, Benedikt; Casao, Cristina M; Davis, Seth J; von Korff, Maria

    2013-01-01

    Photoperiodic flowering is a major factor determining crop performance and is controlled by interactions between environmental signals and the circadian clock. We proposed Hvlux1, an ortholog of the Arabidopsis circadian gene LUX ARRHYTHMO, as a candidate underlying the early maturity 10 (eam10) locus in barley (Hordeum vulgare L.). The link between eam10 and Hvlux1 was discovered using high-throughput sequencing of enriched libraries and segregation analysis. We conducted functional, phylogenetic, and diversity studies of eam10 and HvLUX1 to understand the genetic control of photoperiod response in barley and to characterize the evolution of LUX-like genes within barley and across monocots and eudicots. We demonstrate that eam10 causes circadian defects and interacts with the photoperiod response gene Ppd-H1 to accelerate flowering under long and short days. The results of phylogenetic and diversity analyses indicate that HvLUX1 was under purifying selection, duplicated at the base of the grass clade, and diverged independently of LUX-like genes in other plant lineages. Taken together, these findings contribute to improved understanding of the barley circadian clock, its interaction with the photoperiod pathway, and evolution of circadian systems in barley and across monocots and eudicots. PMID:23731278

  9. Concerted gene expression of hippocampal steroid receptors during spatial learning in male Wistar rats: a correlation analysis

    Directory of Open Access Journals (Sweden)

    Gert eLubec

    2016-05-01

    Full Text Available Adrenal and gonadal steroid receptor activities are significantly involved and interact in the regulation of learning, memory and stress. Thus, a coordinated expression of steroid receptor genes during a learning task can be expected. Although coexpression of steroid receptors in response to behavioral tasks has been reported the correlative connection is unclear. According to the inverted U-shape model of the impact of stress upon learning and memory we hypothesized that glucocorticoid receptor expression should be correlated to corticosterone levels in a linear or higher order manner. Other cognition modulating steroid receptors like estrogen receptors should be correlated to glucocorticoid receptors in a quadratic manner, which describes a parabola and thus a U-shaped connection. Therefore, we performed a correlational meta-analyis of data of a previous study (Meyer and Korz, 2013a of steroid receptor gene expressions during spatial learning, which provides a sufficient data basis in order to perform such correlational connections. In that study male rats of different ages were trained in a spatial holeboard or remained untrained and the hippocampal gene expression of different steroid receptors as well as serum corticosterone levels were measured. Expressions of mineralocorticoid (MR and glucocorticoid (GR receptors were positively and linearly correlated with blood serum corticosterone levels in spatially trained but not in untrained animals. Training induced a cubic (best fit relationship between mRNA levels of estrogen receptor α (ERα and androgen receptor (AR with MR mRNA. GR gene expression was linearly correlated with MR expression under both conditions. ERα m RNA levels were negatively and linearily and MR and GR gene expressions were cubicely correlated with reference memory errors (RME. Due to only three age classes correlations with age could not be performed. The findings support the U-shape theory of steroid receptor

  10. Conserved and Divergent Rhythms of Crassulacean Acid Metabolism-Related and Core Clock Gene Expression in the Cactus Opuntia ficus-indica1[C][W

    Science.gov (United States)

    Mallona, Izaskun; Egea-Cortines, Marcos; Weiss, Julia

    2011-01-01

    The cactus Opuntia ficus-indica is a constitutive Crassulacean acid metabolism (CAM) species. Current knowledge of CAM metabolism suggests that the enzyme phosphoenolpyruvate carboxylase kinase (PPCK) is circadian regulated at the transcriptional level, whereas phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), NADP-malic enzyme (NADP-ME), and pyruvate phosphate dikinase (PPDK) are posttranslationally controlled. As little transcriptomic data are available from obligate CAM plants, we created an expressed sequence tag database derived from different organs and developmental stages. Sequences were assembled, compared with sequences in the National Center for Biotechnology Information nonredundant database for identification of putative orthologs, and mapped using Kyoto Encyclopedia of Genes and Genomes Orthology and Gene Ontology. We identified genes involved in circadian regulation and CAM metabolism for transcriptomic analysis in plants grown in long days. We identified stable reference genes for quantitative polymerase chain reaction and found that OfiSAND, like its counterpart in Arabidopsis (Arabidopsis thaliana), and OfiTUB are generally appropriate standards for use in the quantification of gene expression in O. ficus-indica. Three kinds of expression profiles were found: transcripts of OfiPPCK oscillated with a 24-h periodicity; transcripts of the light-active OfiNADP-ME and OfiPPDK genes adapted to 12-h cycles, while transcript accumulation patterns of OfiPEPC and OfiMDH were arrhythmic. Expression of the circadian clock gene OfiTOC1, similar to Arabidopsis, oscillated with a 24-h periodicity, peaking at night. Expression of OfiCCA1 and OfiPRR9, unlike in Arabidopsis, adapted best to a 12-h rhythm, suggesting that circadian clock gene interactions differ from those of Arabidopsis. Our results indicate that the evolution of CAM metabolism could be the result of modified circadian regulation at both the transcriptional and posttranscriptional

  11. Conserved and divergent rhythms of crassulacean acid metabolism-related and core clock gene expression in the cactus Opuntia ficus-indica.

    Science.gov (United States)

    Mallona, Izaskun; Egea-Cortines, Marcos; Weiss, Julia

    2011-08-01

    The cactus Opuntia ficus-indica is a constitutive Crassulacean acid metabolism (CAM) species. Current knowledge of CAM metabolism suggests that the enzyme phosphoenolpyruvate carboxylase kinase (PPCK) is circadian regulated at the transcriptional level, whereas phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), NADP-malic enzyme (NADP-ME), and pyruvate phosphate dikinase (PPDK) are posttranslationally controlled. As little transcriptomic data are available from obligate CAM plants, we created an expressed sequence tag database derived from different organs and developmental stages. Sequences were assembled, compared with sequences in the National Center for Biotechnology Information nonredundant database for identification of putative orthologs, and mapped using Kyoto Encyclopedia of Genes and Genomes Orthology and Gene Ontology. We identified genes involved in circadian regulation and CAM metabolism for transcriptomic analysis in plants grown in long days. We identified stable reference genes for quantitative polymerase chain reaction and found that OfiSAND, like its counterpart in Arabidopsis (Arabidopsis thaliana), and OfiTUB are generally appropriate standards for use in the quantification of gene expression in O. ficus-indica. Three kinds of expression profiles were found: transcripts of OfiPPCK oscillated with a 24-h periodicity; transcripts of the light-active OfiNADP-ME and OfiPPDK genes adapted to 12-h cycles, while transcript accumulation patterns of OfiPEPC and OfiMDH were arrhythmic. Expression of the circadian clock gene OfiTOC1, similar to Arabidopsis, oscillated with a 24-h periodicity, peaking at night. Expression of OfiCCA1 and OfiPRR9, unlike in Arabidopsis, adapted best to a 12-h rhythm, suggesting that circadian clock gene interactions differ from those of Arabidopsis. Our results indicate that the evolution of CAM metabolism could be the result of modified circadian regulation at both the transcriptional and posttranscriptional

  12. Physiological links of circadian clock and biological clock of aging

    Directory of Open Access Journals (Sweden)

    Fang Liu

    2017-01-01

    Full Text Available ABSTRACT Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.

  13. Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2.

    Science.gov (United States)

    Katsumata, Yuriko; Nelson, Peter T; Ellingson, Sally R; Fardo, David W

    2017-05-01

    Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the GRN, TMEM106B, ABCC9, and KCNMB2 genes, which were reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer's Disease Genetics Consortium, linked to autopsy-derived neuropathological outcomes from the National Alzheimer's Coordinating Center. Of the 3251 subjects included in the study, 271 (8.3%) were identified as an HS-Aging case. The significant gene-based association between the ABCC9 gene and HS-Aging appeared to be driven by a region in which a significant haplotype-based association was found. We tested this haplotype as an expression quantitative trait locus using 2 different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, indicating a possible toxic gain of function. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Effects of dietary supplementation with docosahexaenoic acid (DHA on hippocampal gene expression in streptozotocin induced diabetic C57Bl/6 mice

    Directory of Open Access Journals (Sweden)

    Jency Thomas

    2015-08-01

    Full Text Available A body of evidence has accumulated indicating diabetes is associated with cognitive impairments. Effective strategies are therefore needed that will delay or prevent the onset of these diabetes-related deficits. In this regard, dietary modification with the naturally occurring compound, docosahexaenoic acid (DHA, holds significant promise as it has been shown to have anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The hippocampus, a limbic structure involved in cognitive functions such as memory formation, is particularly vulnerable to the neurotoxic effects related to diabetes, and we have previously shown that streptozotocin-induced diabetes alters hippocampal gene expression, including genes involved in synaptic plasticity and neurogenesis. In the present study, we explored the effects of dietary supplementation with DHA on hippocampal gene expression in C57Bl/6 diabetic mice. Diabetes was established using streptozotocin (STZ and once stable, the dietary intervention group received AIN93G diet supplemented with DHA (50 mg/kg/day for 6 weeks. Microarray based genome-wide expression analysis was carried out on the hippocampus of DHA supplemented diabetic mice and confirmed by real time polymerase chain reaction (RT-qPCR. Genome-wide analysis identified 353 differentially expressed genes compared to non-supplemented diabetic mice. For example, six weeks of dietary DHA supplementation resulted in increased hippocampal expression of Igf II and Sirt1 and decreased expression of Tnf-α, Il6, Mapkapk2 and ApoE, compared to non-supplemented diabetic mice. Overall, DHA supplementation appears to alter hippocampal gene expression in a way that is consistent with it being neuroprotective in the context of the metabolic and inflammatory insults associated with diabetes.

  15. Influence of night-shift and napping at work on urinary melatonin, 17-β-estradiol and clock gene expression in pre-menopausal nurses.

    Science.gov (United States)

    Bracci, M; Copertaro, A; Manzella, N; Staffolani, S; Strafella, E; Nocchi, L; Barbaresi, M; Copertaro, B; Rapisarda, V; Valentino, M; Santarelli, L

    2013-01-01

    Night-workers experience disruption of the sleep-wake cycle and light at night which may increase breast cancer risk by suppressing the nocturnal melatonin surge, resulting in higher levels of circulating estrogens. Night-work may also deregulate peripheral clock genes which have been found to be altered in breast cancer. This study investigated urinary 6-sulfatoxymelatonin (aMT6s), serum 17-beta-estradiol levels in premenopausal shift nurses at the end of the night-shift compared to a control group of daytime nurses. Peripheral clock gene expression in lymphocytes were also investigated. All participants were sampled in the follicular phase of the menstrual cycle. The effect of nurses’ ability to take a short nap during the night-shift was also explored. The shift-work group had significantly lower aMT6s levels than daytime nurses independently of a nap. Night-shift napping significantly influences 17-beta-estradiol levels resulting in higher outcomes in nurses who do not take a nap compared to napping group and daytime workers. Peripheral clock genes expression investigated was not significantly different among the groups. Our findings suggest that shift nurses experience changes in aMT6s levels after a night-shift. Napping habits influence 17-beta-estradiol levels at the end of a night-shift. These findings might be related to the increased cancer risk reported in night-shift workers and suggest that a short nap during night-shifts may exert a positive effect.

  16. Clock genes in depression

    DEFF Research Database (Denmark)

    Christiansen, Sofie Laage; Bouzinova, Elena

    2017-01-01

    Data demonstrate that abnormal regulation of the circadian system can result in cardiovascular disease, metabolic syndrome, obesity, immune dysfunction, increased risk for cancer, reproductive complications, etc. It is highly individual among depressed patients and may be expressed as a phase...... in the brain and liver: expression of Per2 is sensitive to stress and changes in Bmal1 mostly associated with depressive behavior. The Per1 expression is sustainable in maintaining the circadian rhythm. A normalization of the expression patterns is likely to be essential for the recovery from the pathological...... state. Depression is a high prevalent disorder. The number of incidents is rising due to changes in lifestyle. The symptomatology is inconsistent and it is difficult to agree on one hypothesis. The disturbances of the 24 h circadian rhythm may be a factor in the development of major depressive disorder...

  17. [Clocks, Behavior, and Cognition].

    Science.gov (United States)

    Futamura, Akinori; Shiromaru, Azusa; Kuroda, Takeshi; Honma, Motoyasu; Kinno, Ryuta; Ono, Kenjiro; Kawamura, Mitsuru

    2017-06-01

    The nerve center responsible for controlling our circadian rhythm is located in a cluster of cells known as the suprachiasmatic nucleus in the hypothalamus. Various physiological functions such as sleep, arousal, blood pressure, body temperature, and hormone secretion are regulated in a 24-hour rhythm by this circuit. Somatic cells of other organs have a peripheral clock gene and by synchronizing the rhythm of the central and peripheral clocks, it is possible to live a healthy life. Due to aging and degenerative disease, circadian rhythm gradually collapses. Factors that can contribute to this include reduced expression of the time gene associated with photo stimulation, a reduction in neurotransmitter levels, and reduced melatonin production. Biological clocks play an important role in our emotions, cognitive function, and behavior. Sleep disorders and metabolic disease related to the circadian rhythm affect metabolic and endocrine activities via the autonomic nervous system and the intestinal bacterial flora. Shift work disorder is associated with insomnia and excessive drowsiness as individuals often work during their sleeping hours. Now time management is placed at the center of our society, and it is important to evaluate the medical risk of engaging in shift work. In frontotemporal dementia (FTD), the stereotypical behaviors may be associated with time. In some patients, multiple timed behaviors occupy a considerable part of the patient's daily life. Stereotypical behaviors in FTD are often considered in contrast to obsessive-compulsive disease (OCD). Studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function.

  18. Sub-toxic ethanol exposure modulates gene expression and enzyme activity of antioxidant systems to provide neuroprotection in hippocampal HT22 cells

    Directory of Open Access Journals (Sweden)

    Veronica Casañas-Sanchez

    2016-07-01

    Full Text Available Ethanol is known to cause severe systemic damage often explained as secondary to oxidative stress. Brain is particularly vulnerable to ethanol-induced reactive oxygen species (ROS because the high amounts of lipids, and because nerve cell membranes contain high amounts of peroxidable fatty acids. Usually these effects of ethanol are associated to high and/or chronic exposure to ethanol. However, as we show in this manuscript, a low and acute dose of ethanol trigger a completely different response in hippocampal cells. Thus, we have observed that 0.1% ethanol exposure to HT22 cells, a murine hippocampal-derived cell line, increases the transcriptional expression of different genes belonging to the classical, glutathione/glutaredoxin and thioredoxin/peroxiredoxin antioxidant systems, these including Sod1, Sod2, Gpx1, Gclc and Txnrd1. Paralleling these changes, enzyme activities of total superoxide dismutase (tSOD, catalase, total glutathione peroxidase (tGPx, glutathione-S-reductase (GSR and total thioredoxin reductase (tTXNRD, were all increased, while the generation of thiobarbituric acid reactive substances (TBARS, as indicators of lipid peroxidation, and glutathione levels remained unaltered. Ethanol exposure did not affect cell viability or cell growing as assessed by real-time cell culture monitoring, indicating that low ethanol doses are not deleterious for hippocampal cells, but rather prevented glutamate-induced excitotoxicity. In summary, we conclude that sub-toxic exposure to ethanol may well be neuroprotective against oxidative insults in hippocampal cells.

  19. Sub-toxic Ethanol Exposure Modulates Gene Expression and Enzyme Activity of Antioxidant Systems to Provide Neuroprotection in Hippocampal HT22 Cells

    Science.gov (United States)

    Casañas-Sánchez, Verónica; Pérez, José A.; Quinto-Alemany, David; Díaz, Mario

    2016-01-01

    Ethanol is known to cause severe systemic damage often explained as secondary to oxidative stress. Brain is particularly vulnerable to ethanol-induced reactive oxygen species (ROS) because the high amounts of lipids, and because nerve cell membranes contain high amounts of peroxidable fatty acids. Usually these effects of ethanol are associated to high and/or chronic exposure to ethanol. However, as we show in this manuscript, a low and acute dose of ethanol trigger a completely different response in hippocampal cells. Thus, we have observed that 0.1% ethanol exposure to HT22 cells, a murine hippocampal-derived cell line, increases the transcriptional expression of different genes belonging to the classical, glutathione/glutaredoxin and thioredoxin/peroxiredoxin antioxidant systems, these including Sod1, Sod2, Gpx1, Gclc, and Txnrd1. Paralleling these changes, enzyme activities of total superoxide dismutase (tSOD), catalase, total glutathione peroxidase (tGPx), glutathione-S-reductase (GSR), and total thioredoxin reductase (tTXNRD), were all increased, while the generation of thiobarbituric acid reactive substances (TBARS), as indicators of lipid peroxidation, and glutathione levels remained unaltered. Ethanol exposure did not affect cell viability or cell growing as assessed by real-time cell culture monitoring, indicating that low ethanol doses are not deleterious for hippocampal cells, but rather prevented glutamate-induced excitotoxicity. In summary, we conclude that sub-toxic exposure to ethanol may well be neuroprotective against oxidative insults in hippocampal cells. PMID:27512374

  20. Sub-toxic Ethanol Exposure Modulates Gene Expression and Enzyme Activity of Antioxidant Systems to Provide Neuroprotection in Hippocampal HT22 Cells.

    Science.gov (United States)

    Casañas-Sánchez, Verónica; Pérez, José A; Quinto-Alemany, David; Díaz, Mario

    2016-01-01

    Ethanol is known to cause severe systemic damage often explained as secondary to oxidative stress. Brain is particularly vulnerable to ethanol-induced reactive oxygen species (ROS) because the high amounts of lipids, and because nerve cell membranes contain high amounts of peroxidable fatty acids. Usually these effects of ethanol are associated to high and/or chronic exposure to ethanol. However, as we show in this manuscript, a low and acute dose of ethanol trigger a completely different response in hippocampal cells. Thus, we have observed that 0.1% ethanol exposure to HT22 cells, a murine hippocampal-derived cell line, increases the transcriptional expression of different genes belonging to the classical, glutathione/glutaredoxin and thioredoxin/peroxiredoxin antioxidant systems, these including Sod1, Sod2, Gpx1, Gclc, and Txnrd1. Paralleling these changes, enzyme activities of total superoxide dismutase (tSOD), catalase, total glutathione peroxidase (tGPx), glutathione-S-reductase (GSR), and total thioredoxin reductase (tTXNRD), were all increased, while the generation of thiobarbituric acid reactive substances (TBARS), as indicators of lipid peroxidation, and glutathione levels remained unaltered. Ethanol exposure did not affect cell viability or cell growing as assessed by real-time cell culture monitoring, indicating that low ethanol doses are not deleterious for hippocampal cells, but rather prevented glutamate-induced excitotoxicity. In summary, we conclude that sub-toxic exposure to ethanol may well be neuroprotective against oxidative insults in hippocampal cells.

  1. Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

    Directory of Open Access Journals (Sweden)

    Dicker Bridget L

    2007-06-01

    Full Text Available Abstract Background Alzheimer's disease (AD is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ in extracellular plaques. Mutations in amyloid precursor protein (APP and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. Results Adeno-associated viral (AAV vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits. Conclusion The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in

  2. Ramadan fasting in Saudi Arabia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in cardiometabolic risk factors.

    Science.gov (United States)

    Ajabnoor, Ghada M A; Bahijri, Suhad; Shaik, Noor Ahmad; Borai, Anwar; Alamoudi, Aliaa A; Al-Aama, Jumana Y; Chrousos, George P

    2017-01-01

    During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance. To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors. Healthy young volunteers (5 females, 18 males; mean age +SEM = 23.2 +1.2 years) were evaluated before Ramadan and two weeks into it. Blood samples were collected at 9 am (±1 hour) and twelve hours later for determination of serum lipid profile, high sensitivity CRP (hsCRP), and adiponectin. The expression of CLOCK, DUSP1 and IL-1α was evaluated in circulating leukocytes. Mean levels of GGT and morning adiponectin decreased, while those of LDL-c/ HDL-c and atherogenic index (AI) increased significantly in Ramadan compared to Shabaan. There was no significant difference between morning and evening adiponectin during Ramadan, while the diurnal rhythm of hsCRP was lost. CLOCK gene expression mean was significantly higher in morning than in evening during Shabaan. Mean morning and evening DUSP1 mRNA levels showed significant increase during Ramadan compared to Shabaan, however, its diurnal rhythm was maintained. Morning IL-1α mRNA expression remained significantly higher than in the evening during Ramadan, but was markedly decreased compared to Shabaan. Ramadan fasting in Saudi Arabia is associated with improvements in some cardiometabolic risk factors, such as circulating GGT and hsCRP and leukocyte expression of IL-1α mRNA, suggesting that intermittent fasting might have a beneficial component. These benefits may be offset by the previously reported dysregulation in the circadian rhythm, excess glucocorticoid levels and action, and insulin

  3. TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice.

    Science.gov (United States)

    Conte, Valeria; Raghupathi, Ramesh; Watson, Deborah J; Fujimoto, Scott; Royo, Nicolas C; Marklund, Niklas; Stocchetti, Nino; McIntosh, Tracy K

    2008-01-01

    The ability of brain-derived neurotrophic factor (BDNF) to attenuate secondary damage and influence behavioral outcome after experimental traumatic brain injury (TBI) remains controversial. Because TBI can result in decreased expression of the trkB receptor, thereby preventing BDNF from exerting potential neuroprotective effects, the contribution of both BDNF and its receptor trkB to hippocampal neuronal loss and cognitive dysfunction were evaluated. Full-length trkB was overexpressed in the left hippocampus of adult C57Bl/6 mice using recombinant adeno-associated virus serotype 2/5 (rAAV 2/5). EGFP (enhanced green fluorescent protein) expression was present at two weeks after AAV-EGFP injection and remained sustained up to four weeks after the injection. At 2 weeks following gene transduction, mice were subjected to parasagittal controlled cortical impact (CCI) brain injury, followed by either BDNF or PBS infusion into the hippocampus. No differences were observed in learning ability at two weeks post-injury or in motor function from 48 hours to two weeks among treatment groups. The number of surviving pyramidal neurons in the CA2-CA3 region of the hippocampus was also not different among treatment groups. These data suggest that neither overexpression of trkB, BNDF infusion or their combination affects neuronal survival or behavioral outcome following experimental TBI in mice.

  4. Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

    Directory of Open Access Journals (Sweden)

    Heidi Marjonen

    Full Text Available The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v ethanol for the first 8 days of gestation (GD 0.5-8.5. Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60: we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in

  5. Novel transcriptional networks regulated by CLOCK in human neurons.

    Science.gov (United States)

    Fontenot, Miles R; Berto, Stefano; Liu, Yuxiang; Werthmann, Gordon; Douglas, Connor; Usui, Noriyoshi; Gleason, Kelly; Tamminga, Carol A; Takahashi, Joseph S; Konopka, Genevieve

    2017-11-01

    The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. © 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Evolutionary links between circadian clocks and photoperiodic diapause in insects.

    Science.gov (United States)

    Meuti, Megan E; Denlinger, David L

    2013-07-01

    In this article, we explore links between circadian clocks and the clock involved in photoperiodic regulation of diapause in insects. Classical resonance (Nanda-Hamner) and night interruption (Bünsow) experiments suggest a circadian basis for the diapause response in nearly all insects that have been studied. Neuroanatomical studies reveal physical connections between circadian clock cells and centers controlling the photoperiodic diapause response, and both mutations and knockdown of clock genes with RNA interference (RNAi) point to a connection between the clock genes and photoperiodic induction of diapause. We discuss the challenges of determining whether the clock, as a functioning module, or individual clock genes acting pleiotropically are responsible for the photoperiodic regulation of diapause, and how a stable, central circadian clock could be linked to plastic photoperiodic responses without compromising the clock's essential functions. Although we still lack an understanding of the exact mechanisms whereby insects measure day/night length, continued classical and neuroanatomical approaches, as well as forward and reverse genetic experiments, are highly complementary and should enable us to decipher the diverse ways in which circadian clocks have been involved in the evolution of photoperiodic induction of diapause in insects. The components of circadian clocks vary among insect species, and diapause appears to have evolved independently numerous times, thus, we anticipate that not all photoperiodic clocks of insects will interact with circadian clocks in the same fashion.

  7. Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity

    DEFF Research Database (Denmark)

    Kanter-Schlifke, I; Toft Sørensen, Andreas; Ledri, M

    2007-01-01

    Gene therapy-based overexpression of endogenous seizure-suppressing molecules represents a promising treatment strategy for epilepsy. Viral vector-based overexpression of the neuropeptide galanin has been shown to effectively suppress generalized seizures in various animal models of epilepsy. How...

  8. Gene - environment interaction in programming hippocampal plasticity: focus on adult neurogenesis

    Directory of Open Access Journals (Sweden)

    Muriel eKoehl

    2015-08-01

    Full Text Available Interactions between genes and environment are a critical feature of development and both contribute to shape individuality. They are at the chore of vulnerability / resiliency for mental illnesses. During the early postnatal period, several brain structures involved in cognitive and emotional processing, such as the hippocampus, still develop and it is likely that interferences with this neuronal development, which is genetically determined, might lead to long-lasting structural and functional consequences and increase the risk of developing psychopathology. One particular target is adult neurogenesis, which is involved in the regulation of cognitive and emotional processes. Insights into the dynamic interplay between genes and environmental factors in setting up individual rates of neurogenesis have come from laboratory studies exploring experience-dependent changes in adult neurogenesis as a function of individual’s genetic makeup. These studies have implications for our understanding of the mechanisms regulating adult neurogenesis, which could constitute a link between environmental challenges and psychopathology.

  9. Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles.

    Directory of Open Access Journals (Sweden)

    Liqin Zhao

    Full Text Available This study investigated the impact of chronic exposure to continuous (CoP4 versus cyclic progesterone (CyP4 alone or in combination with 17β-estradiol (E2 on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1, redox homeostasis (peroxiredoxin 5; Prdx5, insulin signaling (insulin-like growth factor I; Igf1, and cholesterol trafficking (liver X receptor α subtype; Nr1h3, differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX and E2+CyP4 (up-regulation relative to OVX. In contrast, genes involved in amyloid metabolism (β-secretase; Bace1 differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1. In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.

  10. Study of the association between 3111T/C polymorphism of the CLOCK gene and the presence of overweight in schoolchildren,

    Directory of Open Access Journals (Sweden)

    Nayara P. Giovaninni

    2014-09-01

    Full Text Available Objectives: To evaluate the association between 3111T/C polymorphism of the CLOCK gene and the presence of obesity and sleep duration in children aged 6-13 years. In adults, this genetic variant has been associated with duration of sleep, ghrelin levels, weight, and eating habits. Although short sleep duration has been linked to obesity in children, no study has aimed to identify the possible molecular mechanisms of this association to date. Methods: Weight, height, and circumferences were transformed into Z-scores for age and gender. Genotyping was performed using TaqMan methodology. A questionnaire regarding hours of sleep was provided to parents. The appropriate statistical tests were performed. Results: This study evaluated 370 children (45% males, 55% females, mean age 8.5 ± 1.5 years. The prevalence of overweight was 18%. The duration of sleep was, on average, 9.7 hours, and was inversely related to age (p < 0.001. Genotype distribution was: 4% CC, 31% CT, and 65% TT. There was a trend toward higher prevalence of overweight in children who slept less than nine hours (23% when compared to those who slept more than ten hours (16%, p = 0.06. Genotype was not significantly correlated to any of the assessed outcomes. Conclusions: The CLOCK 3111T/C polymorphism was not significantly associated with overweight or sleep duration in children in this city.

  11. Study of the association between 3111T/C polymorphism of the CLOCK gene and the presence of overweight in schoolchildren.

    Science.gov (United States)

    Giovaninni, Nayara P; Fuly, Jeanne T; Moraes, Leonardo I; Coutinho, Thais N; Trarbach, Ericka B; Jorge, Alexander A de L; Costalonga, Everlayny F

    2014-01-01

    To evaluate the association between 3111T/C polymorphism of the CLOCK gene and the presence of obesity and sleep duration in children aged 6-13 years. In adults, this genetic variant has been associated with duration of sleep, ghrelin levels, weight, and eating habits. Although short sleep duration has been linked to obesity in children, no study has aimed to identify the possible molecular mechanisms of this association to date. Weight, height, and circumferences were transformed into Z-scores for age and gender. Genotyping was performed using TaqMan methodology. A questionnaire regarding hours of sleep was provided to parents. The appropriate statistical tests were performed. This study evaluated 370 children (45% males, 55% females, mean age 8.5 ± 1.5 years). The prevalence of overweight was 18%. The duration of sleep was, on average, 9.7hours, and was inversely related to age (p<0.001). Genotype distribution was: 4% CC, 31% CT, and 65% TT. There was a trend toward higher prevalence of overweight in children who slept less than nine hours (23%) when compared to those who slept more than ten hours (16%, p=0.06). Genotype was not significantly correlated to any of the assessed outcomes. The CLOCK 3111T/C polymorphism was not significantly associated with overweight or sleep duration in children in this city. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  12. Circadian clock gene aryl hydrocarbon receptor nuclear translocator-like polymorphisms are associated with seasonal affective disorder: An Indian family study.

    Science.gov (United States)

    Rajendran, Bhagya; Janakarajan, Veeramahali Natarajan

    2016-01-01

    Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms. In this study, 30 members of close-knit family with SAD, 30 age- and sex-matched controls of the same caste with no prior history of psychiatric illness and 30 age- and sex-matched controls belonging to 17 different castes with no prior history of psychiatric illness were genotyped for five different single nucleotide polymorphisms (SNPs) in ARNTL gene by TaqMan allele-specific genotyping assay. Statistical significance was assessed by more powerful quasi-likelihood score test-XM. Most of the family members carried the risk alleles and we observed a highly significant SNP rs2279287 (A/G) in ARNTL gene with an allelic frequency of 0.75. Polymorphisms in ARNTL gene disrupt circadian rhythms causing SAD and genetic predisposition becomes more deleterious in the presence of adverse environment.

  13. The expression of three opsin genes from the compound eye of Helicoverpa armigera (Lepidoptera: Noctuidae is regulated by a circadian clock, light conditions and nutritional status.

    Directory of Open Access Journals (Sweden)

    Shuo Yan

    Full Text Available Visual genes may become inactive in species that inhabit poor light environments, and the function and regulation of opsin components in nocturnal moths are interesting topics. In this study, we cloned the ultraviolet (UV, blue (BL and long-wavelength-sensitive (LW opsin genes from the compound eye of the cotton bollworm and then measured their mRNA levels using quantitative real-time PCR. The mRNA levels fluctuated over a daily cycle, which might be an adaptation of a nocturnal lifestyle, and were dependent on a circadian clock. Cycling of opsin mRNA levels was disturbed by constant light or constant darkness, and the UV opsin gene was up-regulated after light exposure. Furthermore, the opsin genes tended to be down-regulated upon starvation. Thus, this study illustrates that opsin gene expression is determined by multiple endogenous and exogenous factors and is adapted to the need for nocturnal vision, suggesting that color vision may play an important role in the sensory ecology of nocturnal moths.

  14. Hippocampal gene expression meta-analysis identifies aging and age-associated spatial learning impairment (ASLI genes and pathways.

    Directory of Open Access Journals (Sweden)

    Raihan K Uddin

    Full Text Available A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI.

  15. Entrainment of the Neurospora circadian clock

    NARCIS (Netherlands)

    Merrow, M; Boesl, C; Ricken, J; Messerschmitt, M; Goedel, M; Roenneberg, T

    2006-01-01

    Neurospora crassa has been systematically investigated for circadian entrainment behavior. Many aspects of synchronization can be investigated in this simple, cellular system, ranging from systematic entrainment and drivenness to masking. Clock gene expression during entrainment and entrainment

  16. The Circadian Clock Gene Csnk1e Regulates Rapid Eye Movement Sleep Amount, and Nonrapid Eye Movement Sleep Architecture in Mice

    Science.gov (United States)

    Zhou, Lili; Bryant, Camron D.; Loudon, Andrew; Palmer, Abraham A.; Vitaterna, Martha Hotz; Turek, Fred W.

    2014-01-01

    Study Objectives: Efforts to identify the genetic basis of mammalian sleep have included quantitative trait locus (QTL) mapping and gene targeting of known core circadian clock genes. We combined three different genetic approaches to identify and test a positional candidate sleep gene — the circadian gene casein kinase 1 epsilon (Csnk1e), which is located in a QTL we identified for rapid eye movement (REM) sleep on chromosome 15. Measurements and Results: Using electroencephalographic (EEG) and electromyographic (EMG) recordings, baseline sleep was examined in a 12-h light:12-h dark (LD 12:12) cycle in mice of seven genotypes, including Csnk1etau/tau and Csnk1e-/- mutant mice, Csnk1eB6.D2 and Csnk1eD2.B6 congenic mice, and their respective wild-type littermate control mice. Additionally, Csnk1etau/tau and wild-type mice were examined in constant darkness (DD). Csnk1etau/tau mutant mice and both Csnk1eB6.D2 and Csnk1eD2.B6 congenic mice showed significantly higher proportion of sleep time spent in REM sleep during the dark period than wild-type controls — the original phenotype for which the QTL on chromosome 15 was identified. This phenotype persisted in Csnk1etau/tau mice while under free-running DD conditions. Other sleep phenotypes observed in Csnk1etau/tau mice and congenics included a decreased number of bouts of nonrapid eye movement (NREM) sleep and an increased average NREM sleep bout duration. Conclusions: These results demonstrate a role for Csnk1e in regulating not only the timing of sleep, but also the REM sleep amount and NREM sleep architecture, and support Csnk1e as a causal gene in the sleep QTL on chromosome 15. Citation: Zhou L; Bryant CD; Loudon A; Palmer AA; Vitaterna MH; Turek FW. The circadian clock gene Csnk1e regulates rapid eye movement sleep amount, and nonrapid eye movement sleep architecture in mice. SLEEP 2014;37(4):785-793. PMID:24744456

  17. Ramadan fasting in Saudi Arabia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in cardiometabolic risk factors.

    Directory of Open Access Journals (Sweden)

    Ghada M A Ajabnoor

    Full Text Available During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance.To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors.Healthy young volunteers (5 females, 18 males; mean age +SEM = 23.2 +1.2 years were evaluated before Ramadan and two weeks into it. Blood samples were collected at 9 am (±1 hour and twelve hours later for determination of serum lipid profile, high sensitivity CRP (hsCRP, and adiponectin. The expression of CLOCK, DUSP1 and IL-1α was evaluated in circulating leukocytes.Mean levels of GGT and morning adiponectin decreased, while those of LDL-c/ HDL-c and atherogenic index (AI increased significantly in Ramadan compared to Shabaan. There was no significant difference between morning and evening adiponectin during Ramadan, while the diurnal rhythm of hsCRP was lost. CLOCK gene expression mean was significantly higher in morning than in evening during Shabaan. Mean morning and evening DUSP1 mRNA levels showed significant increase during Ramadan compared to Shabaan, however, its diurnal rhythm was maintained. Morning IL-1α mRNA expression remained significantly higher than in the evening during Ramadan, but was markedly decreased compared to Shabaan.Ramadan fasting in Saudi Arabia is associated with improvements in some cardiometabolic risk factors, such as circulating GGT and hsCRP and leukocyte expression of IL-1α mRNA, suggesting that intermittent fasting might have a beneficial component. These benefits may be offset by the previously reported dysregulation in the circadian rhythm, excess glucocorticoid levels and action

  18. A laboratory simulation of Arabidopsis seed dormancy cycling provides new insight into its regulation by clock genes and the dormancy-related genes DOG1, MFT, CIPK23 and PHYA.

    Science.gov (United States)

    Footitt, Steven; Ölçer-Footitt, Hülya; Hambidge, Angela J; Finch-Savage, William E

    2017-08-01

    Environmental signals drive seed dormancy cycling in the soil to synchronize germination with the optimal time of year, a process essential for species' fitness and survival. Previous correlation of transcription profiles in exhumed seeds with annual environmental signals revealed the coordination of dormancy-regulating mechanisms with the soil environment. Here, we developed a rapid and robust laboratory dormancy cycling simulation. The utility of this simulation was tested in two ways: firstly, using mutants in known dormancy-related genes [DELAY OF GERMINATION 1 (DOG1), MOTHER OF FLOWERING TIME (MFT), CBL-INTERACTING PROTEIN KINASE 23 (CIPK23) and PHYTOCHROME A (PHYA)] and secondly, using further mutants, we test the hypothesis that components of the circadian clock are involved in coordination of the annual seed dormancy cycle. The rate of dormancy induction and relief differed in all lines tested. In the mutants, dog1-2 and mft2, dormancy induction was reduced but not absent. DOG1 is not absolutely required for dormancy. In cipk23 and phyA dormancy, induction was accelerated. Involvement of the clock in dormancy cycling was clear when mutants in the morning and evening loops of the clock were compared. Dormancy induction was faster when the morning loop was compromised and delayed when the evening loop was compromised. © 2017 The Authors Plant, Cell & Environment Published by John Wiley & Sons Ltd.

  19. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

    Directory of Open Access Journals (Sweden)

    Sunil Vasu Kalmady

    Full Text Available Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6 in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic

  20. The correlation of serum S100β protein levels and hippocampal Seladin-1 gene expression in a rat model of sporadic Alzheimer\\\\\\'s disease

    Directory of Open Access Journals (Sweden)

    Soheila Hosseinzadeh

    2015-11-01

    Full Text Available Background: Seladin-1 protein protects the neural cells against amyloid beta toxicity and its expression decreased in vulnerable regions of Alzheimer's disease (AD brains. On the other hand, changes in serum levels of S100 have been considered as a marker of brain damage in neurodegenerative diseases. Furthermore, this study was carried out to determine the relation between the change profile of serum S100β protein levels and hippocampal Seladin-1 gene expression in a rat model of sporadic AD. Methods: In this experimental study that established in Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Science, from March 2011 to April 2013, 72 animals were randomly divided into control, 4, 7, 14, and 21days ICV-STZ/Saline administrated rats. Alzheimer's model was induced by intracerebroventricular (ICV injections of streptozotocin (STZ [3 mg/kg] on days 1 and 3. Serum levels of S100β and hippocampal Seladin-1 gene expression were evalu-ated in experimental groups. The initial and step-through latencies (STL were deter-mined using passive avoidance test. Results: Serum levels of S100β were significantly different between the STZ-7 day and STZ-14 day groups in comparison with the control, saline and STZ-4 day groups. As well as, there was a significant difference between the STZ-7 day group in comparison with the STZ-14 day and STZ-21 day groups (P=0.0001. Hippocampal Seladin-1 gene expression in STZ-14 day and STZ-21 day groups significantly decreased as compared to the control, saline and STZ-4 day groups (P=0.0001. However, significant correla-tion was detected between serum S100β protein decrement and Seladin-1 down regula-tion (P=0.001. Also, the STL was significantly decreased in 21 days ICV-STZ adminis-trated rats as compared to the control or saline groups (P=0.001. Conclusion: Monitoring the changes of serum S100β protein levels by relationship with changes in hippocampal Seladin-1

  1. Regulated DNA Methylation and the Circadian Clock: Implications in Cancer

    Directory of Open Access Journals (Sweden)

    Tammy M. Joska

    2014-09-01

    Full Text Available Since the cloning and discovery of DNA methyltransferases (DNMT, there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has become evident that dynamic DNA methylation accompanies the circadian clock and is found at clock genes in Neurospora, mice and cancer cells. The relationship among the circadian clock, cancer and DNA methylation at clock genes suggests a correlative indication that improper DNA methylation may influence clock gene expression, contributing to the etiology of cancer. The molecular mechanism underlying DNA methylation at clock loci is best studied in the filamentous fungi, Neurospora crassa, and recent data indicate a mechanism analogous to the RNA-dependent DNA methylation (RdDM or RNAi-mediated facultative heterochromatin. Although it is still unclear, DNA methylation at clock genes may function as a terminal modification that serves to prevent the regulated removal of histone modifications. In this capacity, aberrant DNA methylation may serve as a readout of misregulated clock genes and not as the causative agent. This review explores the implications of DNA methylation at clock loci and describes what is currently known regarding the molecular mechanism underlying DNA methylation at circadian clock genes.

  2. Variation in candidate genes CLOCK and ADCYAP1 does not consistently predict differences in migratory behavior in the songbird genus Junco [v1; ref status: indexed, http://f1000r.es/11p

    Directory of Open Access Journals (Sweden)

    Mark P Peterson

    2013-04-01

    Full Text Available Recent studies exploring the molecular genetic basis for migratory variation in animals have identified polymorphisms in two genes (CLOCK and ADCYAP1 that are linked to circadian rhythms and correlate with migratory propensity and phenology among individuals and populations. Results from these initial studies are mixed, however, and additional data are needed to assess the generality and diversity of the molecular mechanisms that regulate the biology of migration. We sequenced CLOCK and ADCYAP1 in 15 populations across the two species of the avian genus Junco, a North American lineage in which multiple recently diverged subspecies and populations range from sedentary to long-distance migrants. We found no consistent associations between allele length and migratory status across the genus for either CLOCK or ADCYAP1. However, within two subspecies groups, populations that migrate longer distances have longer CLOCK alleles on average. Additionally, there was a positive relationship between ADCYAP1 allele length and migratory restlessness (zugunruhe among individuals within one of two captive populations studied—a result similar to those reported previously within captive blackcaps (Sylvia atricapilla. We conclude that, while both ADCYAP1 and CLOCK may correlate with migratory propensity within or among certain populations or species, previously identified relationships between migratory behavior and sequence variants cannot be easily generalized across taxa.

  3. Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

    DEFF Research Database (Denmark)

    Yang, Yaoming; Duguay, David; Bédard, Nathalie

    2012-01-01

    Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock...... of the circadian clock, both at the level of the core pacemaker and its response to external cues....... feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2) in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO) display a longer free...

  4. Lego clocks : building a clock from parts

    NARCIS (Netherlands)

    Brunner, Michael; Simons, Mirre J. P.; Merrow, Martha

    2008-01-01

    A new finding opens up speculation that the molecular mechanism of circadian clocks in Synechococcus elongatus is composed of multiple oscillator systems (Kitayama and colleagues, this issue, pp. 1513-1521), as has been described in many eukaryotic clock model systems. However, an alternative

  5. Phytochrome gene expression and phylogenetic analysis in the short-day plant Pharbitis nil (Convolvulaceae): Differential regulation by light and an endogenous clock.

    Science.gov (United States)

    Zheng, Cheng Chao; Potter, Daniel; O'Neill, Sharman D

    2009-07-01

    To investigate the role of distinct phytochrome pools in photoperiodic timekeeping, we characterized four phytochrome genes in the short-day plant Pharbitis nil. Each PHY gene had different photosensory properties and sensitivity to night break that inhibits flowering. During extended dark periods, PHYE, PHYB, and PHYC mRNA accumulation exhibited a circadian rhythmicity indicative of control by an endogenous clock. Phylogenetic analysis recovered four clades of angiosperm phytochrome genes, phyA, phyB, phyC, and phyE. All except the phyE clade included sequences from both monocots and eudicots. In addition, phyA is sister to phyC and phyE sister to phyB, with gymnosperm sequences sister to either the phyA-phyC clade or to the phyB-phyE clade. These results suggest that a single duplication occurred in an ancestral seed plant before the divergence of extant gymnosperms from angiosperms and that two subsequent duplications occurred in an ancestral angiosperm before the divergence of monocots from eudicots. Thus in P. nil, a multigene family with different patterns of mRNA abundance in light and darkness contributes to the total phytochrome pool: one pool is light labile (phyA), whereas the other is light stable (phyB and phyE). In addition, PHYC mRNA represents a third phytochrome pool with intermediate photosensory properties.

  6. DNA methylation of the serotonin transporter gene in peripheral cells and stress-related changes in hippocampal volume: a study in depressed patients and healthy controls.

    Directory of Open Access Journals (Sweden)

    Linda Booij

    Full Text Available Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD (23 females and 36 matched healthy controls (21 females were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.

  7. Do Caucasian and Asian clocks tick differently?

    Directory of Open Access Journals (Sweden)

    A.A. Barbosa

    Full Text Available The Period 3 and Clock genes are important components of the mammalian molecular circadian system. Studies have shown association between polymorphisms in these clock genes and circadian phenotypes in different populations. Nevertheless, differences in the pattern of allele frequency and genotyping distribution are systematically observed in studies with different ethnic groups. To investigate and compare the pattern of distribution in a sample of Asian and Caucasian populations living in Brazil, we evaluated two well-studied polymorphisms in the clock genes: a variable number of tandem repeats (VNTR in PER3 and a single nucleotide polymorphism (SNP in CLOCK. The aim of this investigation was to search for clues about human evolutionary processes related to circadian rhythms. We selected 109 Asian and 135 Caucasian descendants. The frequencies of the shorter allele (4 repeats in the PER3 gene and the T allele in the CLOCK gene among Asians (0.86 and 0.84, respectively were significantly higher than among Caucasians (0.69 and 0.71, respectively. Our results directly confirmed the different distribution of these polymorphisms between the Asian and Caucasian ethnic groups. Given the genetic differences found between groups, two points became evident: first, ethnic variations may have implications for the interpretation of results in circadian rhythm association studies, and second, the question may be raised about which evolutionary conditions shaped these genetic clock variations.

  8. Do Caucasian and Asian clocks tick differently?

    Science.gov (United States)

    Barbosa, A A; Pedrazzoli, M; Koike, B D V; Tufik, S

    2010-01-01

    The Period 3 and Clock genes are important components of the mammalian molecular circadian system. Studies have shown association between polymorphisms in these clock genes and circadian phenotypes in different populations. Nevertheless, differences in the pattern of allele frequency and genotyping distribution are systematically observed in studies with different ethnic groups. To investigate and compare the pattern of distribution in a sample of Asian and Caucasian populations living in Brazil, we evaluated two well-studied polymorphisms in the clock genes: a variable number of tandem repeats (VNTR) in PER3 and a single nucleotide polymorphism (SNP) in CLOCK. The aim of this investigation was to search for clues about human evolutionary processes related to circadian rhythms. We selected 109 Asian and 135 Caucasian descendants. The frequencies of the shorter allele (4 repeats) in the PER3 gene and the T allele in the CLOCK gene among Asians (0.86 and 0.84, respectively) were significantly higher than among Caucasians (0.69 and 0.71, respectively). Our results directly confirmed the different distribution of these polymorphisms between the Asian and Caucasian ethnic groups. Given the genetic differences found between groups, two points became evident: first, ethnic variations may have implications for the interpretation of results in circadian rhythm association studies, and second, the question may be raised about which evolutionary conditions shaped these genetic clock variations.

  9. Do Caucasian and Asian clocks tick differently?

    Directory of Open Access Journals (Sweden)

    A.A. Barbosa

    2010-01-01

    Full Text Available The Period 3 and Clock genes are important components of the mammalian molecular circadian system. Studies have shown association between polymorphisms in these clock genes and circadian phenotypes in different populations. Nevertheless, differences in the pattern of allele frequency and genotyping distribution are systematically observed in studies with different ethnic groups. To investigate and compare the pattern of distribution in a sample of Asian and Caucasian populations living in Brazil, we evaluated two well-studied polymorphisms in the clock genes: a variable number of tandem repeats (VNTR in PER3 and a single nucleotide polymorphism (SNP in CLOCK. The aim of this investigation was to search for clues about human evolutionary processes related to circadian rhythms. We selected 109 Asian and 135 Caucasian descendants. The frequencies of the shorter allele (4 repeats in the PER3 gene and the T allele in the CLOCK gene among Asians (0.86 and 0.84, respectively were significantly higher than among Caucasians (0.69 and 0.71, respectively. Our results directly confirmed the different distribution of these polymorphisms between the Asian and Caucasian ethnic groups. Given the genetic differences found between groups, two points became evident: first, ethnic variations may have implications for the interpretation of results in circadian rhythm association studies, and second, the question may be raised about which evolutionary conditions shaped these genetic clock variations.

  10. Daily rhythm variations of the clock gene PER1 and cancer-related genes during various stages of carcinogenesis in a golden hamster model of buccal mucosa carcinoma

    Directory of Open Access Journals (Sweden)

    Ye H

    2015-06-01

    Full Text Available Hua Ye, Kai Yang, Xue-Mei Tan, Xiao-Juan Fu, Han-Xue LiDepartment of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaBackground: Recent studies have demonstrated that the clock gene PER1 regulates various tumor-related genes. Abnormal expressions and circadian rhythm alterations of PER1 are closely related to carcinogenesis. However, the dynamic circadian variations of PER1 and tumor-related genes at different stages of carcinogenesis remain unknown. This study was conducted to investigate the daily rhythm variation of PER1 and expression of tumor-related genes VEGF, KI67, C-MYC, and P53 in different stages of carcinogenesis.Materials and methods: Dimethylbenzanthracene was used to establish a golden hamster model of buccal mucosa carcinogenesis. Hamsters with normal buccal mucosa, precancerous lesion, and cancerous lesion were sacrificed at six different time points during a 24-hour period of a day. Pathological examination was conducted using routine hematoxylin and eosin staining. PER1, VEGF, KI67, C-MYC, and P53 mRNAs were detected by real-time reverse transcriptase polymerase chain reaction, and a cosinor analysis was applied to analyze the daily rhythm.Results: PER1, VEGF, C-MYC, and P53 mRNA exhibited daily rhythmic expression in three carcinogenesis stages, and KI67 mRNA exhibited daily rhythmic expression in the normal and precancerous stages. The daily rhythmic expression of KI67 was not observed in cancerous stages. The mesor and amplitude of PER1 and P53 mRNA expression decreased upon the development of cancer (P<0.05, whereas the mesor and amplitude of VEGF, KI67, and C-MYC mRNA increased upon the development of cancer (P<0.05. Compared with the normal tissues, the acrophases of PER1, VEGF, and C-MYC mRNA occurred earlier, whereas the acrophases of P53 and KI67 mRNA lagged remarkably in the precancerous lesions. In the cancer stage, the acrophases

  11. Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice

    Directory of Open Access Journals (Sweden)

    June Zhou

    2017-09-01

    Full Text Available Traumatic brain injury (TBI causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group underwent sham or unilateral controlled cortical impact (CCI injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. Expressions of several genes important for brain glucose utilization were determined by qRT-PCR. In results, (1 mRNA levels of three key enzymes in glucose metabolism [hexo kinase (HK 1, pyruvate kinase, and pyruvate dehydrogenase (PDH] were all increased 6 h after injury in the contralateral cortex, followed by decreases at subsequent times in the ipsilateral cortex and hippocampus; (2 capillary glucose transporter Glut-1 mRNA increased, while neuronal glucose transporter Glut-3 mRNA decreased, at various times in the ipsilateral cortex and hippocampus; (3 astrocyte lactate transporter MCT-1 mRNA increased, whereas neuronal lactate transporter MCT-2 mRNA decreased in the ipsilateral cortex and hippocampus; (4 HK2 (an isoform of hexokinase expression increased at all time points in the ipsilateral cortex and hippocampus. GPR81 (lactate receptor mRNA increased at various time points in the ipsilateral cortex and hippocampus. These temporal alterations in gene expression corresponded closely to the patterns of impaired brain glucose utilization reported in both TBI patients and experimental TBI rodents. The observed changes in hippocampal gene expression were delayed and prolonged, when compared with those in the cortex. The patterns of alterations were specific

  12. Network features of the mammalian circadian clock.

    Directory of Open Access Journals (Sweden)

    Julie E Baggs

    2009-03-01

    Full Text Available The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. To assess the robustness of a human molecular clock, we systematically depleted known clock components and observed that circadian oscillations are maintained over a wide range of disruptions. We developed a novel strategy termed Gene Dosage Network Analysis (GDNA in which small interfering RNA (siRNA-induced dose-dependent changes in gene expression were used to build gene association networks consistent with known biochemical constraints. The use of multiple doses powered the analysis to uncover several novel network features of the circadian clock, including proportional responses and signal propagation through interacting genetic modules. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that these network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation.

  13. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling.

    Science.gov (United States)

    Colangelo, Vittorio; Schurr, Jill; Ball, Melvyn J; Pelaez, Ricardo Palacios; Bazan, Nicolas G; Lukiw, Walter J

    2002-11-01

    Alterations in transcription, RNA editing, translation, protein processing, and clearance are a consistent feature of Alzheimer's disease (AD) brain. To extend our initial study (Alzheimer Reports [2000] 3:161-167), RNA samples isolated from control and AD hippocampal cornu ammonis 1 (CA1) were analyzed for 12633 gene and expressed sequence tag (EST) expression levels using DNA microarrays (HG-U95Av2 Genechips; Affymetrix, Santa Clara, CA). Hippocampal CA1 tissues were carefully selected from several hundred potential specimens obtained from domestic and international brain banks. To minimize the effects of individual differences in gene expression, RNA of high spectral quality (A(260/280) > or= 1.9) was pooled from CA1 of six control or six AD subjects. Results were compared as a group; individual gene expression patterns for the most-changed RNA message levels were also profiled. There were no significant differences in age, postmortem interval (mean data were analyzed using GeneSpring (Silicon Genetics, Redwood City, CA) and Microarray Data Mining Tool (Affymetrix) software. Compared to controls and 354 background/alignment markers, AD brain showed a generalized depression in brain gene transcription, including decreases in RNA encoding transcription factors (TFs), neurotrophic factors, signaling elements involved in synaptic plasticity such as synaptophysin, metallothionein III, and metal regulatory factor-1. Three- or morefold increases in RNAs encoding DAXX, cPLA(2), CDP5, NF-kappaBp52/p100, FAS, betaAPP, DPP1, NFIL6, IL precursor, B94, HB15, COX-2, and CEX-1 signals were strikingly apparent. These data support the hypothesis of widespread transcriptional alterations, misregulation of RNAs involved in metal ion homeostasis, TF signaling deficits, decreases in neurotrophic support and activated apoptotic and neuroinflammatory signaling in moderately affected AD hippocampal CA1. Copyright 2002 Wiley-Liss, Inc.

  14. Differential Phasing between Circadian Clocks in the Brain and Peripheral Organs in Humans

    OpenAIRE

    Hughey, Jacob J; Butte, Atul J

    2016-01-01

    The daily timing of mammalian physiology is coordinated by circadian clocks throughout the body. Although measurements of clock gene expression indicate that these clocks in mice are normally in phase with each other, the situation in humans remains unclear. We used publicly available data from five studies, comprising over 1000 samples, to compare the phasing of circadian gene expression in human brain and human blood. Surprisingly, after controlling for age, clock gene expression in brain w...

  15. Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

    Science.gov (United States)

    Ozburn, Angela R; Purohit, Kush; Parekh, Puja K; Kaplan, Gabrielle N; Falcon, Edgardo; Mukherjee, Shibani; Cates, Hannah M; McClung, Colleen A

    2016-01-01

    Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) is a genetic variation of the human CLOCK gene that is significantly associated with increased frequency of manic episodes in BD patients (2). The 3111T/C SNP is located in the 3'-untranslated region of the CLOCK gene. In this study, we sought to examine the functional implications of the human CLOCK 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock(-/-) knockout mice) with pcDNA plasmids containing the human CLOCK gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24-h time period. We found that the CLOCK3111C SNP resulted in higher mRNA levels than the CLOCK 3111T SNP. Furthermore, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with CLOCK 3111C expression, indicating that the 3'-UTR SNP affects the expression, function, and stability of CLOCK mRNA.

  16. FUNCTIONAL IMPLICATIONS OF THE CLOCK 3111T/C SINGLE-NUCLEOTIDE POLYMORPHISM

    Directory of Open Access Journals (Sweden)

    Angela Renee Ozburn

    2016-04-01

    Full Text Available Circadian rhythm disruptions are prominently associated with Bipolar Disorder (BD. Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (Roybal et al., 2007. The Clock 3111T/C single-nucleotide polymorphism (SNP; rs1801260 is a genetic variation of the human Clock gene that is significantly associated with increased frequency of manic episodes in BD patients (Benedetti et al., 2003. The 3111T/C SNP is located in the 3’ untranslated region of the Clock gene. In this study, we sought to examine the functional implications of the human Clock 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock -/- knockout mice with pcDNA plasmids containing the human Clock gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24 hour time period. We found that the Clock3111C SNP resulted in higher mRNA levels than the Clock 3111T SNP. Further, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with Clock 3111C expression, indicating the 3’UTR SNP affects the expression, function and stability of Clock mRNA.

  17. Impact of a cis-associated gene expression SNP in 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance

    Science.gov (United States)

    Li, Ming; Luo, Xiong-jian; Landén, Mikael; Bergen, Sarah E.; Hultman, Christina M.; Li, Xiao; Zhang, Wen; Yao, Yong-Gang; Zhang, Chen; Liu, Jiewei; Mattheisen, Manuel; Cichon, Sven; Mühleisen, Thomas W.; Degenhardt, Franziska A.; Nöthen, Markus M.; Schulze, Thomas G.; Grigoroiu-Serbanescu, Maria; Li, Hao; Fuller, Chris K.; Chen, Chunhui; Dong, Qi; Chen, Chuansheng; Jamain, Stéphane; Leboyer, Marion; Bellivier, Frank; Etain, Bruno; Kahn, Jean-Pierre; Henry, Chantal; Preisig, Martin; Kutalik, Zoltán; Castelao, Enrique; Wright, Adam; Mitchell, Philip B.; Fullerton, Janice M.; Schofield, Peter R.; Montgomery, Grant W.; Medland, Sarah E.; Gordon, Scott D.; Martin, Nicholas G.; Rietschel, Marcella; Liu, Chunyu; Kleinman, Joel E.; Hyde, Thomas M.; Weinberger, Daniel R.; Su, Bing

    2016-01-01

    Summary Bipolar disorder (BPD) is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for BPD among the expression quantitative trait loci (eQTL) in the brain. Aims We sought to assess the impact of eQTL variants on BPD risk by combining data from both BPD genome-wide association study (GWAS) and brain eQTL. Method To detect single-nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with BPD, we jointly analyzed data from a BPD GWAS (7,481 cases and 9,250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (N=5,775) and cognitive performance (N=342) among healthy subjects. Results Integrative analysis revealed a significant association between a brain eQTL rs6088662 in 20q11.22 and BPD (Log Bayes Factor=5.48; BPD p-val=5.85×10−5). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and BPD susceptibility (p-val=3.54×10−8). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy subjects. Conclusions Our findings suggest that 20q11.22 is likely a risk region for BPD, highlighting the informativeness of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex diseases such as BPD. PMID:26338991

  18. Omega 3 polyunsaturated fatty acid improves spatial learning and hippocampal Peroxisome Proliferator Activated Receptors (PPARα and PPARγ gene expression in rats

    Directory of Open Access Journals (Sweden)

    Hajjar Toktam

    2012-09-01

    Full Text Available Abstract Background This study examined the effects of dietary polyunsaturated fatty acids (PUFA as different n-6: n-3 ratios on spatial learning and gene expression of peroxisome- proliferator-activated receptors (PPARs in the hippocampus of rats. Thirty male Sprague–Dawley rats were randomly allotted into 3 groups of ten animals each and received experimental diets with different n-6: n-3 PUFA ratios of either 65:1, 22:1 or 4.5:1. After 10 weeks, the spatial memory of the animals was assessed using the Morris Water Maze test. The expression of PPARα and PPARγ genes were determined using real-time PCR. Results Decreasing dietary n-6: n-3 PUFA ratios improved the cognitive performance of animals in the Morris water maze test along with the upregulation of PPARα and PPARγ gene expression. The animals with the lowest dietary n-6: n-3 PUFA ratio presented the highest spatial learning improvement and PPAR gene expression. Conclusion It can be concluded that modulation of n-6: n-3 PUFA ratios in the diet may lead to increased hippocampal PPAR gene expression and consequently improved spatial learning and memory in rats.

  19. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    Science.gov (United States)

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. GPS Composite Clock Analysis

    OpenAIRE

    Wright, James R.

    2008-01-01

    The GPS composite clock defines GPS time, the timescale used today in GPS operations. GPS time is illuminated by examination of its role in the complete estimation and control problem relative to UTC/TAI. The phase of each GPS clock is unobservable from GPS pseudorange measurements, and the mean phase of the GPS clock ensemble (GPS time) is unobservable. A new and useful observability definition is presented, together with new observability theorems, to demonstrate explicitly that GPS time is...

  1. Precision Clock Evaluation Facility

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: Tests and evaluates high-precision atomic clocks for spacecraft, ground, and mobile applications. Supports performance evaluation, environmental testing,...

  2. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior

    DEFF Research Database (Denmark)

    Baek, Jean-Ha; Schmidt, Eva; Viceconte, Nikenza

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells...... also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation...... of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues...

  3. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

    Science.gov (United States)

    Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-06-01

    Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

  4. Photoperiodic plasticity in circadian clock neurons in insects

    Directory of Open Access Journals (Sweden)

    Sakiko eShiga

    2013-08-01

    Full Text Available Since Bünning’s observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Based on molecular and neuronal studies in Drosophila melanogaster, photoperiodic changes have been reported for expression patterns of the circadian clock genes, subcellular distribution of clock proteins, fiber distribution, or the number of plausible clock neurons in different species. Photoperiod sets peaks of per or tim mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.

  5. The impact of nutrients on clock genes and metabolism: their role for the prevention and treatment of metabolic diseases

    OpenAIRE

    Castillo Figueroa, Ana Lucía

    2017-01-01

    spa] La expresión de los ritmos biológicos es una capacidad intrínseca de los seres vivos, el funcionamiento correcto de estos ritmos circadianos permite a los organismos predecir y anticiparse a los cambios medio ambientales, así como adaptar temporalmente sus funciones conductuales y fisiológicas a diferentes cambios. Éstos ritmos circadianos son generados por un conjunto de genes reloj. Extensa investigación en animales y seres humanos han vinculado la regulación energética y el reloj biol...

  6. Clocked combustor can array

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Won-Wook; McMahan, Kevin Weston; Srinivasan, Shiva Kumar

    2017-01-17

    The present application provides a clocked combustor can array for coherence reduction in a gas turbine engine. The clocked combustor can array may include a number of combustor cans positioned in a circumferential array. A first set of the combustor cans may have a first orientation and a second set of the combustor cans may have a second orientation.

  7. Biological Clocks & Circadian Rhythms

    Science.gov (United States)

    Robertson, Laura; Jones, M. Gail

    2009-01-01

    The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…

  8. Optical Clocks in Space

    NARCIS (Netherlands)

    Schiller, S.; Görlitz, A.; Nevsky, A.; Koelemeij, J. C J; Wicht, A.; Gill, K.P.; Klein, H. A.; Margolis, H. S.; Mileti, G.; Sterr, U.; Riehle, F.; Peik, E.; Tamm, Chr; Ertmer, W.; Rasel, E.; van der Klein, M; Salomon, C.; Tino, G. M.; Lemonde, P.; Holzwarth, R.; Hänsch, T. W.

    The performance of optical clocks has strongly progressed in recent years, and accuracies and instabilities of 1 part in 1018 are expected in the near future. The operation of optical clocks in space provides new scientific and technological opportunities. In particular, an earth-orbiting satellite

  9. PARP Around the Clock

    OpenAIRE

    Kumar, Vivek; Takahashi, Joseph S.

    2010-01-01

    Cells possess internal ~24-hour or circadian clocks that synchronize physiological processes with daily cycles of light and nutrient availability. In this issue, Asher et al. (2010) find that PARP-1 (Poly(ADP-ribose) polymerase-1) modifies components of the clock machinery in response to feeding, providing a mechanism for how metabolic rhythms coordinate with circadian rhythms.

  10. Egyptian "Star Clocks"

    Science.gov (United States)

    Symons, Sarah

    Diagonal, transit, and Ramesside star clocks are tables of astronomical information occasionally found in ancient Egyptian temples, tombs, and papyri. The tables represent the motions of selected stars (decans and hour stars) throughout the Egyptian civil year. Analysis of star clocks leads to greater understanding of ancient Egyptian constellations, ritual astronomical activities, observational practices, and pharaonic chronology.

  11. Influence of simulated microgravity on clock genes expression rhythmicity and underlying blood circulating miRNAs-mRNA co-expression regulatory mechanism in C57BL/6J mice

    Science.gov (United States)

    Lv, Ke; Qu, Lina

    Purpose: It is vital for astronauts to maintain the optimal alertness and neurobehavioral function. Among various factors that exist in the space flight and long-duration mission environment, gravity changes may probably an essential environmental factor to interfere with internal circadian rhythms homeostasis and sleep quality, but the underlying mechanism is unclear. Mammals' biological clock is controlled by the suprachiasmatic nucleus (SCN), and peripheral organs adjust their own rhythmicity with the central signals. Nevertheless the mechanism underlying this synchronizition process is still unknown. microRNAs (miRNAs) are about 19˜22nt long regulatory RNAs that serve as critical modulators of post-transcriptional gene regulation. Recently, circulating miRNAs were found to have the regulatory role between cells and peripheral tissues, besides its function inside the cells. This study aims to investigate the regulatory signal transduction role of miRNAs between SCN and peripheral biological clock effecter tissues and to further decipher the mechanism of circadian disturbance under microgravity. Method: Firstly, based on the assumption that severe alterations in the expression of genes known to be involved in circadian rhythms may affect the expression of other genes, the labeled cDNA from liver and suprachiasmatic nucleus (SCN) of clock-knockout mice and control mice in different time points were cohybridized to microarrays. The fold change exceeding 2 (FC>2) was used to identify genes with altered expression levels in the knockout mice compared with control mice. Secondly, male C57BL/6J mice at 8 weeks of age were individually caged and acclimatized to the laboratory conditions (12h light/dark cycle) before being used for continuous core body temperature and activity monitoring. The mice were individually caged and tail suspended using a strip of adhesive surgical tape attached to a chain hanging from a pulley. Peripheral blood and liver tissues collection

  12. Characterization of the Gene Expression Profile of Human Hippocampus in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

    Directory of Open Access Journals (Sweden)

    Julio Lachos

    2011-01-01

    At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp, ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1α, IL-1β, IL-6, and IL-18 and cytokines (TNF-α and TGF-β1 were found to be up-regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1β, and IL-6 was also confirmed by immunohistochemistry (IHC. Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE.

  13. The circadian clock in oral health and diseases.

    Science.gov (United States)

    Papagerakis, S; Zheng, L; Schnell, S; Sartor, M A; Somers, E; Marder, W; McAlpin, B; Kim, D; McHugh, J; Papagerakis, P

    2014-01-01

    Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called "clock genes". Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between "oral clocks" and diseases such as head and neck cancer and Sjögren's syndrome.

  14. Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.

    Science.gov (United States)

    Laermans, Jorien; Broers, Charlotte; Beckers, Kelly; Vancleef, Laurien; Steensels, Sandra; Thijs, Theo; Tack, Jan; Depoortere, Inge

    2014-01-01

    In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers.

  15. Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.

    Directory of Open Access Journals (Sweden)

    Jorien Laermans

    Full Text Available BACKGROUND: In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF, a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS: Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD. Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test. Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS: The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. CONCLUSIONS: This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and

  16. [Physiological and pathophysiological role of the circadian clock system].

    Science.gov (United States)

    Halmos, Tamás; Suba, Ilona

    2012-09-02

    It has been well known for ages that in living organisms the rhythmicity of biological processes is linked to the ~ 24-hour light-dark cycle. However, the exact function of the circadian clock system has been explored only in the past decades. It came to light that the photosensitive primary "master clock" is situated in the suprachiasmatic photosensitive nuclei of the special hypothalamic region, and that it is working according to ~24-hour changes of light and darkness. The master clock sends its messages to the peripheral "slave clocks". In many organs, like pancreatic β-cells, the slave clocks have autonomic functions as well. Two essential components of the clock system are proteins encoded by the CLOCK and BMAL1 genes. CLOCK genes are in interaction with endonuclear receptors such as peroxisoma-proliferator activated receptors and Rev-erb-α, as well as with the hypothalamic-pituitary-adrenal axis, regulating the adaptation to stressors, energy supply, metabolic processes and cardiovascular system. Melatonin, the product of corpus pineale has a significant role in the functions of the clock system. The detailed discovery of the clock system has changed our previous knowledge about the development of many diseases. The most explored fields are hypertension, cardiovascular diseases, metabolic processes, mental disorders, cancers, sleep apnoe and joint disorders. CLOCK genes influence ageing as well. The recognition of the periodicity of biological processes makes the optimal dosing of certain drugs feasible. The more detailed discovery of the interaction of the clock system might further improve treatment and prevention of many disorders.

  17. MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis.

    Science.gov (United States)

    Kubík, Stěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

    2014-01-01

    Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated

  18. Ketogenic diet change cPLA2/clusterin and autophagy related gene expression and correlate with cognitive deficits and hippocampal MFs sprouting following neonatal seizures.

    Science.gov (United States)

    Ni, Hong; Zhao, Dong-Jing; Tian, Tian

    2016-02-01

    Because the ketogenic diet (KD) was affecting expression of energy metabolism- related genes in hippocampus and because lipid membrane peroxidation and its associated autophagy stress were also found to be involved in energy depletion, we hypothesized that KD might exert its neuroprotective action via lipid membrane peroxidation and autophagic signaling. Here, we tested this hypothesis by examining the long-term expression of lipid membrane peroxidation-related cPLA2 and clusterin, its downstream autophagy marker Beclin-1, LC3 and p62, as well as its execution molecule Cathepsin-E following neonatal seizures and chronic KD treatment. On postnatal day 9 (P9), 48 Sprague-Dawley rats were randomly assigned to two groups: flurothyl-induced recurrent seizures group and control group. On P28, they were further randomly divided into the seizure group without ketogenic diet (RS+ND), seizure plus ketogenic diet (RS+KD), the control group without ketogenic diet (NS+ND), and the control plus ketogenic diet (NS+KD). Morris water maze test was performed during P37-P43. Then mossy fiber sprouting and the protein levels were detected by Timm staining and Western blot analysis, respectively. Flurothyl-induced RS+ND rats show a long-term lower amount of cPLA2 and LC3II/I, and higher amount of clusterin, Beclin-1, p62 and Cathepsin-E which are in parallel with hippocampal mossy fiber sprouting and cognitive deficits. Furthermore, chronic KD treatment (RS+KD) is effective in restoring these molecular, neuropathological and cognitive changes. The results imply that a lipid membrane peroxidation and autophagy-associated pathway is involved in the aberrant hippocampal mossy fiber sprouting and cognitive deficits following neonatal seizures, which might be a potential target of KD for the treatment of neonatal seizure-induced brain damage. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3.

    Science.gov (United States)

    Turco, M; Biscontin, A; Corrias, M; Caccin, L; Bano, M; Chiaromanni, F; Salamanca, M; Mattei, D; Salvoro, C; Mazzotta, G; De Pittà, C; Middleton, B; Skene, D J; Montagnese, S; Costa, R

    2017-07-31

    PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER3 4, PER3 5; rs228697 SNP: PER3 C, PER3 G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER3 4 /PER3 4 and PER3 5 /PER3 5 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19 PER3 4 /PER3 4 and 11 PER3 5 /PER3 5 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3 G variant and morningness (OR = 2.10), and between the PER3 G-PER3 4 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms between PER3 5 /PER3 5 and PER3 4 /PER3 4 subjects at baseline. After light administration, PER3 4 /PER3 4 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

  20. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.

    Science.gov (United States)

    López-Yoldi, Miguel; Stanhope, Kimber L; Garaulet, Marta; Chen, X Guoxia; Marcos-Gómez, Beatriz; Carrasco-Benso, María Paz; Santa Maria, Eva M; Escoté, Xavier; Lee, Vivien; Nunez, Marinelle V; Medici, Valentina; Martínez-Ansó, Eduardo; Sáinz, Neira; Huerta, Ana E; Laiglesia, Laura M; Prieto, Jesús; Martínez, J Alfredo; Bustos, Matilde; Havel, Peter J; Moreno-Aliaga, Maria J

    2017-04-01

    Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged obese CT-1-deficient (CT-1(-/-)) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young lean CT-1(-/-) mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1(-/-) mice. However, the pattern was altered in CT-1(-/-) mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects. © FASEB.

  1. Novel genetic loci associated with hippocampal volume

    Science.gov (United States)

    Hibar, Derrek P.; Adams, Hieab H. H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C.; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivières, Sylvane; Vernooij, Meike W.; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S.; Armstrong, Nicola J.; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H.; Beiser, Alexa; Bernard, Manon; Blanton, Susan H.; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brickman, Adam M.; Carmichael, Owen; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L.; Gottesman, Rebecca F.; Grimm, Oliver; Griswold, Michael E.; Guadalupe, Tulio; Gutman, Boris A.; Hass, Johanna; Haukvik, Unn K.; Hoehn, David; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N.; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Macare, Christine; Marquand, Andre F.; Matarin, Mar; Mather, Karen A.; Mattheisen, Manuel; McKay, David R.; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C.; Nyquist, Paul; Loohuis, Loes M. Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S.; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J.; Royle, Natalie A.; Rundek, Tatjana; Sämann, Philipp G.; Saremi, Arvin; Satizabal, Claudia L.; Schmaal, Lianne; Schork, Andrew J.; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V.; Sprooten, Emma; Strike, Lachlan T.; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J.; Van der Meer, Dennis; Van Donkelaar, Marjolein M. J.; Van Eijk, Kristel R.; Van Erp, Theo G. M.; Van Rooij, Daan; Walton, Esther; Westlye, Lars T.; Whelan, Christopher D.; Windham, Beverly G.; Winkler, Anderson M.; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R.; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P.; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A.; Arepalli, Sampath; Assareh, Amelia A.; Barral, Sandra; Bastin, Mark E.; Becker, Diane M.; Becker, James T.; Bennett, David A.; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I.; Brodaty, Henry; Brouwer, Rachel M.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Bulayeva, Kazima B.; Cahn, Wiepke; Calhoun, Vince D.; Cannon, Dara M.; Cavalleri, Gianpiero L.; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R.; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E.; Czisch, Michael; Dale, Anders M.; Davies, Gareth E.; De Craen, Anton J. M.; De Geus, Eco J. C.; De Jager, Philip L.; De Zubicaray, Greig I.; Deary, Ian J.; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C.; Duggirala, Ravi; Dyer, Thomas D.; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O.; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E.; Fleischman, Debra A.; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M.; Fox, Peter T.; Francks, Clyde; Fukunaga, Masaki; Gibbs, J. Raphael; Glahn, David C.; Gollub, Randy L.; Göring, Harald H. H.; Green, Robert C.; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K.; Hansell, Narelle K.; Hardy, John; Hartman, Catharina A.; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G.; Heslenfeld, Dirk J.; Ho, Beng-Choon; Hoekstra, Pieter J.; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Pol, Hilleke E. Hulshoff; Ikeda, Masashi; Jack Jr, Clifford R.; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G.; Jukema, J. Wouter; Kahn, René S.; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L.; Lopez, Oscar L.; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S.; McDonald, Colm; McIntosh, Andrew M.; McMahon, Francis J.; McMahon, Katie L.; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W.; Morris, Derek W.; Mosley, Thomas H.; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Nalls, Michael A.; Nauck, Matthias; Nichols, Thomas E.; Niessen, Wiro J.; Nöthen, Markus M.; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L.; Ophoff, Roel A.; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W. J. H.; Pike, G. Bruce; Potkin, Steven G.; Psaty, Bruce M.; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L.; Romanczuk-Seiferth, Nina; Rotter, Jerome I.; Ryten, Mina; Sacco, Ralph L.; Sachdev, Perminder S.; Saykin, Andrew J.; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R.; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M.; Smith, Colin; Smoller, Jordan W.; Soininen, Hilkka; Steen, Vidar M.; Stott, David J.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G.; Hernández, Maria C. Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J. A.; Van Haren, Neeltje E. M.; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N.; Vellas, Bruno; Veltman, Dick J.; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M.; Wassink, Thomas H.; Weale, Michael E.; Weinberger, Daniel R.; Weiner, Michael W.; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y.; Wright, Clinton B.; Zielke, Ronald H.; Zonderman, Alan B.; Martin, Nicholas G.; Van Duijn, Cornelia M.; Wright, Margaret J.; Longstreth, W. T.; Schumann, Gunter; Grabe, Hans J.; Franke, Barbara; Launer, Lenore J.; Medland, Sarah E.; Seshadri, Sudha; Thompson, Paul M.; Ikram, M. Arfan

    2017-01-01

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID:28098162

  2. Novel genetic loci associated with hippocampal volume.

    Science.gov (United States)

    Hibar, Derrek P; Adams, Hieab H H; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L; Hofer, Edith; Renteria, Miguel E; Bis, Joshua C; Arias-Vasquez, Alejandro; Ikram, M Kamran; Desrivières, Sylvane; Vernooij, Meike W; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H; Beiser, Alexa; Bernard, Manon; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Gutman, Boris A; Hass, Johanna; Haukvik, Unn K; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre F; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; McKay, David R; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C; Nyquist, Paul; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Saremi, Arvin; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Craen, Anton J M; De Geus, Eco J C; De Jager, Philip L; De Zubicaray, Greig I; Deary, Ian J; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J A; Van Haren, Neeltje E M; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Vellas, Bruno; Veltman, Dick J; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, Ronald H; Zonderman, Alan B; Martin, Nicholas G; Van Duijn, Cornelia M; Wright, Margaret J; Longstreth, W T; Schumann, Gunter; Grabe, Hans J; Franke, Barbara; Launer, Lenore J; Medland, Sarah E; Seshadri, Sudha; Thompson, Paul M; Ikram, M Arfan

    2017-01-18

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  3. TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells.

    Science.gov (United States)

    Yoshida, Kohsuke; Nakai, Ayako; Kaneshiro, Kenta; Hashimoto, Naonori; Suzuki, Kohjin; Uchida, Koto; Hashimoto, Teppei; Kawasaki, Yoshiko; Tateishi, Koji; Nakagawa, Natsuko; Shibanuma, Nao; Sakai, Yoshitada; Hashiramoto, Akira

    2018-01-08

    Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca 2+ chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α. Oscillation phase and amplitude of Bmal1, transcriptional activator Rorα, transcriptional repressor Rev-erbα, and histone acetyltransferases (p300 and Cbp) were evaluated by quantitative real-time PCR. As results, TNF-α did not influence the oscillation phase of Rev-erbα, while enhanced those of Rorα, resulting in over-expression of Bmal1. When Ca 2+ influx was inhibited by BAPTA-AM, TNF-α-mediated up-regulation of Rorα was cancelled, however, that of Bmal1 was still apparent. When we further explored another pathway between TNF-α and Bmal1, TNF-α suppressed the expression of Rev-erbα in the absence of Ca 2+ influx, as well as those of p300 and Cbp genes. Finally, actions of TNF-α, in increasing Bmal1/Rorα and decreasing Rev-erbα, were cancelled by C646 treatment or silencing of both p300 and Cbp. In conclusion, we determined a novel role of TNF-α in inducing Bmal1 via dual calcium dependent pathways; Rorα was up-regulated in the presence of Ca 2+ influx and Rev-erbα was down-regulated in the absence of that. Results proposed that inhibition of p300/CBP could be new therapeutic targets for RA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Optical clocks and relativity.

    Science.gov (United States)

    Chou, C W; Hume, D B; Rosenband, T; Wineland, D J

    2010-09-24

    Observers in relative motion or at different gravitational potentials measure disparate clock rates. These predictions of relativity have previously been observed with atomic clocks at high velocities and with large changes in elevation. We observed time dilation from relative speeds of less than 10 meters per second by comparing two optical atomic clocks connected by a 75-meter length of optical fiber. We can now also detect time dilation due to a change in height near Earth's surface of less than 1 meter. This technique may be extended to the field of geodesy, with applications in geophysics and hydrology as well as in space-based tests of fundamental physics.

  5. Circadian Clock Involvement in Zooplankton Diel Vertical Migration.

    Science.gov (United States)

    Häfker, N Sören; Meyer, Bettina; Last, Kim S; Pond, David W; Hüppe, Lukas; Teschke, Mathias

    2017-07-24

    Biological clocks are a ubiquitous ancient and adaptive mechanism enabling organisms to anticipate environmental cycles and to regulate behavioral and physiological processes accordingly [1]. Although terrestrial circadian clocks are well understood, knowledge of clocks in marine organisms is still very limited [2-5]. This is particularly true for abundant species displaying large-scale rhythms like diel vertical migration (DVM) that contribute significantly to shaping their respective ecosystems [6]. Here we describe exogenous cycles and endogenous rhythms associated with DVM of the ecologically important and highly abundant planktic copepod Calanus finmarchicus. In the laboratory, C. finmarchicus shows circadian rhythms of DVM, metabolism, and most core circadian clock genes (clock, period1, period2, timeless, cryptochrome2, and clockwork orange). Most of these genes also cycle in animals assessed in the wild, though expression is less rhythmic at depth (50-140 m) relative to shallow-caught animals (0-50 m). Further, peak expressions of clock genes generally occurred at either sunset or sunrise, coinciding with peak migration times. Including one of the first field investigations of clock genes in a marine species [5, 7], this study couples clock gene measurements with laboratory and field data on DVM. While the mechanistic connection remains elusive, our results imply a high degree of causality between clock gene expression and one of the planet's largest daily migrations of biomass. We thus suggest that circadian clocks increase zooplankton fitness by optimizing the temporal trade-off between feeding and predator avoidance, especially when environmental drivers are weak or absent [8]. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature.

    Science.gov (United States)

    Caccamo, Antonella; De Pinto, Vito; Messina, Angela; Branca, Caterina; Oddo, Salvatore

    2014-06-04

    Elevated mammalian target of rapamycin (mTOR) signaling has been found in Alzheimer's disease (AD) patients and is linked to diabetes and aging, two known risk factors for AD. However, whether hyperactive mTOR plays a role in the cognitive deficits associated with AD remains elusive. Here, we genetically reduced mTOR signaling in the brains of Tg2576 mice, a widely used animal model of AD. We found that suppression of mTOR signaling reduced amyloid-β deposits and rescued memory deficits. Mechanistically, the reduction in mTOR signaling led to an increase in autophagy induction and restored the hippocampal gene expression signature of the Tg2576 mice to wild-type levels. Our results implicate hyperactive mTOR signaling as a previous unidentified signaling pathway underlying gene-expression dysregulation and cognitive deficits in AD. Furthermore, hyperactive mTOR signaling may represent a molecular pathway by which aging contributes to the development of AD. Copyright © 2014 the authors 0270-6474/14/347988-11$15.00/0.

  7. The genetic basis of the circadian clock : identification of frq and FRQ as clock components in Neurospora

    NARCIS (Netherlands)

    Dunlap, Jay C.; Loros, Jennifer J.; Aronson, Benjamin D.; Merrow, Martha; Crosthwaite, Susan; Bell-Pedersen, Deborah; Johnson, Keith; Lindgren, Kristin; Garceau, Norman Y.

    1995-01-01

    Genetic approaches to the identification of clock components have succeeded in two model systems, Neurospora and Drosophila. In each organism, genes identified through screens for clock-affecting mutations (frq in Neurospora, per in Drosophila) have subsequently been shown to have characteristics of

  8. The Circadian Clock Mutation Promotes Intestinal Dysbiosis.

    Science.gov (United States)

    Voigt, Robin M; Summa, Keith C; Forsyth, Christopher B; Green, Stefan J; Engen, Phillip; Naqib, Ankur; Vitaterna, Martha H; Turek, Fred W; Keshavarzian, Ali

    2016-02-01

    Circadian rhythm disruption is a prevalent feature of modern day society that is associated with an increase in pro-inflammatory diseases, and there is a clear need for a better understanding of the mechanism(s) underlying this phenomenon. We have previously demonstrated that both environmental and genetic circadian rhythm disruption causes intestinal hyperpermeability and exacerbates alcohol-induced intestinal hyperpermeability and liver pathology. The intestinal microbiota can influence intestinal barrier integrity and impact immune system function; thus, in this study, we sought to determine whether genetic alteration of the core circadian clock gene, Clock, altered the intestinal microbiota community. Male Clock(Δ19) -mutant mice (mice homozygous for a dominant-negative-mutant allele) or littermate wild-type mice were fed 1 of 3 experimental diets: (i) a standard chow diet, (ii) an alcohol-containing diet, or (iii) an alcohol-control diet in which the alcohol calories were replaced with dextrose. Stool microbiota was assessed with 16S ribosomal RNA gene amplicon sequencing. The fecal microbial community of Clock-mutant mice had lower taxonomic diversity, relative to wild-type mice, and the Clock(Δ19) mutation was associated with intestinal dysbiosis when mice were fed either the alcohol-containing or the control diet. We found that alcohol consumption significantly altered the intestinal microbiota in both wild-type and Clock-mutant mice. Our data support a model by which circadian rhythm disruption by the Clock(Δ19) mutation perturbs normal intestinal microbial communities, and this trend was exacerbated in the context of a secondary dietary intestinal stressor. Copyright © 2016 by the Research Society on Alcoholism.

  9. Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT Administration

    Directory of Open Access Journals (Sweden)

    Maria Concetta Geloso

    2013-08-01

    Full Text Available Trimethyltin (TMT is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways.

  10. Oscillating perceptions: the ups and downs of the CLOCK protein in ...

    Indian Academy of Sciences (India)

    2008-12-31

    Dec 31, 2008 ... A functional mouse CLOCK protein has long been thought to be essential for mammalian circadian clockwork function, based mainly on studies of mice bearing a dominant negative, antimorphic mutation in the Clock gene. However, new discoveries using recently developed Clock-null mutant mice have ...

  11. Oscillating perceptions: the ups and downs of the CLOCK protein in ...

    Indian Academy of Sciences (India)

    A functional mouse CLOCK protein has long been thought to be essential for mammalian circadian clockwork function, based mainly on studies of mice bearing a dominant negative, antimorphic mutation in the Clock gene. However, new discoveries using recently developed Clock-null mutant mice have shaken up this ...

  12. The E3 ubiquitin ligase CTRIP controls CLOCK levels and PERIOD oscillations in Drosophila.

    Science.gov (United States)

    Lamaze, Angélique; Lamouroux, Annie; Vias, Carine; Hung, Hsiu-Cheng; Weber, Frank; Rouyer, François

    2011-06-01

    In the Drosophila circadian clock, the CLOCK/CYCLE complex activates the period and timeless genes that negatively feedback on CLOCK/CYCLE activity. The 24-h pace of this cycle depends on the stability of the clock proteins. RING-domain E3 ubiquitin ligases have been shown to destabilize PERIOD or TIMELESS. Here we identify a clock function for the circadian trip (ctrip) gene, which encodes a HECT-domain E3 ubiquitin ligase. ctrip expression in the brain is mostly restricted to clock neurons and its downregulation leads to long-period activity rhythms in constant darkness. This altered behaviour is associated with high CLOCK levels and persistence of phosphorylated PERIOD during the subjective day. The control of CLOCK protein levels does not require PERIOD. Thus, CTRIP seems to regulate the pace of the oscillator by controlling the stability of both the activator and the repressor of the feedback loop.

  13. The role of biological clock in glucose homeostasis 

    Directory of Open Access Journals (Sweden)

    Piotr Chrościcki

    2013-06-01

    Full Text Available The mechanism of the biological clock is based on a rhythmic expression of clock genes and clock-controlled genes. As a result of their transcripto-translational associations, endogenous rhythms in the synthesis of key proteins of various physiological and metabolic processes are created. The major timekeeping mechanism for these rhythms exists in the central nervous system. The master circadian clock, localized in suprachiasmatic nucleus (SCN, regulates multiple metabolic pathways, while feeding behavior and metabolite availability can in turn regulate the circadian clock. It is also suggested that in the brain there is a food entrainable oscillator (FEO or oscillators, resulting in activation of both food anticipatory activity and hormone secretion that control digestion processes. Moreover, most cells and tissues express autonomous clocks. Maintenance of the glucose homeostasis is particularly important for the proper function of the body, as this sugar is the main source of energy for the brain, retina, erythrocytes and skeletal muscles. Thus, glucose production and utilization are synchronized in time. The hypothalamic excited orexin neurons control energy balance of organism and modulate the glucose production and utilization. Deficiency of orexin action results in narcolepsy and weight gain, whereas glucose and amino acids can affect activity of the orexin cells. Large-scale genetic studies in rodents and humans provide evidence for the involvement of disrupted clock gene expression rhythms in the pathogenesis of obesity and type 2 diabetes. In general, the current lifestyle of the developed modern societies disturbs the action of biological clock

  14. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome

    Science.gov (United States)

    Genetic variation at the Circadian Locomotor Output Cycles Kaput (CLOCK) locus has been associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular diseases. In fact, it has been suggested that the disruption of the circadian system may play a causal ro...

  15. Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism

    OpenAIRE

    Ozburn, Angela R.; Purohit, Kush; Parekh, Puja K.; Kaplan, Gabrielle N.; Falcon, Edgardo; Mukherjee, Shibani; Cates, Hannah M.; Colleen A McClung

    2016-01-01

    Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional–translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260...

  16. FUNCTIONAL IMPLICATIONS OF THE CLOCK 3111T/C SINGLE-NUCLEOTIDE POLYMORPHISM

    OpenAIRE

    Angela Renee Ozburn; Kush ePurohit; Parekh, Puja K.; Kaplan, Gabrielle N.; Edgardo eFalcon; Shibani eMukherjee; Cates, Hannah M.; Colleen A McClung

    2016-01-01

    Circadian rhythm disruptions are prominently associated with Bipolar Disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (Roybal et al., 2007). The Clock 3111T/C single-nucleotide polymorphi...

  17. Hippocampal Gene Expression of Deiodinases 2 and 3 and Effects of 3,5-Diiodo-L-Thyronine T2 in Mouse Depression Paradigms

    Directory of Open Access Journals (Sweden)

    Natalyia Markova

    2013-01-01

    Full Text Available Central thyroid hormone signaling is important in brain function/dysfunction, including affective disorders and depression. In contrast to 3,3′,5-triiodo-L-thyronine (T3, the role of 3,5-diiodo-L-thyronine (T2, which until recently was considered an inactive metabolite of T3, has not been studied in these pathologies. However, both T3 and T2 stimulate mitochondrial respiration, a factor counteracting the pathogenesis of depressive disorder, but the cellular origins in the CNS, mechanisms, and kinetics of the cellular action for these two hormones are distinct and independent of each other. Here, Illumina and RT PCR assays showed that hippocampal gene expression of deiodinases 2 and 3, enzymes involved in thyroid hormone regulation, is increased in resilience to stress-induced depressive syndrome and after antidepressant treatment in mice that might suggest elevated T2 and T3 turnover in these phenotypes. In a separate experiment, bolus administration of T2 at the doses 750 and 1500 mcg/kg but not 250 mcg/kg in naive mice reduced immobility in a two-day tail suspension test in various settings without changing locomotion or anxiety. This demonstrates an antidepressant-like effect of T2 that could be exploited clinically. In a wider context, the current study suggests important central functions of T2, whose biological role only lately is becoming to be elucidated.

  18. Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

    Directory of Open Access Journals (Sweden)

    Yaoming Yang

    2012-06-01

    Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2 in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1. USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues.

  19. Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2.

    Science.gov (United States)

    Yang, Yaoming; Duguay, David; Bédard, Nathalie; Rachalski, Adeline; Baquiran, Gerardo; Na, Chan Hyun; Fahrenkrug, Jan; Storch, Kai-Florian; Peng, Junmin; Wing, Simon S; Cermakian, Nicolas

    2012-08-15

    Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2) in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO) display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1). USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues.

  20. Docosahexaenoic (DHA modulates phospholipid-hydroperoxide glutathione peroxidase (Gpx4 gene expression to ensure self-protection from oxidative damage in hippocampal cells

    Directory of Open Access Journals (Sweden)

    Veronica eCasañas-Sanchez

    2015-07-01

    Full Text Available Docosahexaenoic acid (DHA, 22:6n-3 is a unique polyunsaturated fatty acid particularly abundant in nerve cell membrane phospholipids. DHA is a pleiotropic molecule that, not only modulates the physicochemical properties and architecture of neuronal plasma membrane, but it is also involved in multiple facets of neuronal biology, from regulation of synaptic function to neuroprotection and modulation of gene expression. As a highly unsaturated fatty acid due to the presence of six double bonds, DHA is susceptible for oxidation, especially in the highly pro-oxidant environment of brain parenchyma. We have recently reported the ability of DHA to regulate the transcriptional program controlling neuronal antioxidant defenses in a hippocampal cell line, especially the glutathione/glutaredoxin system. Within this antioxidant system, DHA was particularly efficient in triggering the upregulation of Gpx4 gene, which encodes for the nuclear, cytosolic and mitochondrial isoforms of phospholipid-hydroperoxide glutathione peroxidase (PH-GPx/GPx4, the main enzyme protecting cell membranes against lipid peroxidation and capable to reduce oxidized phospholipids in situ. We show here that this novel property of DHA is also significant in the hippocampus of wild-type mice and APP/PS1 transgenic mice, a familial model of Alzheimer’s disease. By doing this, DHA stimulates a mechanism to self-protect from oxidative damage even in the neuronal scenario of high aerobic metabolism and in the presence of elevated levels of transition metals, which inevitably favor the generation of reactive oxygen species. Noticeably, DHA also upregulated a novel Gpx4 splicing variant, harboring part of the first intronic region, which according to the ‘sentinel RNA hypothesis’ would expand the ability of Gpx4 (and DHA to provide neuronal antioxidant defense independently of conventional nuclear splicing in cellular compartments, like dendritic zones, located away from nuclear

  1. Clock upregulates intercellular adhesion molecule-1 expression and promotes mononuclear cells adhesion to endothelial cells.

    Science.gov (United States)

    Gao, Yinghua; Meng, Dan; Sun, Ning; Zhu, Zhu; Zhao, Ran; Lu, Chao; Chen, Sifeng; Hua, Luchun; Qian, Ruizhe

    2014-01-10

    Clock is a basic helix-loop-helix (bHLH) transcription factor that plays important role in circadian rhythms of various physiological functions. Previous study showed that the expression of intercellular adhesion molecule-1 (ICAM-1) was reduced in the liver tissues of Clock mutant mice. However, how Clock regulates ICAM-1 expression and whether Clock affects cell adhesion function remain unknown. In the present study, we found that exogenous expression of Clock upregulated the gene expressions of ICAM-1 and other adhesion-related genes including VCAM1 and CCL-2, and increased the transcriptional activity of ICAM-1 in mouse brain microvascular endothelial cell lines. In contrast, loss of Clock decreased these gene expressions and ICAM-1 transcriptional activity. Chromatin immunoprecipitation (ChIP) assay revealed that Clock binds to the E-box-like enhancer of ICAM-1 gene. ICAM-1 gene showed rhythmic expression in endothelial cells after serum shock in vitro, suggesting ICAM-1 may be a Clock-controlled gene. Clock regulates the adhesion of mononuclear cells to endothelial cells via ICAM-1. Together, our findings show that Clock is a positive regulator of ICAM-1, and promotes the adhesion of mononuclear cells to endothelial cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Enhancing circadian clock function in cancer cells inhibits tumor growth.

    Science.gov (United States)

    Kiessling, Silke; Beaulieu-Laroche, Lou; Blum, Ian D; Landgraf, Dominic; Welsh, David K; Storch, Kai-Florian; Labrecque, Nathalie; Cermakian, Nicolas

    2017-02-14

    Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock. We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events. Here we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression.

  3. DNA microarray-based experimental strategy for trustworthy expression profiling of the hippocampal genes by astaxanthin supplementation in adult mouse

    Directory of Open Access Journals (Sweden)

    Jang Soo Yook

    2016-03-01

    Full Text Available Naturally occurring astaxantin (ASX is one of the noticeable carotenoid and dietary supplement, which has strong antioxidant and anti-inflammatory properties, and neuroprotective effects in the brain through crossing the blood–brain barrier. Specially, we are interested in the role of ASX as a brain food. Although ASX has been suggested to have potential benefit to the brain function, the underlying molecular mechanisms and events mediating such effect remain unknown. Here we examined molecular factors in the hippocampus of adult mouse fed ASX diets (0.1% and 0.5% doses using DNA microarray (Agilent 4 × 44 K whole mouse genome chip analysis. In this study, we described in detail our experimental workflow and protocol, and validated quality controls with the housekeeping gene expression (Gapdh and Beta-actin on the dye-swap based approach to advocate our microarray data, which have been uploaded to Gene Expression Omnibus (accession number GSE62197 as a gene resource for the scientific community. This data will also form an important basis for further detailed experiments and bioinformatics analysis with an aim to unravel the potential molecular pathways or mechanisms underlying the positive effects of ASX supplementation on the brain, in particular the hippocampus.

  4. Amygdala electrical stimulation inducing spatial memory recovery produces an increase of hippocampal bdnf and arc gene expression.

    Science.gov (United States)

    Mercerón-Martínez, D; Almaguer-Melian, W; Alberti-Amador, E; Estupiñán, B; Fernández, I; Bergado, J A

    2016-06-01

    Amygdala seems to promote the consolidation of plastic modification in different brain areas and these long-term brain changes require a rapid de novo RNA and protein synthesis. We have previously shown that basolateral amygdala electrical stimulation produces a partial recovery of spatial memory in fimbria-fornix lesioned animals and it is also able to increase the BDNF protein content in the hippocampus. The emerging question is whether these increased BDNF protein content arises from previously synthesized RNA or from de novo RNA expression. Now we address the question if amygdala electrical stimulation 15min after daily water maze training produces a rapid de novo RNA synthesis in the hippocampus, a critical brain area for spatial memory recovery in fimbria-fornix lesioned animals. In addition, we also study RNA arc expression, a gene which is essential for memory and neural plasticity processes. To this purpose, we study amygdala stimulation effects on the expression of plasticity related-early-genes bdnf and arc in the hippocampus of fimbria-fornix lesioned animals trained in a water-maze for 4days. We also checked on the expression of both genes in non-lesioned, untrained animals (acute condition) at 0.5, 1, 2 and 24h after basolateral amygdala electrical stimulation. Our data from trained animals confirm that daily amygdala electrical stimulation 15min after water maze training produces a partial memory recovery and that is coupled to an increase of bdnf and arc genes expression in the hippocampus. Additionally, the acute study shows that a single session of amygdala stimulation induces a transient increase of both genes (peaking at 30min). These results confirm the memory improving effect of amygdala stimulation in fimbria-fornix-lesioned animals and sustain the assumption that the memory improving effect is mediated by newly synthetized BDNF acting on a memory relevant structure like the hippocampus. The increased amount of BDNF within the hippocampus

  5. Cryptochromes and Biological Clocks

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 7; Issue 9. Cryptochromes and Biological Clocks. V R Bhagwat. General Article Volume 7 Issue 9 September 2002 pp 36-48. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/007/09/0036-0048. Keywords.

  6. Decamp Clock Board Firmware

    Energy Technology Data Exchange (ETDEWEB)

    Vicente, J. de; Castilla, J.; Martinez, G.

    2007-09-27

    Decamp (Dark Energy Survey Camera) is a new instrument designed to explore the universe aiming to reveal the nature of Dark Energy. The camera consists of 72 CCDs and 520 Mpixels. The readout electronics of DECam is based on the Monsoon system. Monsoon is a new image acquisition system developed by the NOAO (National Optical Astronomical Observatory) for the new generation of astronomical cameras. The Monsoon system uses three types of boards inserted in a Eurocard format based crate: master control board, acquisition board and clock board. The direct use of the Monsoon system for DECam readout electronics requires nine crates mainly due to the high number of clock boards needed. Unfortunately, the available space for DECam electronics is constrained to four crates at maximum. The major drawback to achieve such desired compaction degree resides in the clock board signal density. This document describes the changes performed at CIEMAT on the programmable logic of the Monsoon clock board aiming to meet such restricted space constraints. (Author) 5 refs.

  7. Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia.

    Science.gov (United States)

    Gaskin, Philip Lr; Toledo-Rodriguez, Maria; Alexander, Stephen Ph; Fone, Kevin Cf

    2016-11-01

    Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model. Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2-4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60-75) and drug-free hippocampal gene expression on PND 70. Acute lamotrigine (10-15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia. Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  8. The Circadian Clock in Cancer Development and Therapy

    Science.gov (United States)

    Fu, Loning; Kettner, Nicole M.

    2014-01-01

    Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, as the world industrialized, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function and aging that are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anti-cancer therapies. PMID:23899600

  9. The promoter activities of sucrose phosphate synthase genes in rice, OsSPS1 and OsSPS11, are controlled by light and circadian clock, but not by sucrose

    Directory of Open Access Journals (Sweden)

    Madoka eYonekura

    2013-03-01

    Full Text Available Although sucrose plays a role in sugar sensing and its signaling pathway, little is known about the regulatory mechanisms of the expressions of plant sucrose-related genes. Our previous study on the expression of the sucrose phosphate synthase gene family in rice (OsSPSs suggested the involvement of sucrose sensing and/or circadian rhythm in the transcriptional regulation of OsSPS. To examine whether the promoters of OsSPSs can be controlled by sugars and circadian clock, we produced transgenic rice plants harboring a promoter–luciferase construct for OsSPS1 or OsSPS11 and analyzed the changes in the promoter activities by monitoring bioluminescence from intact transgenic plants in real time. Transgenic plants fed sucrose, glucose, or mannitol under continuous light conditions showed no changes in bioluminescence intensity; meanwhile, the addition of sucrose increased the concentration of sucrose in the plants, and the mRNA levels of OsSPS remained constant. These results suggest that these OsSPS promoters may not be regulated by sucrose levels in the tissues. Next, we investigated the changes in the promoter activities under 12-h light/12-h dark cycles and continuous light conditions. Under the light–dark cycle, both OsSPS1 and OsSPS11 promoter activities were low in the dark and increased rapidly after the beginning of the light period. When the transgenic rice plants were moved to the continuous light condition, both POsSPS1::LUC and POsSPS11::LUC reporter plants exhibited circadian bioluminescence rhythms; bioluminescence peaked during the subjective day with a 27-h period: in the early morning as for OsSPS1 promoter and midday for OsSPS11 promoter. These results indicate that these OsSPS promoters are controlled by both light illumination and circadian clock and that the regulatory mechanism of promoter activity differs between the 2 OsSPS genes.

  10. The skeletal muscle circadian clock: current insights

    Directory of Open Access Journals (Sweden)

    Nakao R

    2017-11-01

    Full Text Available Reiko Nakao,1 Takeshi Nikawa,2 Katsutaka Oishi1,3,4 1Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST, Tsukuba, 2Department of Nutritional Physiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 3Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, 4Department of Computational and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan Abstract: Skeletal muscle functions in locomotion, postural support, and energy metabolism. The loss of skeletal muscle mass and function leads to diseases such as sarcopenia and metabolic disorders. Inactivity (lack of exercise and an imbalanced diet (increased fat or decreased protein intake are thought to be involved in the prevalence of such pathologies. On the other hand, recent epidemiological studies of humans have suggested that circadian disruption caused by shift work, jet lag, and sleep disorders is associated with obesity and metabolic syndrome. Experimental studies of mice deficient in clock genes have also identified skeletal muscle defects, suggesting a molecular link between circadian clock machinery and skeletal muscle physiology. Furthermore, accumulating evidence about chronotherapy, including chronopharmacology, chrononutrition, and chronoexercise, has indicated that timing is important to optimize medical intervention for various diseases. The present review addresses current understanding of the functional roles of the molecular clock with respect to skeletal muscle and the potential of chronotherapy for diseases associated with skeletal muscle. Keywords: biological rhythm, metabolic syndrome, physical activity, neural signal, chronotherapy

  11. Circadian clock characteristics are altered in human thyroid malignant nodules.

    Science.gov (United States)

    Mannic, Tiphaine; Meyer, Patrick; Triponez, Frederic; Pusztaszeri, Marc; Le Martelot, Gwendal; Mariani, Olivia; Schmitter, Daniel; Sage, Daniel; Philippe, Jacques; Dibner, Charna

    2013-11-01

    The circadian clock represents the body's molecular time-keeping system. Recent findings revealed strong changes of clock gene expression in various types of human cancers. Due to emerging evidence on the connection between the circadian oscillator, cell cycle, and oncogenic transformation, we aimed to characterize the circadian clockwork in human benign and malignant thyroid nodules. Clock transcript levels were assessed by quantitative RT-PCR in thyroid tissues. To provide molecular characteristics of human thyroid clockwork, primary thyrocytes established from normal or nodular thyroid tissue biopsies were subjected to in vitro synchronization with subsequent clock gene expression analysis by circadian bioluminescence reporter assay and by quantitative RT-PCR. The expression levels of the Bmal1 were up-regulated in tissue samples of follicular thyroid carcinoma (FTC), and in papillary thyroid carcinoma (PTC), as compared with normal thyroid and benign nodules, whereas Cry2 was down-regulated in FTC and PTC. Human thyrocytes derived from normal thyroid tissue exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression and endogenous clock transcripts. Thyrocytes established from FTC and PTC exhibited clock transcript oscillations similar to those of normal thyroid tissue and benign nodules (except for Per2 altered in PTC), whereas cells derived from poorly differentiated thyroid carcinoma exhibited altered circadian oscillations. This is the first study demonstrating a molecular makeup of the human thyroid circadian clock. Characterization of the thyroid clock machinery alterations upon thyroid nodule malignant transformation contributes to understanding the connections between circadian clocks and oncogenic transformation. Moreover, it might help in improving the thyroid nodule preoperative diagnostics.

  12. The Circadian Clock-controlled Transcriptome of Developing Soybean Seeds

    Directory of Open Access Journals (Sweden)

    Karen A. Hudson

    2010-07-01

    Full Text Available A number of metabolic and physiological processes in plants are controlled by the circadian clock, which enables a plant to anticipate daily changes in the environment. Relatively little is known about circadian rhythms in developing seeds, which may be important for determining the extent and timing of nutrient storage in grain. Microarray expression profiling was used to identify genes expressed in developing soybean ( seeds that are controlled by the circadian clock. Genes with predicted functions in protein synthesis, fatty acid metabolism, and photosynthesis totaling 1.8% of the mRNAs detected in seed were found to be expressed in a circadian rhythm. Known circadian and light-controlled promoter elements were identified as over-represented in the promoters of clock-controlled seed genes, with the over-represented elements varying according to the phase of circadian expression. A subset of circadian-regulated genes were found to be expressed in different phases in developing seeds with respect to leaves from the same plants, many of which have roles in photosynthesis and carbon metabolism. These results help to characterize the genes and processes in seeds that may be regulated by the circadian clock, and provide some insight into organ-specific phasing of clock controlled gene expression.

  13. Chronic inhibition of endoplasmic reticulum calcium-release channels and calcium-ATPase lengthens the period of hepatic clock gene Per1

    Directory of Open Access Journals (Sweden)

    Díaz-Muñoz Mauricio

    2011-07-01

    Full Text Available Abstract Background The role played by calcium as a regulator of circadian rhythms is not well understood. The effect of the pharmacological inhibition of the ryanodine receptor (RyR, inositol 1,4,5-trisphosphate receptor (IP3R, and endoplasmic-reticulum Ca2+-ATPase (SERCA, as well as the intracellular Ca2+-chelator BAPTA-AM was explored on the 24-h rhythmicity of the liver-clock protein PER1 in an experimental model of circadian synchronization by light and restricted-feeding schedules. Methods Liver explants from Period1-luciferase (Per1-luc transgenic rats with either free food access or with a restricted meal schedule were treated for several days with drugs to inhibit the activity of IP3Rs (2-APB, RyRs (ryanodine, or SERCA (thapsigargin as well as to suppress intracellular calcium fluctuations (BAPTA-AM. The period of Per1-luc expression was measured during and after drug administration. Results Liver explants from rats fed ad libitum showed a lengthened period in response to all the drugs tested. The pharmacological treatments of the explants from meal-entrained rats induced the same pattern, with the exception of the ryanodine treatment which, unexpectedly, did not modify the Per1-luc period. All effects associated with drug application were reversed after washout, indicating that none of the pharmacological treatments was toxic to the liver cultures. Conclusions Our data suggest that Ca2+ mobilized from internal deposits modulates the molecular circadian clock in the liver of rats entrained by light and by restricted meal access.

  14. GeneChip analysis of hippocampal gene expression profiles of short- and long-attack-latency mice : Technical and biological implications

    NARCIS (Netherlands)

    Feldker, DEM; Datson, NA; Veenema, AH; Proutski, [No Value; Lathouwers, D; de Kloet, ER; Vreugdenhil, E

    2003-01-01

    To gain insight into the molecular mechanisms underlying the behavioral differences between two mouse lines genetically selected for long and short attack latency (LAL and SAL mice, respectively), we have recently applied the large-scale gene expression profiling method known as serial analysis of

  15. Helicobacter pylori infection and low dietary iron alter behavior, induce iron deficiency anemia, and modulate hippocampal gene expression in female C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Monika Burns

    Full Text Available Helicobacter pylori (H.pylori, a bacterial pathogen, is a causative agent of gastritis and peptic ulcer disease and is a strong risk factor for development of gastric cancer. Environmental conditions, such as poor dietary iron resulting in iron deficiency anemia (IDA, enhance H.pylori virulence and increases risk for gastric cancer. IDA affects billions of people worldwide, and there is considerable overlap between regions of high IDA and high H.pylori prevalence. The primary aims of our study were to evaluate the effect of H.pylori infection on behavior, iron metabolism, red blood cell indices, and behavioral outcomes following comorbid H. pylori infection and dietary iron deficiency in a mouse model. C57BL/6 female mice (n = 40 were used; half were placed on a moderately iron deficient (ID diet immediately post-weaning, and the other half were maintained on an iron replete (IR diet. Half were dosed with H.pylori SS1 at 5 weeks of age, and the remaining mice were sham-dosed. There were 4 study groups: a control group (-Hp, IR diet as well as 3 experimental groups (-Hp, ID diet; +Hp, IR diet; +Hp,ID diet. All mice were tested in an open field apparatus at 8 weeks postinfection. Independent of dietary iron status, H.pylori -infected mice performed fewer exploratory behaviors in the open field chamber than uninfected mice (p<0.001. Hippocampal gene expression of myelination markers and dopamine receptor 1 was significantly downregulated in mice on an ID diet (both p<0.05, independent of infection status. At 12 months postinfection, hematocrit (Hct and hemoglobin (Hgb concentration were significantly lower in +Hp, ID diet mice compared to all other study groups. H.pylori infection caused IDA in mice maintained on a marginal iron diet. The mouse model developed in this study is a useful model to study the neurologic, behavioral, and hematologic impact of the common human co-morbidity of H. pylori infection and IDA.

  16. The circadian clock and pathology of the ageing brain.

    Science.gov (United States)

    Kondratova, Anna A; Kondratov, Roman V

    2012-03-07

    Ageing leads to a functional deterioration of many brain systems, including the circadian clock--an internal time-keeping system that generates ∼24-hour rhythms in physiology and behaviour. Numerous clinical studies have established a direct correlation between abnormal circadian clock functions and the severity of neurodegenerative and sleep disorders. Latest data from experiments in model organisms, gene expression studies and clinical trials imply that dysfunctions of the circadian clock contribute to ageing and age-associated pathologies, thereby suggesting a functional link between the circadian clock and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of physiological processes such as brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation.

  17. A Light Clock Satisfying the Clock Hypothesis of Special Relativity

    Science.gov (United States)

    West, Joseph

    2007-01-01

    The design of the FMEL, a floor-mirrored Einstein-Langevin "light clock", is introduced. The clock provides a physically intuitive manner to calculate and visualize the time dilation effects for a spatially extended set of observers (an accelerated "frame") undergoing unidirectional acceleration or observers on a rotating cylinder of constant…

  18. A functional genomics strategy reveals clockwork orange as a transcriptional regulator in the Drosophila circadian clock.

    Science.gov (United States)

    Matsumoto, Akira; Ukai-Tadenuma, Maki; Yamada, Rikuhiro G; Houl, Jerry; Uno, Kenichiro D; Kasukawa, Takeya; Dauwalder, Brigitte; Itoh, Taichi Q; Takahashi, Kuniaki; Ueda, Ryu; Hardin, Paul E; Tanimura, Teiichi; Ueda, Hiroki R

    2007-07-01

    The Drosophila circadian clock consists of integrated autoregulatory feedback loops, making the clock difficult to elucidate without comprehensively identifying the network components in vivo. Previous studies have adopted genome-wide screening for clock-controlled genes using high-density oligonucleotide arrays that identified hundreds of clock-controlled genes. In an attempt to identify the core clock genes among these candidates, we applied genome-wide functional screening using an RNA interference (RNAi) system in vivo. Here we report the identification of novel clock gene candidates including clockwork orange (cwo), a transcriptional repressor belonging to the basic helix-loop-helix ORANGE family. cwo is rhythmically expressed and directly regulated by CLK-CYC through canonical E-box sequences. A genome-wide search for its target genes using the Drosophila genome tiling array revealed that cwo forms its own negative feedback loop and directly suppresses the expression of other clock genes through the E-box sequence. Furthermore, this negative transcriptional feedback loop contributes to sustaining a high-amplitude circadian oscillation in vivo. Based on these results, we propose that the competition between cyclic CLK-CYC activity and the adjustable threshold imposed by CWO keeps E-box-mediated transcription within the controllable range of its activity, thereby rendering a Drosophila circadian clock capable of generating high-amplitude oscillation.

  19. Mechanisms linking circadian clocks, sleep, and neurodegeneration.

    Science.gov (United States)

    Musiek, Erik S; Holtzman, David M

    2016-11-25

    Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer's disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging. Copyright © 2016, American Association for the Advancement of Science.

  20. Empathy in hippocampal amnesia.

    Science.gov (United States)

    Beadle, J N; Tranel, D; Cohen, N J; Duff, M C

    2013-01-01

    Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. The scientific investigation of empathy has focused on characterizing its cognitive and neural substrates, and has pointed to the importance of a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate). While the hippocampus has rarely been the focus of empathy research, the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity) make it well-suited to meet some of the crucial demands of empathy, and a careful investigation of this possibility could make a significant contribution to the neuroscientific understanding of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female) with focal, bilateral hippocampal (HC) damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. Unlike healthy comparison participants, in response to the empathy inductions hippocampal patients reported no increase in empathy ratings or prosocial behavior. The results provide preliminary evidence for a role for hippocampal declarative memory in empathy.

  1. Analysis list: CLOCK [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available CLOCK Blood,Digestive tract + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/CLOCK....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/CLOCK.5.tsv http://dbarchive.biosc...iencedbc.jp/kyushu-u/hg19/target/CLOCK.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/CLOCK.Blo...od.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/CLOCK.Digestive_tract

  2. Modelling the widespread effects of TOC1 signalling on the plant circadian clock and its outputs.

    Science.gov (United States)

    Pokhilko, Alexandra; Mas, Paloma; Millar, Andrew J

    2013-03-19

    24-hour biological clocks are intimately connected to the cellular signalling network, which complicates the analysis of clock mechanisms. The transcriptional regulator TOC1 (TIMING OF CAB EXPRESSION 1) is a founding component of the gene circuit in the plant circadian clock. Recent results show that TOC1 suppresses transcription of multiple target genes within the clock circuit, far beyond its previously-described regulation of the morning transcription factors LHY (LATE ELONGATED HYPOCOTYL) and CCA1 (CIRCADIAN CLOCK ASSOCIATED 1). It is unclear how this pervasive effect of TOC1 affects the dynamics of the clock and its outputs. TOC1 also appears to function in a nested feedback loop that includes signalling by the plant hormone Abscisic Acid (ABA), which is upregulated by abiotic stresses, such as drought. ABA treatments both alter TOC1 levels and affect the clock's timing behaviour. Conversely, the clock rhythmically modulates physiological processes induced by ABA, such as the closing of stomata in the leaf epidermis. In order to understand the dynamics of the clock and its outputs under changing environmental conditions, the reciprocal interactions between the clock and other signalling pathways must be integrated. We extended the mathematical model of the plant clock gene circuit by incorporating the repression of multiple clock genes by TOC1, observed experimentally. The revised model more accurately matches the data on the clock's molecular profiles and timing behaviour, explaining the clock's responses in TOC1 over-expression and toc1 mutant plants. A simplified representation of ABA signalling allowed us to investigate the interactions of ABA and circadian pathways. Increased ABA levels lengthen the free-running period of the clock, consistent with the experimental data. Adding stomatal closure to the model, as a key ABA- and clock-regulated downstream process allowed to describe TOC1 effects on the rhythmic gating of stomatal closure. The integrated

  3. Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue.

    Science.gov (United States)

    Hughes, Michael E; Hong, Hee-Kyung; Chong, Jason L; Indacochea, Alejandra A; Lee, Samuel S; Han, Michael; Takahashi, Joseph S; Hogenesch, John B

    2012-01-01

    The circadian regulatory network is organized in a hierarchical fashion, with a central oscillator in the suprachiasmatic nuclei (SCN) orchestrating circadian oscillations in peripheral tissues. The nature of the relationship between central and peripheral oscillators, however, is poorly understood. We used the tetOFF expression system to specifically restore Clock function in the brains of Clock(Δ19) mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whether brain-specific rescue of circadian rhythmicity was sufficient to restore circadian transcriptional output in the liver. Compared to Clock mutants, Clock-rescue mice showed significantly larger numbers of cycling transcripts with appropriate phase and period lengths, including many components of the core circadian oscillator. This indicates that the SCN oscillator overcomes local circadian defects and signals directly to the molecular clock. Interestingly, the vast majority of core clock genes in liver were responsive to Clock expression in the SCN, suggesting that core clock genes in peripheral tissues are intrinsically sensitive to SCN cues. Nevertheless, most circadian output in the liver was absent or severely low-amplitude in Clock-rescue animals, demonstrating that the majority of peripheral transcriptional rhythms depend on a fully functional local circadian oscillator. We identified several new system-driven rhythmic genes in the liver, including Alas1 and Mfsd2. Finally, we show that 12-hour transcriptional rhythms (i.e., circadian "harmonics") are disrupted by Clock loss-of-function. Brain-specific rescue of Clock converted 12-hour rhythms into 24-hour rhythms, suggesting that signaling via the central circadian oscillator is required to generate one of the two daily peaks of expression. Based on these data, we conclude that 12-hour rhythms

  4. Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue.

    Directory of Open Access Journals (Sweden)

    Michael E Hughes

    Full Text Available The circadian regulatory network is organized in a hierarchical fashion, with a central oscillator in the suprachiasmatic nuclei (SCN orchestrating circadian oscillations in peripheral tissues. The nature of the relationship between central and peripheral oscillators, however, is poorly understood. We used the tetOFF expression system to specifically restore Clock function in the brains of Clock(Δ19 mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whether brain-specific rescue of circadian rhythmicity was sufficient to restore circadian transcriptional output in the liver. Compared to Clock mutants, Clock-rescue mice showed significantly larger numbers of cycling transcripts with appropriate phase and period lengths, including many components of the core circadian oscillator. This indicates that the SCN oscillator overcomes local circadian defects and signals directly to the molecular clock. Interestingly, the vast majority of core clock genes in liver were responsive to Clock expression in the SCN, suggesting that core clock genes in peripheral tissues are intrinsically sensitive to SCN cues. Nevertheless, most circadian output in the liver was absent or severely low-amplitude in Clock-rescue animals, demonstrating that the majority of peripheral transcriptional rhythms depend on a fully functional local circadian oscillator. We identified several new system-driven rhythmic genes in the liver, including Alas1 and Mfsd2. Finally, we show that 12-hour transcriptional rhythms (i.e., circadian "harmonics" are disrupted by Clock loss-of-function. Brain-specific rescue of Clock converted 12-hour rhythms into 24-hour rhythms, suggesting that signaling via the central circadian oscillator is required to generate one of the two daily peaks of expression. Based on these data, we conclude

  5. The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression.

    Science.gov (United States)

    Gebel, Stephan; Gerstmayer, Bernhard; Kuhl, Peter; Borlak, Jürgen; Meurrens, Kris; Müller, Thomas

    2006-10-01

    Gene expression profiling in animal models exposed to cigarette mainstream smoke (CS) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes. Here we report on differential gene expression in lungs of rats exposed for 2, 7, and 13 weeks to 300 and 600 microg total particulate matter/l CS with sacrifice 2, 6, or 20 h after the last exposure. Regarding antioxidant and xenobiotic-metabolizing (phase I/II) enzymes, a stereotypic, mostly transient, expression pattern of differentially expressed genes was observed after each exposure period. The expression patterns were generally dose dependent for antioxidant and phase II genes and not dose dependent for phase I genes at the CS concentrations tested. However, with increasing length of exposure, there was a distinct, mostly sustained and dose-sensitive, expression of genes implicated in innate and adaptive immune responses, clearly pointing to an emerging inflammatory response. Notably, this inflammatory response included the expression of lung disease-related genes not yet linked to CS exposure, such as galectin-3, arginase 1, and chitinase, as well as genes encoding proteolytic enzymes. Finally, our experiments also revealed a CS exposure-dependent shift in the cyclical expression of genes involved in controlling the circadian rhythm. Altogether, these results provide further insight into the molecular mechanisms of CS-dependent disease onset and development and thus may also be useful for defining CS-specific molecular biomarkers of disease.

  6. Protein phosphatase 1 (PP1 is a post-translational regulator of the mammalian circadian clock.

    Directory of Open Access Journals (Sweden)

    Isabelle Schmutz

    Full Text Available Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1 as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.

  7. Circadian rhythms and clocks in adipose tissues: current insights

    Directory of Open Access Journals (Sweden)

    Kiehn JT

    2017-04-01

    Full Text Available Jana-Thabea Kiehn,* Christiane E Koch,* Marina Walter, Alexandra Brod, Henrik Oster Chronophysiology Group, Medical Department I, University of Lübeck, Lübeck, Germany *These authors contributed equally to this work Abstract: Endogenous circadian timekeepers are found in most cells and organs of the body, including the different types of adipose tissues. This clock network orchestrates 24-hour rhythms of physiology and behavior to adapt the organism to daily recurring changes in the environment. Energy intake and expenditure as well as adipose physiology are under circadian control and, therefore, energy homeostasis and circadian clock function are closely linked. In this review, we summarize the current knowledge about the regulation and targets of adipocyte circadian clocks and how circadian rhythm disruption affects energy homeostasis and adipose tissue function. We provide a more detailed overview of metabolic phenotypes of different mouse models of circadian clock dysfunction and discuss the implications of (adipose clock disruption on adipocyte–brain cross talk and metabolic homeostasis. Keywords: food intake, metaflammation, clock genes, adipocyte–brain cross talk, adipokines

  8. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  9. Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

    Science.gov (United States)

    Alon, Shahar; Vallone, Daniela; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G.; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C.; Burgess, Harold A.; Foulkes, Nicholas S.; Gothilf, Yoav

    2016-01-01

    The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior. PMID:27870848

  10. Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior.

    Directory of Open Access Journals (Sweden)

    Zohar Ben-Moshe Livne

    2016-11-01

    Full Text Available The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.

  11. Tuning genetic clocks employing DNA binding sites.

    Directory of Open Access Journals (Sweden)

    Shridhar Jayanthi

    Full Text Available Periodic oscillations play a key role in cell physiology from the cell cycle to circadian clocks. The interplay of positive and negative feedback loops among genes and proteins is ubiquitous in these networks. Often, delays in a negative feedback loop and/or degradation rates are a crucial mechanism to obtain sustained oscillations. How does nature control delays and kinetic rates in feedback networks? Known mechanisms include proper selection of the number of steps composing a feedback loop and alteration of protease activity, respectively. Here, we show that a remarkably simple means to control both delays and effective kinetic rates is the employment of DNA binding sites. We illustrate this design principle on a widely studied activator-repressor clock motif, which is ubiquitous in natural systems. By suitably employing DNA target sites for the activator and/or the repressor, one can switch the clock "on" and "off" and precisely tune its period to a desired value. Our study reveals a design principle to engineer dynamic behavior in biomolecular networks, which may be largely exploited by natural systems and employed for the rational design of synthetic circuits.

  12. BDNF val(66)met affects hippocampal volume and emotion-related hippocampal memory activity

    NARCIS (Netherlands)

    Molendijk, M. L.; van Tol, M-J; Penninx, B. W. J. H.; van der Wee, N. J. A.; Aleman, A.; Veltman, D. J.; Spinhoven, P.; Elzinga, B. M.

    The val(66)met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life

  13. The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression

    National Research Council Canada - National Science Library

    Gebel, Stephan; Gerstmayer, Bernhard; Kuhl, Peter; Borlak, Jürgen; Meurrens, Kris; Müller, Thomas

    2006-01-01

    ...) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes...

  14. The circadian clock modulates enamel development.

    Science.gov (United States)

    Lacruz, Rodrigo S; Hacia, Joseph G; Bromage, Timothy G; Boyde, Alan; Lei, Yaping; Xu, Yucheng; Miller, Joseph D; Paine, Michael L; Snead, Malcolm L

    2012-06-01

    Fully mature enamel is about 98% mineral by weight. While mineral crystals appear very early during its formative phase, the newly secreted enamel is a soft gel-like matrix containing several enamel matrix proteins of which the most abundant is amelogenin (Amelx). Histological analysis of mineralized dental enamel reveals markings called cross-striations associated with daily increments of enamel formation, as evidenced by injections of labeling dyes at known time intervals. The daily incremental growth of enamel has led to the hypothesis that the circadian clock might be involved in the regulation of enamel development. To identify daily rhythms of clock genes and Amelx, we subjected murine ameloblast cells to serum synchronization to analyze the expression of the circadian transcription factors Per2 and Bmal1 by real-time PCR. Results indicate that these key genetic regulators of the circadian clock are expressed in synchronized murine ameloblast cell cultures and that their expression profile follows a circadian pattern with acrophase and bathyphase for both gene transcripts in antiphase. Immunohistological analysis confirms the protein expression of Bmal and Cry in enamel cells. Amelx expression in 2-day postnatal mouse molars dissected every 4 hours for a duration of 48 hours oscillated with an approximately 24-hour period, with a significant approximately 2-fold decrease in expression during the dark period compared to the light period. The expression of genes involved in bicarbonate production (Car2) and transport (Slc4a4), as well as in enamel matrix endocytosis (Lamp1), was greater during the dark period, indicating that ameloblasts express these proteins when Amelx expression is at the nadir. The human and mouse Amelx genes each contain a single nonconserved E-box element within 10 kb upstream of their respective transcription start sites. We also found that within 2 kb of the transcription start site of the human NFYA gene, which encodes a positive

  15. Phylogenetic footprint of the plant clock system in angiosperms: evolutionary processes of Pseudo-Response Regulators

    Directory of Open Access Journals (Sweden)

    Saito Shigeru

    2010-05-01

    Full Text Available Abstract Background Plant circadian clocks regulate many photoperiodic and diurnal responses that are conserved among plant species. The plant circadian clock system has been uncovered in the model plant, Arabidopsis thaliana, using genetics and systems biology approaches. However, it is still not clear how the clock system had been organized in the evolutionary history of plants. We recently revealed the molecular phylogeny of LHY/CCA1 genes, one of the essential components of the clock system. The aims of this study are to reconstruct the phylogenetic relationships of angiosperm clock-associated PRR genes, the partner of the LHY/CCA1 genes, and to clarify the evolutionary history of the plant clock system in angiosperm lineages. Results In the present study, to investigate the molecular phylogeny of PRR genes, we performed two approaches: reconstruction of phylogenetic trees and examination of syntenic relationships. Phylogenetic analyses revealed that PRR genes had diverged into three clades prior to the speciation of monocots and eudicots. Furthermore, copy numbers of PRR genes have been independently increased in monocots and eudicots as a result of ancient chromosomal duplication events. Conclusions Based on the molecular phylogenies of both PRR genes and LHY/CCA1 genes, we inferred the evolutionary process of the plant clock system in angiosperms. This scenario provides evolutionary information that a common ancestor of monocots and eudicots had retained the basic components required for reconstructing a clock system and that the plant circadian clock may have become a more elaborate mechanism after the speciation of monocots and eudicots because of the gene expansion that resulted from polyploidy events.

  16. Clock polymorphism in Pacific salmon: evidence for variable selection along a latitudinal gradient.

    Science.gov (United States)

    O'Malley, Kathleen G; Ford, Michael J; Hard, Jeffrey J

    2010-12-22

    Seasonal timing of life-history events is often under strong natural selection. The Clock gene is a central component of an endogenous circadian clock that senses changes in photoperiod (day length) and mediates seasonal behaviours. Among Pacific salmonids (Oncorhynchus spp.), seasonal timing of migration and breeding is influenced by photoperiod. To expand a study of 42 North American Chinook salmon (Oncorhynchus tshawytscha) populations, we tested whether duplicated Clock genes contribute to population differences in reproductive timing. Specifically, we examined geographical variation along a similar latitudinal gradient in the polyglutamine domain (PolyQ) of OtsClock1a and OtsClock1b among 53 populations of three species: chum (Oncorhynchus keta), coho (Oncorhynchus kisutch) and pink salmon (Oncorhynchus gorbuscha). We found evidence for variable selection on OtsClock1b that corresponds to latitudinal variation in reproductive timing among these species. We evaluated the contribution of day length and a freshwater migration index to OtsClock1b PolyQ domain variation using regression trees and found that day length at spawning explains much of the variation in OtsClock1b allele frequency among chum and Chinook, but not coho and pink salmon populations. Our findings suggest that OtsClock1b mediates seasonal adaptation and influences geographical variation in reproductive timing in some of these highly migratory species.

  17. Acceleration effects on atomic clocks

    CERN Document Server

    Dahia, F

    2014-01-01

    We consider a free massive particle inside a box which is dragged by Rindler observers. Admitting that the particle obeys the Klein-Gordon equation, we find the frequencies of the stationary states of this system. Transitions between the stationary states are employed to set a standard frequency for a toy atomic clock. Comparing the energy spectrum of the accelerated system with the energy spectrum of an identical system in an inertial frame, we determine the influence of the instantaneous acceleration on the rate of atomic clocks. We argue that our result does not violate the clock hypothesis.

  18. Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2.

    Science.gov (United States)

    Hoffman, Aaron E; Zheng, Tongzhang; Stevens, Richard G; Ba, Yue; Zhang, Yawei; Leaderer, Derek; Yi, Chunhui; Holford, Theodore R; Zhu, Yong

    2009-04-15

    Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non-Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28-4.27), P = 0.006; rs7123390, OR, 2.40 (1.39-4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57-5.63, P = 0.001)]. Each of these associations remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E(-9)) and hematologic disease (B-H P = 8.01E(-8)). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development.

  19. Investigations of the CLOCK and BMAL1 Proteins Binding to DNA: A Molecular Dynamics Simulation Study.

    Science.gov (United States)

    Xue, Tuo; Song, Chunnian; Wang, Qing; Wang, Yan; Chen, Guangju

    2016-01-01

    The circadian locomotor output cycles kaput (CLOCK), and brain and muscle ARNT-like 1 (BMAL1) proteins are important transcriptional factors of the endogenous circadian clock. The CLOCK and BMAL1 proteins can regulate the transcription-translation activities of the clock-related genes through the DNA binding. The hetero-/homo-dimerization and DNA combination of the CLOCK and BMAL1 proteins play a key role in the positive and negative transcriptional feedback processes. In the present work, we constructed a series of binary and ternary models for the bHLH/bHLH-PAS domains of the CLOCK and BMAL1 proteins, and the DNA molecule, and carried out molecular dynamics simulations, free energy calculations and conformational analysis to explore the interaction properties of the CLOCK and BMAL1 proteins with DNA. The results show that the bHLH domains of CLOCK and BMAL1 can favorably form the heterodimer of the bHLH domains of CLOCK and BMAL1 and the homodimer of the bHLH domains of BMAL1. And both dimers could respectively bind to DNA at its H1-H1 interface. The DNA bindings of the H1 helices in the hetero- and homo-bHLH dimers present the rectangular and diagonal binding modes, respectively. Due to the function of the α-helical forceps in these dimers, the tight gripping of the H1 helices to the major groove of DNA would cause the decrease of interactions at the H1-H2 interfaces in the CLOCK and BMAL1 proteins. The additional PAS domains in the CLOCK and BMAL1 proteins affect insignificantly the interactions of the CLOCK and BMAL1 proteins with the DNA molecule due to the flexible and long loop linkers located at the middle of the PAS and bHLH domains. The present work theoretically explains the interaction mechanisms of the bHLH domains of the CLOCK and BMAL1 proteins with DNA.

  20. A comparative view of insect circadian clock systems.

    Science.gov (United States)

    Tomioka, Kenji; Matsumoto, Akira

    2010-05-01

    Recent studies revealed that the neuronal network controlling overt rhythms shows striking similarity in various insect orders. The pigment-dispersing factor seems commonly involved in regulating locomotor activity. However, there are considerable variations in the molecular oscillatory mechanism, and input and output pathways among insects. In Drosophila, autoregulatory negative feedback loops that consist of clock genes, such as period and timeless are believed to create 24-h rhythmicity. Although similar clock genes have been found in some insects, the behavior of their product proteins shows considerable differences from that of Drosophila. In other insects, mammalian-type cryptochrome (cry2) seems to work as a transcriptional repressor in the feedback loop. For photic entrainment, Drosophila type cryptochrome (cry1) plays the major role in Drosophila while the compound eyes are the major photoreceptor in others. Further comparative study will be necessary to understand how this variety of clock mechanisms derived from an ancestral one.

  1. Empathy in hippocampal amnesia

    Directory of Open Access Journals (Sweden)

    Janelle N Beadle

    2013-03-01

    Full Text Available The scientific investigation of empathy has become a cornerstone in the field of social cognition. Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. Scientific investigations of empathy have focused on characterizing its cognitive and neural substrates, pointing to a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate. While the hippocampus has rarely been the focus of empathy research, we propose that there are compelling reasons to inquire about the contribution of the hippocampus to social cognition. We propose that the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity make it well-suited to meet the demands of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female with focal, bilateral hippocampal (HC damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. In response to the empathy inductions, unlike healthy comparison participants, hippocampal patients reported no increase in empathy ratings or prosocial behavior from the control condition. Taken together, these results provide preliminary evidence for a role of hippocampal declarative memory in empathy.

  2. Simulating Future GPS Clock Scenarios with Two Composite Clock Algorithms

    Science.gov (United States)

    2010-11-01

    Alexandria, Virginia), pp. 223-242. [8] C. A. Greenhall, 2007, “A Kalman filter clock ensemble algorithm that admits measurement noise,” Metrologia ...43, S311-S321. [9] J. A. Davis, C. A. Greenhall, and P. W. Stacey, 2005, “A Kalman filter clock algorithm for use in the presence of flicker frequency modulation noise,” Metrologia , 42, 1-10.

  3. Distinguishing Depressive Pseudodementia from Alzheimer Disease: A Comparative Study of Hippocampal Volumetry and Cognitive Tests

    Directory of Open Access Journals (Sweden)

    Sevki Sahin

    2017-07-01

    Full Text Available Background and Aim: Depressive pseudodementia (DPD is a condition which may develop secondary to depression. The aim of this study was to contribute to the differential diagnosis between Alzheimer disease (AD and DPD by comparing the neurocognitive tests and hippocampal volume. Materials and Methods: Patients who met criteria of AD/DPD were enrolled in the study. All patients were assessed using the Wechsler Memory Scale (WMS, clock-drawing test, Stroop test, Benton Facial Recognition Test (BFRT, Boston Naming Test, Mini-Mental State Examination (MMSE, and Geriatric Depression Scale (GDS. Hippocampal volume was measured by importing the coronal T1-weighted magnetic resonance images to the Vitrea 2 workstation. Results: A significant difference was found between the AD and DPD groups on the WMS test, clock-drawing test, Stroop test, Boston Naming Test, MMSE, GDS, and left hippocampal volume. A significant correlation between BFRT and bilateral hippocampal volumes was found in the AD group. No correlation was found among parameters in DPD patients. Conclusions: Our results suggest that evaluation of facial recognition and left hippocampal volume may provide more reliable evidence for distinguishing DPD from AD. Further investigations combined with functional imaging techniques including more patients are needed.

  4. Ras-mediated deregulation of the circadian clock in cancer.

    Directory of Open Access Journals (Sweden)

    Angela Relógio

    Full Text Available Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

  5. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    Science.gov (United States)

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  6. FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice.

    Science.gov (United States)

    Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui; Ptáček, Louis J

    2017-04-11

    The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Photosynthetic entrainment of the Arabidopsis thaliana circadian clock.

    Science.gov (United States)

    Haydon, Michael J; Mielczarek, Olga; Robertson, Fiona C; Hubbard, Katharine E; Webb, Alex A R

    2013-10-31

    Circadian clocks provide a competitive advantage in an environment that is heavily influenced by the rotation of the Earth, by driving daily rhythms in behaviour, physiology and metabolism in bacteria, fungi, plants and animals. Circadian clocks comprise transcription-translation feedback loops, which are entrained by environmental signals such as light and temperature to adjust the phase of rhythms to match the local environment. The production of sugars by photosynthesis is a key metabolic output of the circadian clock in plants. Here we show that these rhythmic, endogenous sugar signals can entrain circadian rhythms in Arabidopsis thaliana by regulating the gene expression of circadian clock components early in the photoperiod, thus defining a 'metabolic dawn'. By inhibiting photosynthesis, we demonstrate that endogenous oscillations in sugar levels provide metabolic feedback to the circadian oscillator through the morning-expressed gene PSEUDO-RESPONSE REGULATOR 7 (PRR7), and we identify that prr7 mutants are insensitive to the effects of sucrose on the circadian period. Thus, photosynthesis has a marked effect on the entrainment and maintenance of robust circadian rhythms in A. thaliana, demonstrating that metabolism has a crucial role in regulation of the circadian clock.

  8. FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice

    Directory of Open Access Journals (Sweden)

    Arisa Hirano

    2017-04-01

    Full Text Available The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD binding pocket of CRYPTOCHROME2 (CRY2, a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk, an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis. We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.

  9. Einstein's Clocks and Langevin's Twins

    CERN Document Server

    Weinstein, Galina

    2012-01-01

    In 1905 Einstein presented the Clock Paradox and in 1911 Paul Langevin expanded Einstein's result to human observers, the "Twin Paradox." I will explain the crucial difference between Einstein and Langevin. Einstein did not present the so-called "Twin Paradox." Later Einstein continued to speak about the clock paradox. Einstein might not have been interested in the question: what happens to the observers themselves. The reason for this could be the following; Einstein dealt with measurement procedures, clocks and measuring rods. Einstein's observers were measuring time with these clocks and measuring rods. Einstein might not have been interested in so-called biology of the observers, whether these observers were getting older, younger, or whether they have gone any other changes; these changes appeared to be out of the scope of his "Principle of relativity" or kinematics. The processes and changes occurring within observers seemed to be good for philosophical discussions. Later writers criticized Einstein's c...

  10. Analysis list: Clock [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Clock Liver + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Clock.1.tsv... http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Clock.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Clock....10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Clock.Liver.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Liver.gml ...

  11. Stochastic models for atomic clocks

    Science.gov (United States)

    Barnes, J. A.; Jones, R. H.; Tryon, P. V.; Allan, D. W.

    1983-01-01

    For the atomic clocks used in the National Bureau of Standards Time Scales, an adequate model is the superposition of white FM, random walk FM, and linear frequency drift for times longer than about one minute. The model was tested on several clocks using maximum likelihood techniques for parameter estimation and the residuals were acceptably random. Conventional diagnostics indicate that additional model elements contribute no significant improvement to the model even at the expense of the added model complexity.

  12. RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides.

    Directory of Open Access Journals (Sweden)

    Katharine C Abruzzi

    2017-02-01

    Full Text Available Locomotor activity rhythms are controlled by a network of ~150 circadian neurons within the adult Drosophila brain. They are subdivided based on their anatomical locations and properties. We profiled transcripts "around the clock" from three key groups of circadian neurons with different functions. We also profiled a non-circadian outgroup, dopaminergic (TH neurons. They have cycling transcripts but fewer than clock neurons as well as low expression and poor cycling of clock gene transcripts. This suggests that TH neurons do not have a canonical circadian clock and that their gene expression cycling is driven by brain systemic cues. The three circadian groups are surprisingly diverse in their cycling transcripts and overall gene expression patterns, which include known and putative novel neuropeptides. Even the overall phase distributions of cycling transcripts are distinct, indicating that different regulatory principles govern transcript oscillations. This surprising cell-type diversity parallels the functional heterogeneity of the different neurons.

  13. The Increase in Signaling by Kisspeptin Neurons in the Preoptic Area and Associated Changes in Clock Gene Expression That Trigger the LH Surge in Female Rats Are Dependent on the Facilitatory Action of a Noradrenaline Input.

    Science.gov (United States)

    Kalil, Bruna; Ribeiro, Aline B; Leite, Cristiane M; Uchôa, Ernane T; Carolino, Ruither O; Cardoso, Thais S R; Elias, Lucila L K; Rodrigues, José A; Plant, Tony M; Poletini, Maristela O; Anselmo-Franci, Janete A

    2016-01-01

    In rodents, kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) of the preoptic area are considered to provide a major stimulatory input to the GnRH neuronal network that is responsible for triggering the preovulatory LH surge. Noradrenaline (NA) is one of the main modulators of GnRH release, and NA fibers are found in close apposition to kisspeptin neurons in the RP3V. Our objective was to interrogate the role of NA signaling in the kisspeptin control of GnRH secretion during the estradiol induced LH surge in ovariectomized rats, using prazosin, an α1-adrenergic receptor antagonist. In control rats, the estradiol-induced LH surge at 17 hours was associated with a significant increase in GnRH and kisspeptin content in the median eminence with the increase in kisspeptin preceding that of GnRH and LH. Prazosin, administered 5 and 3 hours prior to the predicted time of the LH surge truncated the LH surge and abolished the rise in GnRH and kisspeptin in the median eminence. In the preoptic area, prazosin blocked the increases in Kiss1 gene expression and kisspeptin content in association with a disruption in the expression of the clock genes, Per1 and Bmal1. Together these findings demonstrate for the first time that NA modulates kisspeptin synthesis in the RP3V through the activation of α1-adrenergic receptors prior to the initiation of the LH surge and indicate a potential role of α1-adrenergic signaling in the circadian-controlled pathway timing of the preovulatory LH surge.

  14. Circadian clocks are seeing the systems biology light

    OpenAIRE

    Hayes, Kevin R.; Baggs, Julie E.; Hogenesch, John B

    2005-01-01

    Circadian rhythms are those biological rhythms that have a periodicity of around 24 hours. Recently, the generation of a circadian transcriptional network - compiled from RNA-expression and promoter-element analysis and phase information - has led to a better understanding of the gene-expression patterns that regulate the precise 24-hour clock.

  15. Lack of Association between Genetic Polymorphism of Circadian Genes (PER2, PER3, CLOCK and OX2R) with Late Onset Depression and Alzheimer's Disease in a Sample of a Brazilian Population (Circadian Genes, Late-Onset Depression and Alzheimer's Disease).

    Science.gov (United States)

    Pereira, Patricia Araújo; Alvim-Soares, António; Bicalho, Maria Aparecida Camargos; Moraes, Edgar Nunes de; Malloy-Diniz, Leandro; Paula, Jonas Jardim de; Romano-Silva, Marco Aurélio; Miranda, Debora Marques

    2016-01-01

    This study aims to evaluate the association between polymorphisms in circadian genes and Alzheimer's disease (AD) and/or late-onset depression (LOD). AD pathology leads to circadian disturbances, with clear negative influence on quality of life. In addition, there is an increasing evidence that regulators of circadian system have effects on AD and LOD pathology. An exploratory case-control study designed to evaluate SNPs in the PER2, PER3, CLOCK and OX2R genes in a sample composed by 249 AD, 222 LOD and 112 healthy individuals. The participants were evaluated using DSM-IV criteria for LOD and NINCDS-ADRDA for AD. In allelic analysis, the OX2R SNP, rs2134294, showed an association of allele C with LOD (p =0.02, OR= 1.6) and AD (p=0.04, OR =1.5). The rs2134294 also showed a genotypic association C/C (p =0.01) for higher risk to develop LOD compared to the control group, with an odd's ratio of 2.7. The rs9370399 (OX2R) has also shown an association between A allele (p=0.03, OR= 1.4) and AD. These results do not persist after a 1,000 permutations test. For other markers of the OX2R gene and for all other markers of this study no association was found. In conclusion, the present study found that the investigated Circadian Genes (PER2, PER3, CLOCK and OX2R) polymorphisms were not associated with LOD or AD.

  16. The retinal clock in mammals: role in health and disease

    Directory of Open Access Journals (Sweden)

    Felder-Schmittbuhl MP

    2017-05-01

    fundamental processes, the coherence from cell to tissue is critical for circadian functions, and disruption of retinal clock organization or its response to light can potentially have a major impact on retinal pathophysiology and vision. Keywords: retina, clock gene, circadian, ipRGC, photoreceptor, light

  17. Does the core circadian clock in the moss Physcomitrella patens (Bryophyta comprise a single loop?

    Directory of Open Access Journals (Sweden)

    Hedman Harald

    2010-06-01

    Full Text Available Abstract Background The endogenous circadian clock allows the organism to synchronize processes both to daily and seasonal changes. In plants, many metabolic processes such as photosynthesis, as well as photoperiodic responses, are under the control of a circadian clock. Comparative studies with the moss Physcomitrella patens provide the opportunity to study many aspects of land plant evolution. Here we present a comparative overview of clock-associated components and the circadian network in the moss P. patens. Results The moss P. patens has a set of conserved circadian core components that share genetic relationship and gene expression patterns with clock genes of vascular plants. These genes include Myb-like transcription factors PpCCA1a and PpCCA1b, pseudo-response regulators PpPRR1-4, and regulatory elements PpELF3, PpLUX and possibly PpELF4. However, the moss lacks homologs of AtTOC1, AtGI and the AtZTL-family of genes, which can be found in all vascular plants studied here. These three genes constitute essential components of two of the three integrated feed-back loops in the current model of the Arabidopsis circadian clock mechanism. Consequently, our results suggest instead a single loop circadian clock in the moss. Possibly as a result of this, temperature compensation of core clock gene expression appears to be decreased in P. patens. Conclusions This study is the first comparative overview of the circadian clock mechanism in a basal land plant, the moss P. patens. Our results indicate that the moss clock mechanism may represent an ancestral state in contrast to the more complex and partly duplicated structure of subsequent land plants. These findings may provide insights into the understanding of the evolution of circadian network topology.

  18. Rhythmic expressed clock regulates the transcription of proliferating cellular nuclear antigen in teleost retina.

    Science.gov (United States)

    Song, Hang; Wang, Defeng; De Jesus Perez, Felipe; Xie, Rongrong; Liu, Zhipeng; Chen, Chun-Chun; Yu, Meijuan; Yuan, Liudi; Fernald, Russell D; Zhao, Sheng

    2017-07-01

    Teleost fish continues to grow their eyes throughout life with the body size. In Astatotilapia burtoni, the fish retina increases by adding new retinal cells at the ciliary marginal zone (CMZ) and in the outer nuclear layer (ONL). Cell proliferation at both sites exhibits a daily rhythm in number of dividing cells. To understand how this diurnal rhythm of new cell production is controlled in retinal progenitor cells, we studied the transcription pattern of clock genes in retina, including clock1a, clock1b, bmal1a (brain and muscle ARNT-Like), and per1b (period1b). We found that these genes have a strong diurnal rhythmic transcription during light-dark cycles but not in constant darkness. An oscillation in pcna transcription was also observed during light-dark cycles, but again not in constant darkness. Our results also indicate an association between Clock proteins and the upstream region of pcna (proliferating cellular nuclear antigen) gene. A luciferase reporter assay conducted in an inducible clock knockdown cell line further demonstrated that the mutation on predicted E-Boxes in pcna promoter region significantly attenuated the transcriptional activation induced by Clock protein. These results suggested that the diurnal rhythmic expression of clock genes in A. burtoni retina could be light dependent and might contribute to the daily regulation of the proliferation of the retina progenitors through key components of cell cycle machinery, for instance, pcna. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Atomic clock ensemble in space

    Science.gov (United States)

    Cacciapuoti, L.; Salomon, C.

    2011-12-01

    Atomic Clock Ensemble in Space (ACES) is a mission using high-performance clocks and links to test fundamental laws of physics in space. Operated in the microgravity environment of the International Space Station, the ACES clocks, PHARAO and SHM, will generate a frequency reference reaching instability and inaccuracy at the 1 · 10-16 level. A link in the microwave domain (MWL) and an optical link (ELT) will make the ACES clock signal available to ground laboratories equipped with atomic clocks. Space-to-ground and ground-to-ground comparisons of atomic frequency standards will be used to test Einstein's theory of general relativity including a precision measurement of the gravitational red-shift, a search for time variations of fundamental constants, and Lorentz Invariance tests. Applications in geodesy, optical time transfer, and ranging will also be supported. ACES has now reached an advanced technology maturity, with engineering models completed and successfully tested and flight hardware under development. This paper presents the ACES mission concept and the status of its main instruments.

  20. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma

    2015-01-01

    The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

  1. Sound Clocks and Sonic Relativity

    Science.gov (United States)

    Todd, Scott L.; Menicucci, Nicolas C.

    2017-10-01

    Sound propagation within certain non-relativistic condensed matter models obeys a relativistic wave equation despite such systems admitting entirely non-relativistic descriptions. A natural question that arises upon consideration of this is, "do devices exist that will experience the relativity in these systems?" We describe a thought experiment in which `acoustic observers' possess devices called sound clocks that can be connected to form chains. Careful investigation shows that appropriately constructed chains of stationary and moving sound clocks are perceived by observers on the other chain as undergoing the relativistic phenomena of length contraction and time dilation by the Lorentz factor, γ , with c the speed of sound. Sound clocks within moving chains actually tick less frequently than stationary ones and must be separated by a shorter distance than when stationary to satisfy simultaneity conditions. Stationary sound clocks appear to be length contracted and time dilated to moving observers due to their misunderstanding of their own state of motion with respect to the laboratory. Observers restricted to using sound clocks describe a universe kinematically consistent with the theory of special relativity, despite the preferred frame of their universe in the laboratory. Such devices show promise in further probing analogue relativity models, for example in investigating phenomena that require careful consideration of the proper time elapsed for observers.

  2. Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle.

    Directory of Open Access Journals (Sweden)

    Jonathan A Hardman

    Full Text Available The human hair follicle (HF exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1 prolonging active hair growth (anagen and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4 also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2 were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock-related disease.

  3. Mid-day siesta in natural populations of D. melanogaster from Africa exhibits an altitudinal cline and is regulated by splicing of a thermosensitive intron in the period clock gene.

    Science.gov (United States)

    Cao, Weihuan; Edery, Isaac

    2017-01-23

    Many diurnal animals exhibit a mid-day 'siesta', generally thought to be an adaptive response aimed at minimizing exposure to heat on warm days, suggesting that in regions with cooler climates mid-day siestas might be a less prominent feature of animal behavior. Drosophila melanogaster exhibits thermal plasticity in its mid-day siesta that is partly governed by the thermosensitive splicing of the 3'-terminal intron (termed dmpi8) from the key circadian clock gene period (per). For example, decreases in temperature lead to progressively more efficient splicing, which increasingly favors activity over sleep during the mid-day. In this study we sought to determine if the adaptation of D. melanogaster from its ancestral range in the lowlands of tropical Africa to the cooler temperatures found at high altitudes involved changes in mid-day sleep behavior and/or dmpi8 splicing efficiency. Using natural populations of Drosophila melanogaster from different altitudes in tropical Africa we show that flies from high elevations have a reduced mid-day siesta and less consolidated sleep. We identified a single nucleotide polymorphism (SNP) in the per 3' untranslated region that has strong effects on dmpi8 splicing and mid-day sleep levels in both low and high altitude flies. Intriguingly, high altitude flies with a particular variant of this SNP exhibit increased dmpi8 splicing efficiency compared to their low altitude counterparts, consistent with reduced mid-day siesta. Thus, a boost in dmpi8 splicing efficiency appears to have played a prominent but not universal role in how African flies adapted to the cooler temperatures at high altitude. Our findings point towards mid-day sleep behavior as a key evolutionary target in the thermal adaptation of animals, and provide a genetic framework for investigating daytime sleep in diurnal animals which appears to be driven by mechanisms distinct from those underlying nighttime sleep.

  4. The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Anna Schnell

    Full Text Available The function of the nuclear receptor Rev-erbα (Nr1d1 in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO animals. We identified fatty acid binding protein 7 (Fabp7, Blbp as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ of the hippocampus, where neuronal progenitor cells (NPCs can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.

  5. SlgA, encoded by the homolog of the human schizophrenia-associated gene PRODH, acts in clock neurons to regulate Drosophila aggression

    Directory of Open Access Journals (Sweden)

    Liesbeth Zwarts

    2017-06-01

    Full Text Available Mutations in the proline dehydrogenase gene PRODH are linked to behavioral alterations in schizophrenia and as part of DiGeorge and velo-cardio-facial syndromes, but the role of PRODH in their etiology remains unclear. Here, we establish a Drosophila model to study the role of PRODH in behavioral disorders. We determine the distribution of the Drosophila PRODH homolog slgA in the brain and show that knockdown and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII. Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of the mechanisms that are impaired in neuropsychiatric disorders.

  6. SlgA, encoded by the homolog of the human schizophrenia-associated gene PRODH, acts in clock neurons to regulate Drosophila aggression.

    Science.gov (United States)

    Zwarts, Liesbeth; Vulsteke, Veerle; Buhl, Edgar; Hodge, James J L; Callaerts, Patrick

    2017-06-01

    Mutations in the proline dehydrogenase gene PRODH are linked to behavioral alterations in schizophrenia and as part of DiGeorge and velo-cardio-facial syndromes, but the role of PRODH in their etiology remains unclear. Here, we establish a Drosophila model to study the role of PRODH in behavioral disorders. We determine the distribution of the Drosophila PRODH homolog slgA in the brain and show that knockdown and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of the mechanisms that are impaired in neuropsychiatric disorders. © 2017. Published by The Company of Biologists Ltd.

  7. NT-3 Facilitates Hippocampal Plasticity and Learning and Memory by Regulating Neurogenesis

    Science.gov (United States)

    Sakata, Kazuko; Akbarian, Schahram; Bates, Brian; Jaenisch, Rudolf; Lu, Bai; Shimazu, Kazuhiro; Zhao, Mingrui

    2006-01-01

    In the adult brain, the expression of NT-3 is largely confined to the hippocampal dentate gyrus (DG), an area exhibiting significant neurogenesis. Using a conditional mutant line in which the "NT-3" gene is deleted in the brain, we investigated the role of NT-3 in adult neurogenesis, hippocampal plasticity, and memory. Bromodeoxyuridine…

  8. Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health

    Science.gov (United States)

    Ribas-Latre, Aleix; Eckel-Mahan, Kristin

    2016-01-01

    Background While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. Scope of review This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively

  9. Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health.

    Science.gov (United States)

    Ribas-Latre, Aleix; Eckel-Mahan, Kristin

    2016-03-01

    While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between

  10. [Temporally Relationship between Renal Local Clock System and Circadian Rhythm of the Water Electrolyte Excretion].

    Science.gov (United States)

    Zhang, Rui-Yu; Mou, Li-Jun; Li, Xue-Mei; Li, Xue-Wang; Qin, Yan

    2015-12-01

    To investigate the relationship of the circadian rhythm of the urine volume and urine electrolytes excretion rate and the daily expression pattern of the clock genes and clock-controlled genes with the water electrolyte transportation circadian pattern in rat kidneys. Male adult SD rats were exposed to in a light:dark (12:12) cycles. We collected two period urine from zeitgeber time (ZT)00:00-ZT12:00 (light time,rest period) and ZT12:00-24:00 (dark time,activity period) and then compared the urinary excretion rates of volume, sodium, potassium, and chloride at light time with those at dark time. Rats were sacrificed every 4 hours throughout a 24-hour day-night cycle. Circadian clock gene CLOCK, BMAL1,Per1,Per2,Cry1,Cry2 and kidney specific clock-controlled gene NHE3,αENaC、NCC,Ptges,V1aR,V2R expression were profiled by real-time quantitative polymerase chain reaction. Data were analysed by a partial Fourier analysis and a stepwise regression technique. Urine volume and urine potassium excretion rate displayed high level at dark time and low at light time in SD rats (P0.05).Clock gene CLOCK,BMAL1,Per1,Per2,Cry1,Cry2(Pclock-controlled gene NHE3, αENaC, NCC, Ptges, V1aR, V2R (Pclock and clock-controlled genes associated with water electrolyte transportation in rats kidney.

  11. Hippocampal MR volumetry

    Science.gov (United States)

    Haller, John W.; Botteron, K.; Brunsden, Barry S.; Sheline, Yvette I.; Walkup, Ronald K.; Black, Kevin J.; Gado, Mokhtar; Vannier, Michael W.

    1994-09-01

    Goal: To estimate hippocampal volumes from in vivo 3D magnetic resonance (MR) brain images and determine inter-rater and intra- rater repeatability. Objective: The precision and repeatability of hippocampal volume estimates using stereologic measurement methods is sought. Design: Five normal control and five schizophrenic subjects were MR scanned using a MPRAGE protocol. Fixed grid stereologic methods were used to estimate hippocampal volumes on a graphics workstation. The images were preprocessed using histogram analysis to standardize 3D MR image scaling from 16 to 8 bits and image volumes were interpolated to 0.5 mm3 isotropic voxels. The following variables were constant for the repeated stereologic measures: grid size, inter-slice distance (1.5 mm), voxel dimensions (0.5 mm3), number of hippocampi measured (10), total number of measurements per rater (40), and number of raters (5). Two grid sizes were tested to determine the coefficient of error associated with the number of sampled 'hits' (approximately 140 and 280) on the hippocampus. Starting slice and grid position were randomly varied to assure unbiased volume estimates. Raters were blind to subject identity, diagnosis, and side of the brain from which the image volumes were extracted and the order of subject presentation was randomized for each of the raters. Inter- and intra-rater intraclass correlation coefficients (ICC) were determined. Results: The data indicate excellent repeatability of fixed grid stereologic hippocampal volume measures when using an inter-slice distance of 1.5 mm and a 6.25 mm2 grid (inter-rater ICCs equals 0.86 - 0.97, intra- rater ICCs equals 0.85 - 0.97). One major advantage of the current study was the use of 3D MR data which significantly improved visualization of hippocampal boundaries by providing the ability to access simultaneous orthogonal views while counting stereological marks within the hippocampus. Conclusion: Stereological estimates of 3D volumes from 2D MR

  12. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.

    Science.gov (United States)

    Koike, Nobuya; Yoo, Seung-Hee; Huang, Hung-Chung; Kumar, Vivek; Lee, Choogon; Kim, Tae-Kyung; Takahashi, Joseph S

    2012-10-19

    The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.

  13. Light and the human circadian clock

    NARCIS (Netherlands)

    Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V

    2013-01-01

    The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the

  14. Integration of metabolic and cardiovascular diurnal rhythms by circadian clock.

    Science.gov (United States)

    Kohsaka, Akira; Waki, Hidefumi; Cui, He; Gouraud, Sabine S; Maeda, Masanobu

    2012-01-01

    Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.

  15. Food-reward signalling in the suprachiasmatic clock.

    Science.gov (United States)

    Mendoza, Jorge; Clesse, Daniel; Pévet, Paul; Challet, Etienne

    2010-03-01

    Under special restricted feeding conditions the mammalian circadian clock, contained in the hypothalamic suprachiasmatic nucleus (SCN), can be entrained by food. During food restriction, hungry animals are very motivated to obtain food. This motivational state could be a key component in altering the SCN timing by feeding. In order to comprehend how hedonic signals of food affect the SCN clock, we evaluated the effects of a daily palatable snack on the behavioural rhythm of mice fed ad libitum with regular food, and housed under constant darkness conditions. As light synchronization of the SCN is modulated by feeding/metabolic cues, the effects of a palatable meal coupled to a light pulse were tested on behavioural and molecular rhythms. A daily palatable snack entrained behavioural rhythms of mice in constant darkness conditions. Furthermore, palatable meal access at the activity onset reduced light-induced behavioural phase-delays and Period genes expression in the SCN. In addition, an increase in the dopamine content and Period genes expression in the forebrain of mice was observed, concomitant with a c-FOS activation in dopaminergic and orexinergic neurons, suggesting that the effects of a palatable snack on the SCN clock are mediated by the reward/arousal central systems. In conclusion, this study establishes an underlying sensitivity of the master circadian clock to changes in motivational states related to palatable food intake.

  16. MicroRNAs: a potential interface between the circadian clock and human health.

    Science.gov (United States)

    Hansen, Katelin F; Sakamoto, Kensuke; Obrietan, Karl

    2011-02-17

    The biochemical activity of a stunning diversity of cell types and organ systems is shaped by a 24-hour (circadian) clock. This rhythmic drive to a good deal of the transcriptome (up to 15% of all coding genes) imparts circadian modulation over a wide range of physiological and behavioral processes (from cell division to cognition). Further, dysregulation of the clock has been implicated in the pathogenesis of a large and diverse array of disorders, such as hypertension, cancer and depression. Indeed, the possibility of utilizing therapeutic approaches that target clock physiology (that is, chronotherapy) has gained broad interest. However, a deeper understanding of the underlying molecular mechanisms that modulate the clock, and give rise to organ-specific clock transcriptomes, will be required to fully realize the power of chronotherapies. Recently, microRNAs have emerged as significant players in circadian clock timing, thus raising the possibility that clock-controlled microRNAs could contribute to disorders of the human circadian timing system. Here, we highlight recent work revealing a key role for microRNAs in clock physiology, and discuss potential approaches to unlocking their utility as effectors of circadian physiology and pathophysiology.

  17. Strategies for Partitioning Clock Models in Phylogenomic Dating: Application to the Angiosperm Evolutionary Timescale

    Science.gov (United States)

    Ho, Simon Y.W.

    2017-01-01

    Abstract Evolutionary timescales can be inferred from molecular sequence data using a Bayesian phylogenetic approach. In these methods, the molecular clock is often calibrated using fossil data. The uncertainty in these fossil calibrations is important because it determines the limiting posterior distribution for divergence-time estimates as the sequence length tends to infinity. Here, we investigate how the accuracy and precision of Bayesian divergence-time estimates improve with the increased clock-partitioning of genome-scale data into clock-subsets. We focus on a data set comprising plastome-scale sequences of 52 angiosperm taxa. There was little difference among the Bayesian date estimates whether we chose clock-subsets based on patterns of among-lineage rate heterogeneity or relative rates across genes, or by random assignment. Increasing the degree of clock-partitioning usually led to an improvement in the precision of divergence-time estimates, but this increase was asymptotic to a limit presumably imposed by fossil calibrations. Our clock-partitioning approaches yielded highly precise age estimates for several key nodes in the angiosperm phylogeny. For example, when partitioning the data into 20 clock-subsets based on patterns of among-lineage rate heterogeneity, we inferred crown angiosperms to have arisen 198–178 Ma. This demonstrates that judicious clock-partitioning can improve the precision of molecular dating based on phylogenomic data, but the meaning of this increased precision should be considered critically. PMID:29036288

  18. Digital clocks: simple Boolean models can quantitatively describe circadian systems

    Science.gov (United States)

    Akman, Ozgur E.; Watterson, Steven; Parton, Andrew; Binns, Nigel; Millar, Andrew J.; Ghazal, Peter

    2012-01-01

    The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day–night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circad