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1

KAYAK-? modulates circadian transcriptional feedback loops in Drosophila pacemaker neurons.  

PubMed

Circadian rhythms are generated by well-conserved interlocked transcriptional feedback loops in animals. In Drosophila, the dimeric transcription factor CLOCK/CYCLE (CLK/CYC) promotes period (per), timeless (tim), vrille (vri), and PAR-domain protein 1 (Pdp1) transcription. PER and TIM negatively feed back on CLK/CYC transcriptional activity, whereas VRI and PDP1 negatively and positively regulate Clk transcription, respectively. Here, we show that the ? isoform of the Drosophila FOS homolog KAYAK (KAY) is required for normal circadian behavior. KAY-? downregulation in circadian pacemaker neurons increases period length by 1.5 h. This behavioral phenotype is correlated with decreased expression of several circadian proteins. The strongest effects are on CLK and the neuropeptide PIGMENT DISPERSING FACTOR, which are both under VRI and PDP1 control. Consistently, KAY-? can bind to VRI and inhibit its interaction with the Clk promoter. Interestingly, KAY-? can also repress CLK activity. Hence, in flies with low KAY-? levels, CLK derepression would partially compensate for increased VRI repression, thus attenuating the consequences of KAY-? downregulation on CLK targets. We propose that the double role of KAY-? in the two transcriptional loops controlling Drosophila circadian behavior brings precision and stability to their oscillations. PMID:23175847

Ling, Jinli; Dubruille, Raphaëlle; Emery, Patrick

2012-11-21

2

Reevaluation of Drosophila melanogaster's Neuronal Circadian Pacemakers Reveals New Neuronal Classes  

PubMed Central

In the brain of the fly Drosophila melanogaster, ?150 clock-neurons are organized to synchronize and maintain behavioral rhythms, but the physiological and neurochemical bases of their interactions are largely unknown. Here we reevaluate the cellular properties of these pacemakers by application of a novel genetic reporter and several phenotypic markers. First, we describe an enhancer trap marker called R32 that specifically reveals several previously undescribed aspects of the fly's central neuronal pacemakers. We find evidence for a previously unappreciated class of neuronal pacemakers, the lateral posterior neurons (LPNs), and establish anatomical, molecular, and developmental criteria to establish a subclass within the dorsal neuron 1 (DN1) group of pacemakers. Furthermore, we show that the neuropeptide IPNamide is specifically expressed by this DN1 subclass. These observations implicate IPNamide as a second candidate circadian transmitter in the Drosophila brain. Finally, we present molecular and anatomical evidence for unrecognized phenotypic diversity within each of four established classes of clock neurons. PMID:16856134

Shafer, Orie Thomas; Helfrich-Förster, Charlotte; Renn, Susan Christine Portia; Taghert, Paul H.

2008-01-01

3

Circadian pacemaker coupling by multi-peptidergic neurons in the cockroach Leucophaea maderae.  

PubMed

Lesion and transplantation studies in the cockroach, Leucophaea maderae, have located its bilaterally symmetric circadian pacemakers necessary for driving circadian locomotor activity rhythms to the accessory medulla of the optic lobes. The accessory medulla comprises a network of peptidergic neurons, including pigment-dispersing factor (PDF)-expressing presumptive circadian pacemaker cells. At least three of the PDF-expressing neurons directly connect the two accessory medullae, apparently as a circadian coupling pathway. Here, the PDF-expressing circadian coupling pathways were examined for peptide colocalization by tracer experiments and double-label immunohistochemistry with antisera against PDF, FMRFamide, and Asn(13)-orcokinin. A fourth group of contralaterally projecting medulla neurons was identified, additional to the three known groups. Group one of the contralaterally projecting medulla neurons contained up to four PDF-expressing cells. Of these, three medium-sized PDF-immunoreactive neurons coexpressed FMRFamide and Asn(13)-orcokinin immunoreactivity. However, the contralaterally projecting largest PDF neuron showed no further peptide colocalization, as was also the case for the other large PDF-expressing medulla cells, allowing the easy identification of this cell group. Although two-thirds of all PDF-expressing medulla neurons coexpressed FMRFamide and orcokinin immunoreactivity in their somata, colocalization of PDF and FMRFamide immunoreactivity was observed in only a few termination sites. Colocalization of PDF and orcokinin immunoreactivity was never observed in any of the terminals or optic commissures. We suggest that circadian pacemaker cells employ axonal peptide sorting to phase-control physiological processes at specific times of the day. PMID:21229364

Soehler, Sandra; Stengl, Monika; Reischig, Thomas

2011-03-01

4

Drosophila TRPA1 functions in temperature control of circadian rhythm in pacemaker neurons  

PubMed Central

Most animals from flies to humans count on circadian clocks to synchronize their physiology and behaviors. Daily light cycles are well-known environmental cues for setting circadian rhythms. Warmer and cooler temperatures that mimic day and night are also effective in entraining circadian activity in most animals. Even vertebrate organisms can be induced to show circadian responses through exposure to temperature cycles. In poikilothermic animals such as Drosophila, temperature differences of only 2–3°C are sufficient to synchronize locomotor rhythms. However, the molecular sensors that participate in temperature regulation of circadian activity in fruit flies or other animals are enigmatic. It is also unclear whether such detectors are limited to the periphery or may be in the central brain. Here, we showed that Drosophila TRPA1 (Transient Receptor Potential Cation Channel A1) was necessary for normal activity patterns during temperature cycles. The trpA1 gene was expressed in a subset of pacemaker neurons in the central brain. In response to temperature entrainment, loss of trpA1 impaired activity, and altered expression of the circadian clock protein Period (Per) in a subset of pacemaker neurons. These findings underscore a role for a thermoTRP in temperature regulation that extends beyond avoidance of noxious or suboptimal temperatures. PMID:23595730

Lee, Youngseok; Montell, Craig

2013-01-01

5

E and M circadian pacemaker neurons use different PDF receptor signalosome components in drosophila.  

PubMed

We used real-time imaging to detect cAMP levels in neurons of intact fly brains to study the mechanisms of circadian pacemaker synchronization by the neuropeptide pigment dispersing factor (PDF) in Drosophila. PDF receptor (PDF-R) is expressed by both M (sLNv) and E (LNd) pacemaker subclasses and is coupled to G(s?) in both cases. We previously reported that PDF-R in M pacemakers elevates cAMP levels by activating the ortholog of mammalian adenylate cyclase 3 (AC3) but that AC3 disruptions had no effect on E pacemaker sensitivity to PDF. Here, we show that PDF-R in E pacemakers activates a different AC isoform, AC78C, an ortholog of mammalian AC8. Knockdown of AC78C by transgenic RNAi substantially reduces, but does not completely abrogate, PDF responses in these E pacemakers. The knockdown effect is intact when restricted to mature stages, suggesting a physiological and not a development role for AC78C in E pacemakers. The AC78C phenotype is rescued by the overexpression of AC78C but not by overexpression of the rutabaga AC. AC78C overexpression does not disrupt PDF responses in these E pacemakers, and neither AC78C knockdown nor its overexpression disrupted locomotor rhythms. Finally, knockdown of 2 AKAPs, nervy and AKAP200, partially reduces LNd PDF responses. These findings begin to identify the components of E pacemaker PDF-R signalosomes and indicate that they are distinct from PDF-R signalosomes in M pacemakers: we propose they contain AC78C and at least 1 other AC. PMID:23929551

Duvall, Laura B; Taghert, Paul H

2013-08-01

6

Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons  

PubMed Central

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior. PMID:25356918

Depetris-Chauvin, Ana; Fernández-Gamba, Ágata; Gorostiza, E. Axel; Herrero, Anastasia; Castaño, Eduardo M.; Ceriani, M. Fernanda

2014-01-01

7

Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.  

PubMed

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior. PMID:25356918

Depetris-Chauvin, Ana; Fernández-Gamba, Agata; Gorostiza, E Axel; Herrero, Anastasia; Castaño, Eduardo M; Ceriani, M Fernanda

2014-10-01

8

Serotonin sets the day state in the neurons that control coupling between the optic lobe circadian pacemakers in the cricket Gryllus bimaculatus.  

PubMed

The bilaterally paired optic lobe circadian pacemakers of the cricket Gryllus bimaculatus mutually exchange photic and circadian information to keep their activity synchronized. The information is mediated by a neural pathway, consisting of the so-called medulla bilateral neurons, connecting the medulla areas of the two optic lobes. We investigated the effects of serotonin on the neural activity in this coupling pathway. Spontaneous and light-induced electrical activity of the neurons in the coupling pathway showed daily variations, being more intense during the night than the day. Microinjection of serotonin or a serotonin-receptor agonist, quipazine, into the optic lobe caused a dose- and time-dependent inhibition of spontaneous and light-induced responses, mimicking the day state. The amount of suppression was greater and the recovery from the suppression occurred faster during the night. Application of metergoline, a non-selective serotonin-receptor antagonist, increased spontaneous activity and light-evoked responses during both the day and the night, with higher effect during the day. In addition, metergoline effectively attenuated the effects of serotonin. These facts suggest that in the cricket's optic lobe, serotonin is released during the daytime and sets the day state in the neurons regulating coupling between the bilaterally paired optic lobe circadian pacemakers. PMID:11948207

Saifullah, A S M; Tomioka, Kenji

2002-05-01

9

The Drosophila Circadian Pacemaker Circuit: Pas de Deux or Tarantella?  

PubMed Central

Molecular genetic analysis of the fruit fly Drosophila melanogaster has revolutionized our understanding of the transcription/translation loop mechanisms underlying the circadian molecular oscillator. More recently, Drosophila has been used to understand how different neuronal groups within the circadian pacemaker circuit interact to regulate the overall behavior of the fly in response to daily cyclic environmental cues as well as seasonal changes. Our present understanding of circadian timekeeping at the molecular and circuit level is discussed with a critical evaluation of the strengths and weaknesses of present models. Two models for circadian neural circuits are compared: one that posits that two anatomically distinct oscillators control the synchronization to the two major daily morning and evening transitions, versus a distributed network model that posits that many cell-autonomous oscillators are coordinated in a complex fashion and respond via plastic mechanisms to changes in environmental cues. PMID:18307108

Sheeba, Vasu; Kaneko, Maki; Sharma, Vijay Kumar; Holmes, Todd C.

2008-01-01

10

Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus.  

PubMed

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co-ordinates the daily rhythms of sleep and wakefulness, as well as physiology and behaviour, that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet-lag but more insidiously with rotational shift-work, can have severely deleterious effects for mental function and long-term health. The present review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time-keeper. It first focuses on the intracellular transcriptional/ translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neurone. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca(2+) ]i ), which are both outputs from, and inputs to, the TTFL, as well as the critical role of vasoactive intestinal peptide (VIP) signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 h) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G-protein-coupled signalling in individual SCN neurones, and how manipulation of Gq/[Ca(2+) ]i -signalling in VIP neurones can re-programme the circuit-level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively few gene products, operating in a clearly defined neuronal circuit, with both cell-autonomous and emergent, circuit-level properties. PMID:24329967

Hastings, M H; Brancaccio, M; Maywood, E S

2014-01-01

11

Differentially timed extracellular signals synchronize pacemaker neuron clocks.  

PubMed

Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species. PMID:25268747

Collins, Ben; Kaplan, Harris S; Cavey, Matthieu; Lelito, Katherine R; Bahle, Andrew H; Zhu, Zhonghua; Macara, Ann Marie; Roman, Gregg; Shafer, Orie T; Blau, Justin

2014-09-01

12

Physiological effects of light on the human circadian pacemaker  

NASA Technical Reports Server (NTRS)

The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.

Shanahan, T. L.; Czeisler, C. A.

2000-01-01

13

The neurochemical basis of photic entrainment of the circadian pacemaker  

NASA Technical Reports Server (NTRS)

Circadian rhythmicity in mammals is controlled by the action of a light-entrainable hypothalamus, in association with two cell clusters known as the supra chiasmatic nuclei (SCN). In the absence of temporal environmental clues, this pacemaker continues to measure time by an endogenous mechanism (clock), driving biochemical, physiological, and behavioral rhythms that reflect the natural period of the pacemaker oscillation. This endogenous period usually differs slightly from 24 hours (i.e., circadian). When mammals are maintained under a 24 hour light-dark (LD) cycle, the pacemaker becomes entrained such that the period of the pacemaker oscillation matches that of the LD cycle. Potentially entraining photic information is conveyed to the SCN via a direct retinal projection, the retinohypothalamic tract (RHT). RHT neurotransmission is thought to be mediated by the release of excitatory amino acids (EAA) in the SCN. In support of this hypothesis, recent experiments using nocturnal rodents have shown that EAA antagonists block the effects of light on pacemaker-driven behavioral rhythms, and attenuate light induced gene expression in SCN cells. An understanding of the neurochemical basis of the photic entrainment process would facilitate the development of pharmacological strategies for maintaining synchrony among shift workers in environments, such as the Space Station, which provide unreliable or conflicting temporal photic clues.

Rea, Michael A.; Buckley, Becky; Lutton, Lewis M.

1992-01-01

14

Pacemaker neurons within newborn spinal pain circuits  

PubMed Central

Spontaneous activity driven by “pacemakerneurons, defined by their intrinsic ability to generate rhythmic burst-firing, contributes to the development of sensory circuits in many regions of the immature CNS. However, it is unknown if pacemaker-like neurons are present within central pain pathways in the neonate. Here we provide evidence that a subpopulation of glutamatergic interneurons within lamina I of the rat spinal cord exhibits oscillatory burst-firing during early life, which occurs independently of fast synaptic transmission. Pacemaker neurons were distinguished by a higher ratio of persistent, voltage-gated Na+ conductance to leak membrane conductance (gNa,P / gleak) compared to adjacent, non-bursting lamina I neurons. The activation of high-threshold (N-type and L-type) voltage-gated Ca2+ channels also facilitated rhythmic burst-firing by triggering intracellular Ca2+ signaling. Bursting neurons received direct projections from high-threshold sensory afferents, but transmitted nociceptive signals with poor fidelity while in the bursting mode. The observation that pacemaker neurons send axon collaterals throughout the neonatal spinal cord raises the possibility that intrinsic burst-firing could provide an endogenous drive to the developing sensorimotor networks which mediate spinal pain reflexes. PMID:21677184

Li, Jie; Baccei, Mark L.

2011-01-01

15

Phase shifting two coupled circadian pacemakers - Implications for jet lag  

NASA Technical Reports Server (NTRS)

Two Van der Pol oscillators with reciprocal linear velocity coupling are utilized to model the response of the human circadian timing system to abrupt displacements of the environmental time cues (zeitgebers). The core temperature rhythm and sleep-wake cycle simulated by the model are examined. The relationship between the masking of circadian rhythms by environmental variables and behavioral and physiological events and the rates of resynchronization is studied. The effects of zeitgeber phase shifts and zeitgeber strength on the resynchronization rates are analyzed. The influence of intrinsic pacemakers periods and coupling strength on resynchronization are investigated. The simulated data reveal that: resynchronization after a time zone shift depends on the magnitude of the shift; the time of day of the shift has little influence on resynchronization; the strength of zeitgebers affects the rate and direction of the resynchronization; the intrinsic pacemaker periods have a significant effect on resynchronization; and increasing the coupling between the oscillators results in an increase in the rate of resynchronization. The model data are compared to transmeridian flight studies data and similar resynchronization patterns are observed.

Gander, P. H.; Kronauer, R. E.; Graeber, R. C.

1985-01-01

16

Putative Pacemakers in the Eyestalk and Brain of the Crayfish Procambarus clarkii Show Circadian Oscillations in Levels of mRNA for Crustacean Hyperglycemic Hormone  

PubMed Central

Crustacean hyperglycemic hormone (CHH) synthesizing cells in the optic lobe, one of the pacemakers of the circadian system, have been shown to be present in crayfish. However, the presence of CHH in the central brain, another putative pacemaker of the multi-oscillatory circadian system, of this decapod and its circadian transcription in the optic lobe and brain have yet to be explored. Therefore, using qualitative and quantitative PCR, we isolated and cloned a CHH mRNA fragment from two putative pacemakers of the multi-oscillatory circadian system of Procambarus clarkii, the optic lobe and the central brain. This CHH transcript synchronized to daily light-dark cycles and oscillated under dark, constant conditions demonstrating statistically significant daily and circadian rhythms in both structures. Furthermore, to investigate the presence of the peptide in the central brain of this decapod, we used immunohistochemical methods. Confocal microscopy revealed the presence of CHH-IR in fibers and cells of the protocerebral and tritocerebal clusters and neuropiles, particularly in some neurons located in clusters 6, 14, 15 and 17. The presence of CHH positive neurons in structures of P. clarkii where clock proteins have been reported suggests a relationship between the circadian clockwork and CHH. This work provides new insights into the circadian regulation of CHH, a pleiotropic hormone that regulates many physiological processes such as glucose metabolism and osmoregulatory responses to stress. PMID:24391849

Nelson-Mora, Janikua; Prieto-Sagredo, Julio; Loredo-Ranjel, Rosaura; Fanjul-Moles, María Luisa

2013-01-01

17

Bright Light Induction of Strong (Type 0) Resetting of the Human Circadian Pacemaker  

NASA Astrophysics Data System (ADS)

The response of the human circadian pacemaker to light was measured in 45 resetting trials. Each trial consisted of an initial endogenous circadian phase assessment, a three-cycle stimulus which included 5 hours of bright light per cycle, and a final phase assessment. The stimulus induced strong (type 0) resetting, with responses highly dependent on the initial circadian phase of light exposure. The magnitude and direction of the phase shifts were modulated by the timing of exposure to ordinary room light, previously thought to be undetectable by the human pacemaker. The data indicate that the sensitivity of the human circadian pacemaker to light is far greater than previously recognized and have important implications for the therapeutic use of light in the management of disorders of circadian regulation.

Czeisler, Charles A.; Kronauer, Richard E.; Allan, James S.; Duffy, Jeanne F.; Jewett, Megan E.; Brown, Emery N.; Ronda, Joseph M.

1989-06-01

18

Sexual Interactions Influence the Molecular Oscillations in DN1 Pacemaker Neurons in Drosophila melanogaster  

PubMed Central

Circadian rhythms can synchronize to environmental time cues, such as light, temperature, humidity, and food availability. Previous studies have suggested that these rhythms can also be entrained by social interactions. Here, we used Drosophila melanogaster as a model to study the influence of socio-sexual interactions on the circadian clock in behavior and pacemaker neurons. If two flies of opposite sex were paired and kept in a small space, the daily activity patterns of the two flies were clearly different from the sum of the activity of single male and female flies. Compared with single flies, paired flies were more active in the night and morning, were more active during females’ active phase, and were less active during males’ active phase. These behavioral phenotypes are related to courtship behavior, but not to the circadian clock. Nevertheless, in male-female pairs of flies with clocks at different speeds (wild-type and perS flies), clock protein cycling in the DN1 pacemaker neurons in the male brain were slightly influenced by their partners. These results suggest that sexual interactions between male-female couples can serve as a weak zeitgeber for the DN1 pacemaker neurons, but the effect is not sufficient to alter rhythms of behavioral activity. PMID:24367668

Hanafusa, Shiho; Kawaguchi, Tomoaki; Umezaki, Yujiro; Tomioka, Kenji; Yoshii, Taishi

2013-01-01

19

Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats  

PubMed Central

Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID:21324006

Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Rojas, Patricia; Chávez-Saldaña, Margarita; Pérez, Oscar Gutiérrez; Montes, Sergio; Ríos, Camilo

2011-01-01

20

Retrograde bone morphogenetic protein signaling shapes a key circadian pacemaker circuit.  

PubMed

The neuropeptide pigment-dispersing factor (PDF) synchronizes molecular oscillations within circadian pacemakers in the Drosophila brain. It is expressed in the small ventral lateral neurons (sLNvs) and large ventral lateral neurons, the former being indispensable for maintaining behavioral rhythmicity under free-running conditions. How PDF circuits develop the specific connectivity traits that endow such global behavioral control remains unknown. Here, we show that mature sLNv circuits require PDF signaling during early development, acting through its cognate receptor PDFR at postsynaptic targets. Yet, axonal defects by PDF knockdown are presynaptic and become apparent only after metamorphosis, highlighting a delayed response to a signal released early on. Presynaptic expression of constitutively active bone morphogenetic protein (BMP) receptors prevents pdfr mutants misrouting phenotype, while sLNv-restricted downregulation of BMP signaling components phenocopied pdf(01). Thus, we have uncovered a novel mechanism that provides an early "tagging" of synaptic targets that will guide circuit refinement later in development. PMID:23303947

Gorostiza, E Axel; Ceriani, M Fernanda

2013-01-01

21

Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals  

PubMed Central

Summary Circadian oscillations in mammalian physiology and behavior are regulated by an endogenous biological clock. Here we show that loss of the PAS protein MOP3 (also known as BMAL1) in mice results in immediate and complete loss of circadian rhythmicity in constant darkness. Additionally, locomotor activity in light–dark (LD) cycles is impaired and activity levels are reduced in Mop3?/? mice. Analysis of Period gene expression in the suprachiasmatic nucleus (SCN) indicates that these behavioral phenotypes arise from loss of circadian function at the molecular level. These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK. Furthermore, these data demonstrate that MOP3 is a non-redundant and essential component of the circadian pacemaker in mammals. PMID:11163178

Bunger, Maureen K.; Wilsbacher, Lisa D.; Moran, Susan M.; Clendenin, Cynthia; Radcliffe, Laurel A.; Hogenesch, John B.; Simon, M. Celeste; Takahashi, Joseph S.; Bradfield, Christopher A.

2013-01-01

22

Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus  

PubMed Central

In mammals, circadian oscillators exist not only in the suprachiasmatic nucleus, which harbors the central pacemaker, but also in most peripheral tissues. It is believed that the SCN clock entrains the phase of peripheral clocks via chemical cues, such as rhythmically secreted hormones. Here we show that temporal feeding restriction under light–dark or dark–dark conditions can change the phase of circadian gene expression in peripheral cell types by up to 12 h while leaving the phase of cyclic gene expression in the SCN unaffected. Hence, changes in metabolism can lead to an uncoupling of peripheral oscillators from the central pacemaker. Sudden large changes in feeding time, similar to abrupt changes in the photoperiod, reset the phase of rhythmic gene expression gradually and are thus likely to act through a clock-dependent mechanism. Food-induced phase resetting proceeds faster in liver than in kidney, heart, or pancreas, but after 1 wk of daytime feeding, the phases of circadian gene expression are similar in all examined peripheral tissues. PMID:11114885

Damiola, Francesca; Le Minh, Nguyet; Preitner, Nicolas; Kornmann, Benoît; Fleury-Olela, Fabienne; Schibler, Ueli

2000-01-01

23

Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior.  

PubMed

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per?¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per?¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output. PMID:24643294

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

2014-03-01

24

Coupling of a Core Post-Translational Pacemaker to a Slave Transcription/Translation Feedback Loop in a Circadian System  

PubMed Central

Cyanobacteria are the only model circadian clock system in which a circadian oscillator can be reconstituted in vitro. The underlying circadian mechanism appears to comprise two subcomponents: a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO and TTFL have been hypothesized to operate as dual oscillator systems in cyanobacteria. However, we find that they have a definite hierarchical interdependency—the PTO is the core pacemaker while the TTFL is a slave oscillator that quickly damps when the PTO stops. By analysis of overexpression experiments and mutant clock proteins, we find that the circadian system is dependent upon the PTO and that suppression of the PTO leads to damped TTFL-based oscillations whose temperature compensation is not stable under different metabolic conditions. Mathematical modeling indicates that the experimental data are compatible with a core PTO driving the TTFL; the combined PTO/TTFL system is resilient to noise. Moreover, the modeling indicates a mechanism by which the TTFL can feed into the PTO such that new synthesis of clock proteins can phase-shift or entrain the core PTO pacemaker. This prediction was experimentally tested and confirmed by entraining the in vivo circadian system with cycles of new clock protein synthesis that modulate the phosphorylation status of the clock proteins in the PTO. In cyanobacteria, the PTO is the self-sustained core pacemaker that can operate independently of the TTFL, but the TTFL damps when the phosphorylation status of the PTO is clamped. However, the TTFL can provide entraining input into the PTO. This study is the first to our knowledge to experimentally and theoretically investigate the dynamics of a circadian clock in which a PTO is coupled to a TTFL. These results have important implications for eukaryotic clock systems in that they can explain how a TTFL could appear to be a core circadian clockwork when in fact the true pacemaker is an embedded biochemical oscillator. PMID:20563306

Xu, Yao; Mori, Tetsuya; Johnson, Carl Hirschie

2010-01-01

25

A Mathematical Model of Communication between Groups of Circadian Neurons in Drosophila melanogaster.  

PubMed

In the fruit fly, circadian behavior is controlled by a small number of specialized neurons, whose molecular clocks are relatively well known. However, much less is known about how these neurons communicate among themselves. In particular, only 1 circadian neuropeptide, pigment-dispersing factor (PDF), has been identified, and most aspects of its interaction with the molecular clock remain to be elucidated. Furthermore, it is speculated that many other peptides should contribute to circadian communication. We have developed a relatively detailed model of the 2 main groups of circadian pacemaker neurons (sLNvs and LNds) to investigate these issues. We have proposed many possible mechanisms for the interaction between the synchronization factors and the molecular clock, and we have compared the outputs with the experimental results reported in the literature both for the wild-type and PDF-null mutant. We have studied how different the properties of each neuron should be to account for the observations reported for the sLNvs in the mutant. We have found that only a few mechanisms, mostly related to the slowing down of nuclear entry of a circadian protein, can synchronize neurons that present these differences. Detailed immunofluorescent recordings have suggested that, whereas in the mutant, LNd neurons are synchronized, in the wild-type, a subset of the LNds oscillate faster than the rest. With our model, we find that a more likely explanation for the same observations is that this subset is being driven outside its synchronization range and displays therefore a complex pattern of oscillation. PMID:25416595

Risau-Gusman, Sebastián; Gleiser, Pablo M

2014-11-21

26

Connectivity of pacemaker neurons in the neonatal rat superficial dorsal horn.  

PubMed

Pacemaker neurons with an intrinsic ability to generate rhythmic burst-firing have been characterized in lamina I of the neonatal spinal cord, where they are innervated by high-threshold sensory afferents. However, little is known about the output of these pacemakers, as the neuronal populations which are targeted by pacemaker axons have yet to be identified. The present study combines patch clamp recordings in the intact neonatal rat spinal cord with tract-tracing to demonstrate that lamina I pacemaker neurons contact multiple spinal motor pathways during early life. Retrograde labeling of premotor interneurons with the trans-synaptic virus PRV-152 revealed the presence of burst-firing in PRV-infected lamina I neurons, thereby confirming that pacemakers are synaptically coupled to motor networks in the spinal ventral horn. Notably, two classes of pacemakers could be distinguished in lamina I based on cell size and the pattern of their axonal projections. While small pacemaker neurons possessed ramified axons which contacted ipsilateral motor circuits, large pacemaker neurons had unbranched axons which crossed the midline and ascended rostrally in the contralateral white matter. Recordings from identified spino-parabrachial and spino-PAG neurons indicated the presence of pacemaker activity within neonatal lamina I projection neurons. Overall, these results show that lamina I pacemakers are positioned to regulate both the level of activity in developing motor circuits as well as the ascending flow of nociceptive information to the brain, thus highlighting a potential role for pacemaker activity in the maturation of pain and sensorimotor networks in the CNS. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc. PMID:25380417

Li, Jie; Kritzer, Elizabeth; Ford, Neil C; Arbabi, Shahriar; Baccei, Mark L

2014-11-01

27

Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans  

NASA Technical Reports Server (NTRS)

Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.

Wright, K. P. Jr; Hughes, R. J.; Kronauer, R. E.; Dijk, D. J.; Czeisler, C. A.

2001-01-01

28

Circadian regulation of the Na+/K+-ATPase alpha subunit in the visual system is mediated by the pacemaker and by retina photoreceptors in Drosophila melanogaster.  

PubMed

We investigated the diurnal oscillation in abundance of the catalytic ? subunit of the sodium/potassium pump (ATP?) in the brain of Drosophila melanogaster. This rhythm is bimodal and is particularly robust in the glia cells of the lamina, the first optic neuropil. We observed loss of ATP? cycling in lamina glia in behaviourally arrhythmic per(01) and tim(01) mutants and in flies overexpressing the pro-apoptotic gene hid in the PDF-positive clock neurons. Moreover, the rhythm of ATP? abundance was altered in cry(01) and Pdf(0) mutants, in flies with a weakened clock mechanism in retina photoreceptor cells and in those subject to downregulation of the neuropeptide ITP by RNAi. This complex, rhythmic regulation of the ? subunit suggests that the sodium/potassium pump may be a key target of the circadian pacemaker to impose daily control on brain activities, such as rhythmic changes in neuronal plasticity, which are best observed in the visual system. PMID:24040028

Damulewicz, Milena; Rosato, Ezio; Pyza, Elzbieta

2013-01-01

29

Glycinergic pacemaker neurons in preBötzinger Complex of neonatal mouse  

PubMed Central

The preBötzinger Complex (preBötC) is essential for normal respiratory rhythm generation in rodents, for which the underlying mechanisms remain unknown. Excitatory preBötC pacemaker neurons are proposed to be necessary for rhythm generation. Here we report the presence of a population of preBötC glycinergic pacemaker neurons. We used rhythmic in vitro transverse slice preparations from transgenic mice where neurons expressing the glycine transporter 2 (GlyT2) gene co-express enhanced green fluorescent protein (EGFP). We combined epifluorescence and whole-cell patch-clamp recording to study preBötC EGFP-labeled, i.e., glycinergic, inspiratory-modulated neurons with pacemaker properties. We defined glycinergic pacemaker neurons as those preBötC EGFP neurons that exhibited: 1) ectopic bursting in rhythmic slices when depolarized during their normally silent period, and; 2) bursting when depolarized in non-rhythmic slices (following AMPA receptor blockade). 42% of EGFP-labeled neurons were inspiratory (n=48 of 115), of which 23% (n=11 of 48 inspiratory; 10% of the total recorded) were pacemakers. We conclude that there is a population of preBötC inspiratory-modulated glycinergic, presumably inhibitory, pacemaker neurons that constitute a substantial fraction of all preBötC pacemaker neurons. These findings challenge contemporary models for respiratory rhythmogenesis that assume the excitatory nature of preBötC pacemaker neurons. Testable and non-trivial predictions of the functional role of excitatory and inhibitory pacemaker neurons need to be proposed and the necessary experiments performed. PMID:20219997

Morgado-Valle, Consuelo; Baca, Serapio M.; Feldman, Jack L.

2010-01-01

30

Systems analysis of circadian time-dependent neuronal epidermal growth factor receptor signaling  

Microsoft Academic Search

BACKGROUND: Identifying the gene regulatory networks governing physiological signal integration remains an important challenge in circadian biology. Epidermal growth factor receptor (EGFR) has been implicated in circadian function and is expressed in the suprachiasmatic nuclei (SCN), the core circadian pacemaker. The transcription networks downstream of EGFR in the SCN are unknown but, by analogy to other SCN inputs, we expect

Daniel E Zak; Haiping Hao; Rajanikanth Vadigepalli; Gregory M Miller; Babatunde A Ogunnaike; James S Schwaber

2006-01-01

31

Two-oscillator structure of the pacemaker controlling the circadian rhythm of N-acetyltransferase in the rat pineal gland  

Microsoft Academic Search

1.The organization of the pacemaker driving the circadian rhythm of N-acetyltransferase activity in the rat pineal gland was studied by observing changes of the rhythm caused by 1 min light pulses applied at night. These pulses proved to be effective phase-shifting signals.2.After 1 min light pulses applied in the first half of the night. N-acetyltransferase activity began to increase anew

Helena Illnerová; Ji?í Van??ek

1982-01-01

32

A Sodium Leak Current Regulates Pacemaker Activity of Adult Central Pattern Generator Neurons in Lymnaea Stagnalis  

PubMed Central

The resting membrane potential of the pacemaker neurons is one of the essential mechanisms underlying rhythm generation. In this study, we described the biophysical properties of an uncharacterized channel (U-type channel) and investigated the role of the channel in the rhythmic activity of a respiratory pacemaker neuron and the respiratory behaviour in adult freshwater snail Lymnaea stagnalis. Our results show that the channel conducts an inward leak current carried by Na+ (ILeak-Na). The ILeak-Na contributed to the resting membrane potential and was required for maintaining rhythmic action potential bursting activity of the identified pacemaker RPeD1 neurons. Partial knockdown of the U-type channel suppressed the aerial respiratory behaviour of the adult snail in vivo. These findings identified the Na+ leak conductance via the U-type channel, likely a NALCN-like channel, as one of the fundamental mechanisms regulating rhythm activity of pacemaker neurons and respiratory behaviour in adult animals. PMID:21526173

Lu, Tom Z.; Feng, Zhong-Ping

2011-01-01

33

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration  

PubMed Central

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator–like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration. PMID:24270424

Musiek, Erik S.; Lim, Miranda M.; Yang, Guangrui; Bauer, Adam Q.; Qi, Laura; Lee, Yool; Roh, Jee Hoon; Ortiz-Gonzalez, Xilma; Dearborn, Joshua T.; Culver, Joseph P.; Herzog, Erik D.; Hogenesch, John B.; Wozniak, David F.; Dikranian, Krikor; Giasson, Benoit I.; Weaver, David R.; Holtzman, David M.; FitzGerald, Garret A.

2013-01-01

34

Morphological heterogeneity of the GABAergic network in the suprachiasmatic nucleus, the brain's circadian pacemaker  

PubMed Central

GABA (gamma-amino-butyric acid) is the predominant neurotransmitter in the mammalian suprachiasmatic nucleus (SCN), with a central role in circadian time-keeping. We therefore undertook an ultrastructural analysis of the GABA-containing innervation in the SCN of mice and rats using immunoperoxidase and immunogold procedures. GABA-immunoreactive (GABA-ir) neurons were identified by use of anti-GABA and anti-GAD (glutamic acid decarboxylase) antisera. The relationship between GABA-ir elements and the most prominent peptidergic neurons in the SCN, containing vasopressin-neurophysin (VP-NP) or vasoactive intestinal polypeptide (VIP), was also studied. Within any given field in the SCN, approximately 40–70% of the neuronal profiles were GABA-ir. In GABA-ir somata, immunogold particles were prominent over mitochondria, sparse over cytoplasm, and scattered as aggregates over nucleoplasm. In axonal boutons, gold particles were concentrated over electron-lucent synaptic vesicles (diameter 40–60 nm) and mitochondria, and in some instances over dense-cored vesicles (DCVs, diameter 90–110 nm). GABA-ir boutons formed either symmetric or asymmetric synaptic contacts with somata, dendritic shafts and spines, and occasionally with other terminals (axo-axonic). Homologous or autaptic connections (GABA on GABA, or GAD on GAD) were common. Although GABA appeared to predominate in most neuronal profiles, colocalisation of GABA within neurons that were predominantly neuropeptide-containing was also evident. About 66% of the VIP-containing boutons and 32% of the vasopressinergic boutons contained GABA. The dense and complex GABAergic network that pervades the SCN is therefore comprised of multiple neuronal phenotypes containing GABA, including a wide variety of axonal boutons that impinge on heterologous and homologous postsynaptic sites. PMID:10697283

CASTEL, MONA; MORRIS, JOHN F.

2000-01-01

35

Follower Neurons in Lobster (Panulirus interruptus) Pyloric Network Regulate Pacemaker Period in Complementary Ways  

E-print Network

Follower Neurons in Lobster (Panulirus interruptus) Pyloric Network Regulate Pacemaker Period November 2002 Weaver, Adam L. and Scott L. Hooper. Follower neurons in lobster (Panulirus interruptus this technique to study cycle period control in the rhythmic pyloric network of the lobster, Panulirus

Hooper, Scott

36

"Caged Calcium" in Aplysia Pacemaker Neurons Characterization of Calcium-activated Potassium and  

E-print Network

"Caged Calcium" in Aplysia Pacemaker Neurons Characterization of Calcium-activated Potassium-Anatomy, Universityof California, Berkeley, California 94720 ABSTRACT We have studied calcium-activated potassium neurons, using photolysis of a calcium chelator (nitr-5 or nitr-7) to release "caged calcium

Zucker, Robert S.

37

Morphology of rostral medullary neurons with intrinsic pacemaker activity in the rat.  

PubMed

Neurons with regular ongoing activity attributable to intrinsic pacemaker properties were recorded in coronal tissue slices within the nucleus reticularis rostroventrolateralis of the rat medulla oblongata (RVL). The cells were injected with horseradish peroxidase or Lucifer yellow and their dendritic and proximal axonal characteristics were investigated (n = 15). These small-to-medium-sized neurons had a simple dendritic arborization (3-6 primary dendrites branching up to 3 times) apparently confined within the limits of nucleus RVL and with limited extension in the rostrocaudal direction. Their axons originated either from the cell body or from a primary dendrite and coursed in a dorsomedial direction without giving rise to local arborizations. It is concluded that RVL pacemaker neurons, presumed to represent a non-adrenergic class of sympathoexcitatory premotor neurons, exhibit characteristics reminiscent of the archetypal 'reticular core' neurons. PMID:1718558

Sun, M K; Stornetta, R L; Guyenet, P G

1991-08-01

38

Synergistic interactions between the molecular and neuronal circadian networks drive robust behavioral circadian rhythms in Drosophila melanogaster.  

PubMed

Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK) and CYCLE (CYC) initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for circadian timekeeping. In order to address this issue, we generated flies in which the amplitude of CLK-driven transcription can be reduced partially (approx. 60%) or strongly (90%) without affecting the average levels of CLK-target genes. The impaired transcriptional oscillations lead to low amplitude protein oscillations that were not sufficient to drive outputs of peripheral oscillators. However, circadian rhythms in locomotor activity were resistant to partial reduction in transcriptional and protein oscillations. We found that the resilience of the brain oscillator is depending on the neuronal communication among circadian neurons in the brain. Indeed, the capacity of the brain oscillator to overcome low amplitude transcriptional oscillations depends on the action of the neuropeptide PDF and on the pdf-expressing cells having equal or higher amplitude of molecular rhythms than the rest of the circadian neuronal groups in the fly brain. Therefore, our work reveals the importance of high amplitude transcriptional oscillations for cell-autonomous circadian timekeeping. Moreover, we demonstrate that the circadian neuronal network is an essential buffering system that protects against changes in circadian transcription in the brain. PMID:24698952

Weiss, Ron; Bartok, Osnat; Mezan, Shaul; Malka, Yuval; Kadener, Sebastian

2014-04-01

39

Stochastic resonance on a modular neuronal network of small-world subnetworks with a subthreshold pacemaker  

NASA Astrophysics Data System (ADS)

We study the phenomenon of stochastic resonance on a modular neuronal network consisting of several small-world subnetworks with a subthreshold periodic pacemaker. Numerical results show that the correlation between the pacemaker frequency and the dynamical response of the network is resonantly dependent on the intensity of additive spatiotemporal noise. This effect of pacemaker-driven stochastic resonance of the system depends extensively on the local and the global network structure, such as the intra- and inter-coupling strengths, rewiring probability of individual small-world subnetwork, the number of links between different subnetworks, and the number of subnetworks. All these parameters play a key role in determining the ability of the network to enhance the noise-induced outreach of the localized subthreshold pacemaker, and only they bounded to a rather sharp interval of values warrant the emergence of the pronounced stochastic resonance phenomenon. Considering the rather important role of pacemakers in real-life, the presented results could have important implications for many biological processes that rely on an effective pacemaker for their proper functioning.

Yu, Haitao; Wang, Jiang; Liu, Chen; Deng, Bin; Wei, Xile

2011-12-01

40

Contribution of the Circadian Pacemaker and the Sleep Homeostat to Sleep Propensity, Sleep Structure, Electroencephalographic Slow Waves, and Sleep Spindle Activity in Humans  

Microsoft Academic Search

The role of the endogenous circadian pacemaker in the tim- ing of the sleep-wake cycle and the regulation of the in- ternal structure of sleep, including REM sleep, EEG slow- wave (0.7545 Hz) and sleep spindle activity (12.75-15.0 Hz) was investigated. Eight men lived in an environment free of time cues for 33-36 d and were scheduled to a 28

Derk-Jan Dijk; Charles A. Czeisler

1995-01-01

41

Hypoxia-activated Ca2+ currents in pacemaker neurones of rat rostral ventrolateral medulla in vitro.  

PubMed Central

We examined the effects of brief periods of hypoxia or application of cyanide on the discharge and membrane properties of medullary pacemaker neurones in slices of the rostral ventrolateral reticular nucleus (RVL) of the medulla oblongata of rats. Stable intracellular recordings were obtained from seventy-nine neurones within the RVL which exhibited spontaneous rhythmic discharge in the absence of excitatory postsynaptic potentials (EPSPs). The membrane potential cycles of these neurones could be reset with an evoked spike without eliciting EPSPs or inhibitory postsynaptic potentials and hence met criteria of RVL pacemaker neurones. Hypoxia, produced by reducing O2 from 95 to 20% for 40 s or exposure to cyanide (30-300 microM for 40 s), reversibly increased neuronal discharge 1.6-fold (20% O2) or 2.6-fold (300 microM cyanide), respectively, in association with membrane depolarization and a significant fall in membrane resistance. The membrane responses to hypoxia and cyanide were observed in the presence of tetrodotoxin (TTX) at a concentration (10 microM) which eliminated spontaneous spikes or spikes evoked by intracellular depolarization. When recorded at a holding potential of -70 mV by single-electrode voltage clamp, hypoxia or cyanide (300 microM) elicited inward currents of 0.44 +/- 0.06 and 0.58 +/- 0.08 nA, respectively, which are attenuated by reducing the concentration of extracellular Ca2+ ions, and abolished by 2 mM CoCl2 and 100 microM NiCl2, but not affected by 50 microM CdCl2, replacement of 83% extracellular Na+, or adenosine deaminase (2U ml-1). We conclude that hypoxia and cyanide directly excite RVL pacemaker neurones in vitro by a common mechanism: activation of Ca2+ channel conductance. Images Figure 5 PMID:8046626

Sun, M K; Reis, D J

1994-01-01

42

CENTRAL AND PERIPHERAL CIRCADIAN CLOCKS IN MAMMALS  

PubMed Central

The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue and systems levels. A common molecular mechanism underlies the cell autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism. PMID:22483041

Mohawk, Jennifer A.; Green, Carla B.; Takahashi, Joseph S.

2013-01-01

43

PDF neuron firing phase-shifts key circadian activity neurons in Drosophila.  

PubMed

Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY. PMID:24939987

Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

2014-01-01

44

Sequential Nuclear Accumulation of the Clock Proteins Period and Timeless in the Pacemaker Neurons of Drosophila melanogaster  

Microsoft Academic Search

Antisera against the circadian clock proteins Period (PER) and Timeless (TIM) were used to construct a detailed time course of PER and TIM expression and subcellular localization in a subset of the ventrolateral neurons (vLNs) in the Drosophila accessory medulla (AMe). These neurons, which express pigment- dispersing factor, play a central role in the control of behavioral rhythms. The data

Orie T. Shafer; Michael Rosbash; James W. Truman

2002-01-01

45

The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum  

PubMed Central

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone. PMID:18565991

Varga, Viktor; Hangya, Balázs; Kránitz, Kinga; Ludányi, Anikó; Zemankovics, Rita; Katona, István; Shigemoto, Ryuichi; Freund, Tamás F; Borhegyi, Zsolt

2008-01-01

46

Glial cells physiologically modulate clock neurons and circadian behavior in a calcium-dependent manner  

PubMed Central

Summary Background An important goal of contemporary neuroscience research is to define the neural circuits and synaptic interactions that mediate behavior. In both mammals and Drosophila, the neuronal circuitry controlling circadian behavior has been the subject of intensive investigation, but roles for glial cells in the networks controlling rhythmic behavior have only begun to be defined in recent studies. Results Here, we show that conditional, glial-specific genetic manipulations affecting membrane (vesicle) trafficking, the membrane ionic gradient or calcium signaling lead to circadian arrhythmicity in adult behaving Drosophila. Correlated and reversible effects on a clock neuron peptide transmitter (PDF) and behavior demonstrate the capacity for glia-to-neuron signaling in the circadian circuitry. These studies also reveal the importance of a single type of glial cell – the astrocyte – and glial internal calcium stores in the regulation of circadian rhythms. Conclusions This is the first demonstration in any system that adult glial cells can physiologically modulate circadian neuronal circuitry and behavior. A role for astrocytes and glial calcium signaling in the regulation of Drosophila circadian rhythms emphasizes the conservation of cellular and molecular mechanisms that regulate behavior in mammals and insects. PMID:21497088

Ng, Fanny S.; Tangredi, Michelle M.; Jackson, F. Rob

2011-01-01

47

Circadian gating of neuronal functionality: a basis for iterative metaplasticity1  

PubMed Central

Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID:25285070

Iyer, Rajashekar; Wang, Tongfei A.; Gillette, Martha U.

2014-01-01

48

Heterogeneous Expression of the Core Circadian Clock Proteins among Neuronal Cell Types in Mouse Retina  

PubMed Central

Circadian rhythms in metabolism, physiology, and behavior originate from cell-autonomous circadian clocks located in many organs and structures throughout the body and that share a common molecular mechanism based on the clock genes and their protein products. In the mammalian neural retina, despite evidence supporting the presence of several circadian clocks regulating many facets of retinal physiology and function, the exact cellular location and genetic signature of the retinal clock cells remain largely unknown. Here we examined the expression of the core circadian clock proteins CLOCK, BMAL1, NPAS2, PERIOD 1(PER1), PERIOD 2 (PER2), and CRYPTOCHROME2 (CRY2) in identified neurons of the mouse retina during daily and circadian cycles. We found concurrent clock protein expression in most retinal neurons, including cone photoreceptors, dopaminergic amacrine cells, and melanopsin-expressing intrinsically photosensitive ganglion cells. Remarkably, diurnal and circadian rhythms of expression of all clock proteins were observed in the cones whereas only CRY2 expression was found to be rhythmic in the dopaminergic amacrine cells. Only a low level of expression of the clock proteins was detected in the rods at any time of the daily or circadian cycle. Our observations provide evidence that cones and not rods are cell-autonomous circadian clocks and reveal an important disparity in the expression of the core clock components among neuronal cell types. We propose that the overall temporal architecture of the mammalian retina does not result from the synchronous activity of pervasive identical clocks but rather reflects the cellular and regional heterogeneity in clock function within retinal tissue. PMID:23189207

Liu, Xiaoqin; Zhang, Zhijing; Ribelayga, Christophe P.

2012-01-01

49

Role of a novel maintained low-voltage-activated inward current permeable to sodium and calcium in pacemaking of insect neurosecretory neurons  

Microsoft Academic Search

Among ionic currents underlying neuronal pacemaker activity, low-threshold-activated calcium currents contribute to setting the threshold for spike firing. In the insect central nervous system, dorsal unpaired median (DUM) neurons are capable of generating spontaneous electrical activity. It has previously been shown that two distinct (transient and maintained) low-voltage-activated (LVA) calcium currents are responsible for the generation of the pacemaker potential.

Antoine Defaix; Bruno Lapied

2005-01-01

50

Circadian Clocks in Antennal Neurons Are Necessary and Sufficient for Olfaction Rhythms in Drosophila  

Microsoft Academic Search

Background: The Drosophila circadian clock is controlled by interlocked transcriptional feedback loops that operate in many neuronal and nonneuronal tissues. These clocks are roughly divided into a central clock, which resides in the brain and is known to control rhythms in locomotor activity, and peripheral clocks, which comprise all other clock tissues and are thought to control other rhythmic outputs.

Shintaro Tanoue; Parthasarathy Krishnan; Balaji Krishnan; Stuart E Dryer; Paul E Hardin

2004-01-01

51

Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.  

PubMed

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine ? hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder. PMID:25673850

Huang, Jian; Zhong, Zhaomin; Wang, Mingyong; Chen, Xifeng; Tan, Yicheng; Zhang, Shuqing; He, Wei; He, Xiong; Huang, Guodong; Lu, Haiping; Wu, Ping; Che, Yi; Yan, Yi-Lin; Postlethwait, John H; Chen, Wenbiao; Wang, Han

2015-02-11

52

"Caged calcium" in Aplysia pacemaker neurons. Characterization of calcium-activated potassium and nonspecific cation currents  

PubMed Central

We have studied calcium-activated potassium current, IK(Ca), and calcium-activated nonspecific cation current, INS(Ca), in Aplysia bursting pacemaker neurons, using photolysis of a calcium chelator (nitr-5 or nitr-7) to release "caged calcium" intracellularly. A computer model of nitr photolysis, multiple buffer equilibration, and active calcium extrusion was developed to predict volume-average and front-surface calcium concentration transients. Changes in arsenazo III absorbance were used to measure calcium concentration changes caused by nitr photolysis in microcuvettes. Our model predicted the calcium increments caused by successive flashes, and their dependence on calcium loading, nitr concentration, and light intensity. Flashes also triggered the predicted calcium concentration jumps in neurons filled with nitr-arsenazo III mixtures. In physiological experiments, calcium- activated currents were recorded under voltage clamp in response to flashes of different intensity. Both IK(Ca) and INS(Ca) depended linearly without saturation upon calcium concentration jumps of 0.1-20 microM. Peak membrane currents in neurons exposed to repeated flashes first increased and then declined much like the arsenazo III absorbance changes in vitro, which also indicates a first-order calcium activation. Each flash-evoked current rose rapidly to a peak and decayed to half in 3-12 s. Our model mimicked this behavior when it included diffusion of calcium and nitr perpendicular to the surface of the neuron facing the flashlamp. Na/Ca exchange extruding about 1 pmol of calcium per square centimeter per second per micromolar free calcium appeared to speed the decline of calcium-activated membrane currents. Over a range of different membrane potentials, IK(Ca) and INS(Ca) decayed at similar rates, indicating similar calcium stoichiometries independent of voltage. IK(Ca), but not INS(Ca), relaxes exponentially to a different level when the voltage is suddenly changed. We have estimated voltage-dependent rate constants for a one-step first-order reaction scheme of the activation of IK(Ca) by calcium. After a depolarizing pulse, INS(Ca) decays at a rate that is well predicted by a model of diffusion of calcium away from the inner membrane surface after it has entered the cell, with active extrusion by surface pumps and uptake into organelles. IK(Ca) decays somewhat faster than INS(Ca) after a depolarization, because of its voltage-dependent relaxation combined with the decay of submembrane calcium. The interplay of these two currents accounts for the calcium-dependent outward-inward tail current sequence after a depolarization, and the corresponding afterpotentials after a burst PMID:2504882

1989-01-01

53

Fractal-like correlations of the fluctuating inter-spike membrane potential of a Helix aspersa pacemaker neuron.  

PubMed

We analyzed the voltage fluctuations of the membrane potential manifested along the inter-spike segment of a pacemaker neuron. Time series of intracellular inter-spike voltage fluctuations were obtained in the current-clamp configuration from the F1 neuron of 12 Helix aspersa specimens. To assess the dynamic or stochastic nature of the voltage fluctuations these series were analyzed by Detrended Fluctuation Analysis (DFA), providing the scaling exponent ?. The median ? result obtained for the inter-spike segments was 0.971 ([0.963, 0.995] lower and upper quartiles). Our results indicate a critical-like dynamic behavior in the inter-spike membrane potential that, far from being random, shows long-term correlations probably linked to the dynamics of the mechanisms involved in the regulation of the membrane potential, thereby endorsing the occurrence of critical-like phenomena at a single-neuron level. PMID:25189698

Seseña-Rubfiaro, Alberto; Echeverría, Juan Carlos; Godínez-Fernández, Jose Rafael

2014-10-01

54

Molecular Mechanisms of Circadian Regulation During Spaceflight  

NASA Technical Reports Server (NTRS)

The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight.

Zanello, S. B.; Boyle, R.

2012-01-01

55

Lhx1 maintains synchrony among circadian oscillator neurons of the SCN.  

PubMed

The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here, we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jet lag paradigm and their behavior rhythms gradually deteriorate under constant condition. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating expression of genes mediating intercellular communication, Lhx1 imparts synchrony among SCN neurons and ensures consolidated rhythms of activity and rest that is resistant to photic noise. PMID:25035422

Hatori, Megumi; Gill, Shubhroz; Mure, Ludovic S; Goulding, Martyn; O'Leary, Dennis D M; Panda, Satchidananda

2014-01-01

56

The circadian system: plasticity at many levels.  

PubMed

Over the years it has become crystal clear that a variety of processes encode time-of-day information, ranging from gene expression, protein stability, or subcellular localization of key proteins, to the fine tuning of network properties and modulation of input signals, ultimately ensuring that physiology and behavior are properly synchronized to a changing environment. The purpose of this review is to put forward examples (as opposed to generate a comprehensive revision of all the available literature) in which the circadian system displays a remarkable degree of plasticity, from cell autonomous to circuit-based levels. In the literature, the term circadian plasticity has been used to refer to different concepts. The obvious one, more literally, refers to any change that follows a circadian (circa=around, diem=day) pattern, i.e. a daily change of a given parameter. The discovery of daily remodeling of neuronal structures will be referred herein as structural circadian plasticity, and represents an additional and novel phenomenon modified daily. Finally, any plasticity that has to do with a circadian parameter would represent a type of circadian plasticity; as an example, adjustments that allow organisms to adapt their daily behavior to the annual changes in photoperiod is a form of circadian plasticity at a higher organizational level, which is an emergent property of the whole circadian system. Throughout this work we will revisit these types of changes by reviewing recent literature delving around circadian control of clock outputs, from the most immediate ones within pacemaker neurons to the circadian modulation of rest-activity cycles. PMID:23727010

Muraro, N I; Pírez, N; Ceriani, M F

2013-09-01

57

Serotonin-caused phase shift of circadian rhythmicity in a photosensitive neuron.  

PubMed

In the sixth abdominal ganglion (sixth AG) of the crayfish, two photosensitive neurons are located and have been identified as caudal photoreceptors (CPRs). We have expanded our investigation on the role of 5-Hydroxytryptamine (5-HT) as a modulator of the spontaneous and light-induced activity of the CPR. We located, by using immunocytochemistry, neurons in the sixth AG that contain the 5HT1A receptor. The expression of these receptors was examined by binding assays with [3H] 8-hydroxy-2 (di-n-propylamino) tetralin ([3H(8-OH-DPAT). We examined the exogenous action of both 5HT and its agonist 8-OH-DPAT on the phase of circadian rhythms of the spontaneous electrical activity and the photoresponse of the CPR in the isolated sixth AG by conventional extracellular recording methods. Experiments were made on the adult crayfish Procambarus clarkii and Cherax quadricarinatus. Thirteen immunopositive neurons were located, principally near the ventral and dorsal surface of the sixth AG, with the mean diameter of their somata 20+/-3 microm. The specific binding data showed the presence of 5-HT1A receptors with a mean level of 22.4+/-6.6 fmol/mg of wet tissue. Spontaneous and light-induced electrical activity of the CPR showed circadian variations with their activity more intense at night than in the day. Exogenous application of 5-HT or 8-OH-DPAT causes a circadian phase-shift in electrical activity of the CPR. Taken together, these results lead us to believe the 5-HT acts as a modulator of circadian electrical activity of the CPR in the isolated sixth AG of crayfish. Moreover, it suggests that the 5-HT1A receptor participates in this modulation. PMID:17598151

Rodríguez-Sosa, Leonardo; Calderón-Rosete, Gabina; Flores, Gonzalo; Porras, M G

2007-10-01

58

Tetrodotoxin-resistant persistent Na+ current underlying pacemaker potentials of fish gonadotrophin-releasing hormone neurones.  

PubMed Central

1. Gonadotrophin-releasing hormone (GnRH)-immunoreactive terminal nerve (TN) cells show endogenous regular beating discharges, which may be related to their putative neuromodulator functions. The ionic mechanism underlying the pacemaker potential was studied using intracellular and patch-pipette current clamp recordings from a whole brain in vitro preparation of a small fish brain. 2. The pacemaker potentials were resistant to 1.5-3 microM tetrodotoxin (TTX) and were not affected by Ca2+ channel blockers (amiloride, Ni2+, Co2+, Cd2+) or in Ca(2+)-free solution. In contrast, the pacemaker potentials were readily blocked by substituting tetramethylammonium or choline for Na+ in the perfusing solution, and the resting membrane potential became more hyperpolarized than the control level. 3. The present results suggest that the TTX-resistant persistent Na+ current, INa(slow), supplies the persistent depolarizing drive and plays an important role in the generation of pacemaker potentials in TN GnRH cells. PMID:7730975

Oka, Y

1995-01-01

59

Experimental assessment of the network properties of the Drosophila circadian clock.  

PubMed

Circadian rhythms are conserved across kingdoms and coordinate physiology and behavior for appropriate time-keeping. The neuronal populations that govern circadian rhythms are described in many animal models, and the current challenge is to understand how they interact to control overt rhythms, remaining plastic enough to respond and adapt to a changing environment. In Drosophila melanogaster, the circadian network comprises about 150 neurons, and the main synchronizer is the neuropeptide pigment-dispersing factor (PDF), released by the well-characterized central pacemaker neurons, the small ventral lateral neurons (sLNvs). However, the rules and properties governing the communication and coupling between this central pacemaker and downstream clusters are not fully elucidated. Here we genetically manipulate the speed of the molecular clock specifically in the central pacemaker neurons of Drosophila and provide experimental evidence of their restricted ability to synchronize downstream clusters. We also demonstrate that the sLNv-controlled clusters have an asymmetric entrainment range and were able to experimentally assess it. Our data imply that different clusters are subjected to different coupling strengths, and display independent endogenous periods. Finally, the manipulation employed here establishes a suitable paradigm to test other network properties as well as the cell-autonomous mechanisms running in different circadian-relevant clusters. J. Comp. Neurol. 523:982-996, 2015. © 2014 Wiley Periodicals, Inc. PMID:25504089

Beckwith, Esteban J; Ceriani, M Fernanda

2015-04-15

60

The role of Period1 in non-photic resetting of the hamster circadian pacemaker in the suprachiasmatic nucleus  

PubMed Central

Non-photic stimuli, such as diurnal wheel running in rodents, phase shift the circadian clock and suppress the expression of Per1 in the suprachiasmatic nucleus (SCN). The goal of the present study was to directly decrease Per1 expression using antisense (AS) oligodeoxynucleotides to determine if such suppression produced non-photic phase shifts. Injections of Per1-AS suppressed expression of Per1 within the SCN and produced phase shifts similar to those resulting from other non-photic manipulation, with large phase advances to injections during the subjective day. These results indicate that the decrease in expression of Per1 is a cause rather than a consequence of non-photic phase shifts. PMID:15193760

Hamada, Toshiyuki; Antle, Michael C.; Silver, Rae

2012-01-01

61

Oscillatory Mechanisms Underlying the Drosophila Circadian Clock  

NSDL National Science Digital Library

This animation depicts a schematic of the Drosophila circadian clock mechanism in a single, pacemaking lateral brain neuron. Circadian clocks allow organisms to exhibit rhythmic behaviors and processes based on a nearly 24-hour cycle in the absence of any light stimulation. In the fruit fly, the basic molecular mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the "positive loop"--controls the rhythmic expression of a positive transcription factor gene, Clock. The second loop--the "negative loop"--controls the transcription of period and timeless, two genes that encode repressor proteins. The loops are intertwined because Period and Timeless repress transcription mediated by the transcription factors Clock and Cycle, whereas the Clock:Cycle heterodimer drives transcription of period and timeless, as well as that of vrille, a repressor of Clock expression. Light cycles can synchronize the Drosophila circadian pathway by directly stimulating cryptochrome-dependent degradation of Timeless.

Russell N. Van Gelder (Washington University Medical School; Department of Ophthalmology and Visual Sciences, Department of Molecular Biology and Pharmacology REV)

2003-11-18

62

Etiology, pathogenesis, and treatment of seasonal and non-seasonal mood disorders: possible role of circadian rhythm abnormalities related to developmental alcohol exposure  

Microsoft Academic Search

Developmental alcohol exposure adversely influences the developing brain. Alcohol exposure during rapid brain growth causes cell loss, alters connections between brain regions, and lowers the production of biological substances responsible for the communication among neurons. It is reasonable to suggest that alcohol may adversely affect the development of suprachiasmatic nuclei (SCN), the master circadian pacemaker. Multiple research reports suggest that

Leo Sher

2004-01-01

63

Lhx1 maintains synchrony among circadian oscillator neurons of the SCN  

PubMed Central

The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here, we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jet lag paradigm and their behavior rhythms gradually deteriorate under constant condition. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating expression of genes mediating intercellular communication, Lhx1 imparts synchrony among SCN neurons and ensures consolidated rhythms of activity and rest that is resistant to photic noise. DOI: http://dx.doi.org/10.7554/eLife.03357.001 PMID:25035422

Hatori, Megumi; Gill, Shubhroz; Mure, Ludovic S; Goulding, Martyn; O'Leary, Dennis D M; Panda, Satchidananda

2014-01-01

64

Dynamic interactions mediated by non-redundant signaling mechanisms couple circadian clock neurons  

PubMed Central

Summary Interactions among suprachiasmatic nucleus (SCN) neurons are required for robust circadian rhythms entrained to local time. To investigate these coupling mechanisms, we developed a novel functional coupling assay that uniquely captures the dynamic process by which SCN neurons interact. As a population, SCN neurons typically display synchronized rhythms with similar peak times, but will peak 6–12h apart after in vivo exposure to long days. Once removed from these conditions, SCN neurons resynchronize through a phase-dependent coupling process mediated by both vasoactive intestinal polypeptide (VIP) and GABAA signaling. Notably, GABAA signaling contributes to coupling when the SCN network in an anti-phase configuration, but opposes synchrony under steady-state conditions. Further, VIP acts together with GABAA signaling to couple the network in an anti-phase configuration, but promotes synchrony under steady-state conditions by counteracting the actions of GABAA signaling. Thus, SCN neurons interact through non-redundant coupling mechanisms influenced by the state of the network. PMID:24267653

Evans, Jennifer A.; Leise, Tanya L.; Castanon-Cervantes, Oscar; Davidson, Alec J.

2013-01-01

65

Network-mediated encoding of circadian time: the suprachiasmatic nucleus (SCN) from genes to neurons to circuits, and back.  

PubMed

The transcriptional architecture of intracellular circadian clocks is similar across phyla, but in mammals interneuronal mechanisms confer a higher level of circadian integration. The suprachiasmatic nucleus (SCN) is a unique model to study these mechanisms, as it operates as a ?24 h clock not only in the living animal, but also when isolated in culture. This "clock in a dish" can be used to address fundamental questions, such as how intraneuronal mechanisms are translated by SCN neurons into circuit-level emergent properties and how the circuit decodes, and responds to, light input. This review addresses recent developments in understanding the relationship between electrical activity, [Ca(2+)]i, and intracellular clocks. Furthermore, optogenetic and chemogenetic approaches to investigate the distinct roles of neurons and glial cells in circuit encoding of circadian time will be discussed, as well as the epigenetic and circuit-level mechanisms that enable the SCN to translate light input into coherent daily rhythms. PMID:25392488

Brancaccio, Marco; Enoki, Ryosuke; Mazuski, Cristina N; Jones, Jeff; Evans, Jennifer A; Azzi, Abdelhalim

2014-11-12

66

Oscillatory Mechanisms Underlying the Murine Circadian Clock  

NSDL National Science Digital Library

This animation depicts a schematic of the murine circadian clock mechanism in a single, pacemaking neuron in the suprachiasmatic nucleus (SCN) of the hypothalamus, where the master pacemaker is located. Circadian clocks allow organisms to display behaviors and processes with a 24-hour rhythm even in the absence of light input. The basic molecular mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the "positive loop"--controls the rhythmic expression of a positive transcription factor gene, Bmal1 (also called Mop3). The second loop--the "negative loop"--controls the transcription of genes in the Period and Cryptochrome families, which encode repressor proteins. The loops are intertwined because the proteins PERIOD and CRYPTOCHROME directly repress transcription mediated by the transcription factors CLOCK and BMAL1, whereas the CLOCK:BMAL1 heterodimer drives transcription of the Period and Cryptochrome genes, as well as that of Rev-erb-alpha, which represses Bmal1 expression. Other proteins, such as casein kinase I ε (CKIε) play essential modulatory roles in mammalian circadian timekeeping.

Russell N. Van Gelder (Washington University Medical School; Department of Ophthalmology and Visual Sciences, Department of Molecular Biology and Pharmacology REV)

2003-11-18

67

Circadian and ultradian rhythms in the crayfish caudal photoreceptor.  

PubMed

The study of circadian clocks in crustaceans has led to the hypothesis of a distributed circadian system of pacemakers. In this review, we investigate the role of the crayfish caudal photoreceptor (CPR) as a candidate to form part of this pacemaking circadian system. Two circadian rhythms are documented for CPR electrical activity. These rhythms correspond to the spontaneous and light-induced discharge of action potentials. The intrinsic characterization of the rhythms is made through the analysis of the firing rate of the corresponding action potentials. The discharges were extracellularly recorded in the isolated 6th abdominal ganglion (AG) in an organ culture kept at constant temperature for up to 5 days. For preparations kept in the dark, spontaneous activity varies in a circadian manner, with a period of 24.7 h and the acrophase at subjective nighttime (2140). For light-induced activity, pulses of constant intensity applied regularly throughout the 24-h cycle show that the firing rate at peak and latency vary rhythmically. The period for this rhythm is 24.24 h and the acrophase is at subjective dawn (0326). Additionally, an ultradian rhythm of a approximately 12-h period was observed for both rhythms. When tested with light pulses of different intensities, the CPR responsiveness at night is almost one log unit greater than in daytime. The effect of temperature on both activities is also described. The phase-shift caused by temperature for these circadian rhythms depends on the application time. These results show that the 6th AG is capable of generating a circadian rhythm of electrical activity in the CPR, which in turn is likely to be part of the crayfish circadian system. A possible interaction of different pacemakers forming the distributed circadian system is also discussed. The role of serotonin as a possible modulator of the CPR electrical activity is documented. In addition, the level of the 5-HT(1A) receptors displays a diurnal rhythm in the 6th AG, with the acrophase at twilight (1849). We suggest that the 5-HT(1A) receptor does participate in this modulation. Finally, the hypothesis of the expression of two circadian oscillators in a single identified neuron is presented. PMID:18563837

Rodríguez-Sosa, Leonardo; Calderón-Rosete, Gabina; Flores, Gonzalo

2008-09-01

68

Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus  

PubMed Central

Sleep and feeding rhythms are highly coordinated across the circadian cycle, but the brain sites responsible for this coordination are unknown. We examined the role of neuropeptide Y (NPY) receptor-expressing neurons in the mediobasal hypothalamus (MBH) in this process by injecting the targeted toxin, NPY-saporin (NPY-SAP), into the arcuate nucleus (Arc). NPY-SAP-lesioned rats were initially hyperphagic, became obese, exhibited sustained disruption of circadian feeding patterns, and had abnormal circadian distribution of sleep-wake patterns. Total amounts of rapid eye movement sleep (REMS) and non-REMS (NREMS) were not altered by NPY-SAP lesions, but a peak amount of REMS was permanently displaced to the dark period, and circadian variation in NREMS was eliminated. The phase reversal of REMS to the dark period by the lesion suggests that REMS timing is independently linked to the function of MBH NPY receptor-expressing neurons and is not dependent on NREMS pattern, which was altered but not phase reversed by the lesion. Sleep-wake patterns were altered in controls by restricting feeding to the light period, but were not altered in NPY-SAP rats by restricting feeding to either the light or dark period, indicating that disturbed sleep-wake patterns in lesioned rats were not secondary to changes in food intake. Sleep abnormalities persisted even after hyperphagia abated during the static phase of the lesion. Results suggest that the MBH is required for the essential task of integrating sleep-wake and feeding rhythms, a function that allows animals to accommodate changeable patterns of food availability. NPY receptor-expressing neurons are key components of this integrative function. PMID:21880863

Mukherjee, S.; Li, A.-J.; Dinh, T. T.; Rooney, E. M.; Simasko, S. M.; Ritter, S.

2011-01-01

69

[Cognitive Function and Calcium. Ca(2 +) -dependent regulatory mechanism of circadian clock oscillation and its relevance to neuronal function].  

PubMed

Circadian clock generates a variety of biological rhythms such as sleep/wake cycles and blood hormone rhythms. The circadian clock also bolsters daily mental activities. In fact, abnormalities of the circadian rhythms are found in several neurological disorders. The circadian clock has two important functions : (i) a cell-autonomous oscillatory function and (ii) a phase-adjusting function that synchronizes the clock oscillation with environmental cycling conditions such as light/dark cycle. Behavioral rhythms are controlled by the central clock in hypothalamic suprachiasmatic nucleus (SCN) . The central clock orchestrates peripheral clocks in the other tissues via neuronal connection and/or actions of humoral factors. The molecular mechanism of the cell-autonomous clock is based on transcriptional feedback regulation of clock genes by their encoded products. Ca(2 +) is essential for not only the light response of the clock but also the cell autonomous oscillation mechanism. This article provides an overview of recent progress in studies of Ca(2 +) -dependent regulatory mechanism of the molecular clockwork. PMID:25634045

Kon, Naohiro; Fukada, Yoshitaka

2015-01-01

70

The Tau Mutation of Casein Kinase 1? Sets the Period of the Mammalian Pacemaker via Regulation of Period1 or Period2 Clock Proteins  

PubMed Central

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker in mammals, coordinating daily metabolic and physiological rhythms with the cycle of sleep and wakefulness. SCN neurons define circadian time via an auto-regulatory feedback loop in which the activation of Period (Per) and Cryptochrome genes is periodically suppressed by their own protein products. Casein kinase 1 (CK1) enzymes have a critical role in circadian pacemaking because they phosphorylate PER proteins and thereby direct their proteasomal degradation. In human pedigrees, individual mutations in either hCK1 or hPER2 lead to advanced sleep phase disorders, whereas in rodents, the Tau mutation of CK1 epsilon (CK1?Tau) accelerates rest-activity cycles and shortens the period of the SCN molecular pacemaker. Biochemical analyses of recombinant PER proteins in cultured cells and endogenous proteins in peripheral tissues have identified PER1 and PER2, but not PER3, as direct substrates of CK1?. The purpose of this study, therefore, was to determine the relative contributions of endogenous PER proteins to the period-accelerating effects of CK1?Tau, both in vivo and in vitro. CK1?Tau mice were mated onto Per1-, Per2-, and Per1-Per2 (Per1/2) double-null backgrounds, in all cases carrying the Per1-luciferase bioluminescent circadian reporter gene. Mice lacking both PER1 and PER2 were behaviorally arrhythmic, confirming the inadequacy of PER3 as a circadian factor. Individual loss of either PER1 or PER2 had no significant effect on the circadian period or quality of wheel-running behavior, and CK1?Tau accelerated behavioral rhythms in both Per1- and Per2-null mice. CK1?Tau also accelerated in vitro molecular pacemaking in SCN lacking either PER1 or PER2, with a greater effect in PER2-dependent (i.e., Per1-null) SCN than in PER1-dependent slices. In double-null slices, some SCN were arrhythmic, whereas others exhibited transient rhythms, which trended nonsignificantly toward a shorter period. Both short-period and long-period rhythms could be identified in individual SCN neurons imaged by charge-coupled device camera. CK1?Tau had no effect, however, on SCN-level or individual neuronal rhythms in the absence of PER1 and PER2. Thus, the CK1?Tau allele has divergent actions, acting via both endogenous PER1 and PER2, but not PER3 protein, to mediate its circadian actions in vivo. Moreover, PER-independent cellular oscillations may contribute to pacemaking, but they are unstable and imprecise, and are not affected by the Tau mutation. PMID:24682205

Maywood, E.S.; Chesham, J.E.; Smyllie, N.J.; Hastings, M.H.

2014-01-01

71

Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice.  

PubMed

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output. PMID:25217530

Gallardo, Christian M; Darvas, Martin; Oviatt, Mia; Chang, Chris H; Michalik, Mateusz; Huddy, Timothy F; Meyer, Emily E; Shuster, Scott A; Aguayo, Antonio; Hill, Elizabeth M; Kiani, Karun; Ikpeazu, Jonathan; Martinez, Johan S; Purpura, Mari; Smit, Andrea N; Patton, Danica F; Mistlberger, Ralph E; Palmiter, Richard D; Steele, Andrew D

2014-01-01

72

Heart pacemaker  

MedlinePLUS

... ounce. A pacemaker usually has 2 parts: The generator contains the battery and the information to control ... are wires that connect the heart to the generator and carry the electrical messages to the heart. ...

73

Programmable Pacemaker  

NASA Technical Reports Server (NTRS)

Released in 1995, the Trilogy cardiac pacemaker is the fourth generation of a unit developed in the 1970s by NASA, Johns Hopkins Applied Physics Laboratory and St. Jude Medical's Cardiac Rhythm Management Division (formerly known as Pacesetter Systems, Inc.). The new system incorporates the company's PDx diagnostic and programming software and a powerful microprocessor that allows more functions to be fully automatic and gives more detailed information on the patient's health and the performance of the pacing systems. The pacemaker incorporates bidirectional telemetry used for space communications for noninvasive communication with the implanted pacemaker, smaller implantable pulse generators from space microminiaturization, and longer-life batteries from technology for spacecraft electrical power systems.

1996-01-01

74

MAMMALIAN CIRCADIAN BIOLOGY: ELUCIDATING GENOME-WIDE LEVELS OF TEMPORAL ORGANIZATION  

PubMed Central

During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle. PMID:15485355

Lowrey, Phillip L.; Takahashi, Joseph S.

2013-01-01

75

Neuronal components of the circadian clock in the scorpion, Androctonus australis: Central origin of the efferent neurosecretory elements projecting to the median eyes  

Microsoft Academic Search

The central origin of efferent neurosecretory fibers (ENSF) supplying the median eyes of the scorpion, Androctonus australis, with circadian information was investigated at the light- and electron-microscopic levels by the use of several tracer techniques. The results obtained convincingly show that the central neurons stained via the optic nerve are the source of the ENSF in the retina. Almost all

S. Heinrichs; G. Fleissner

1987-01-01

76

Circadian Rhythms and Cancer Chronotherapeutics  

Microsoft Academic Search

\\u000a The Circadian Timing System (CTS) controls cellular proliferation and drug metabolism over a 24-h period through molecular\\u000a clocks in each cell. These cellular clocks are coordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei, which\\u000a generate or control circadian physiology. The CTS down-regulates malignant growth in experimental models and in cancer patients.\\u000a It also generates large and predictable 24-h changes in

Francis Lévi; Atilla Altinok; Albert Goldbeter

77

Aging Decreases L-Type Calcium Channel Currents and Pacemaker Firing Fidelity in Substantia Nigra Dopamine Neurons  

PubMed Central

Substantia nigra dopamine neurons are involved in behavioral processes that include cognition, reward learning, and voluntary movement. Selective deterioration of these neurons is responsible for the motor deficits associated with Parkinson's disease (PD). Aging is the leading risk factor for PD, suggesting that adaptations occurring in dopamine neurons during normal aging may predispose individuals to the development of PD. Previous studies suggest that the unique set of ion conductances that drive spontaneous, rhythmic firing of action potentials could predispose substantia nigra dopamine neurons to selective neurodegeneration. Here we show, using patch-clamp electrophysiological recordings in brain slices, that substantia nigra dopamine neurons from mice 25–30 months of age (old) have comparable membrane capacitance and input resistance to neurons from mice 2–7 months of age (young). However, neurons from old mice exhibit slower firing rates, narrower spike widths, and more variable interspike intervals compared with neurons from young mice. Dopamine neurons from old mice also exhibit smaller L-type calcium channel currents, providing a plausible mechanism that likely contributes to the changes in impulse activity. Age-related decrements in the physiological function of dopamine neurons could contribute to the decrease in voluntary movement and other dopamine-mediated behaviors observed in aging populations. Furthermore, as pharmacological antagonism of L-type calcium channels has been proposed as a potential treatment for the early stages of PD, our results could point to a limited temporal window of opportunity for this therapeutic intervention. PMID:25009264

Branch, Sarah Y.; Sharma, Ramaswamy

2014-01-01

78

A Cyanobacterial Circadian Clockwork  

PubMed Central

Cyanobacteria have become a major model system for analyzing clock phenomena. The temporal program in this organism enhances fitness in rhythmic environments and is truly global—essentially all genes are regulated by the circadian system. The topology of the chromosome also oscillates and possibly regulates the rhythm of gene expression. The underlying circadian mechanism appears to consist of both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) and ATP. These three core oscillator proteins have been crystallized and structurally determined, the only full-length circadian proteins to be so characterized. The timing of cell division is gated by a circadian checkpoint, but the circadian pacemaker is not influenced by the status of the cell division cycle. This imperturbability may be due to the presence of the PTO that persists under conditions in which metabolism is repressed. Recent biochemical, biophysical, and structural discoveries bring the cyanobacterial circadian system to the brink of explaining heretofore unexplainable biochemical characteristics of a circadian oscillator: the long time constant, precision, and temperature compensation. PMID:18786387

Johnson, Carl Hirschie; Mori, Tetsuya; Xu, Yao

2008-01-01

79

Interactions between bilaterally paired components of the cockroach circadian system  

Microsoft Academic Search

The hypothesis that bilaterally redundant, and mutually coupled circadian pacemakers are located near the lobula of the optic lobes of the cockroach,Leucophaea maderae, was investigated in a series of lesion experiments.

Terry L. Page

1978-01-01

80

Suprachiasmatic nuclei and Circadian rhythms. The role of suprachiasmatic nuclei on rhythmic activity of neurons in the lateral hypothalamic area, ventromedian nuclei and pineal gland  

NASA Technical Reports Server (NTRS)

Unit activity of lateral hypothalamic area (LHA) and Ventromedian nuclei (VMN) was recorded in urethane anesthetized male rats. A 5 to 10 sec. a 3-5 min and a circadian rhythmicity were observed. In about 15% of all neurons, spontaneous activity of LHA and VMN showed reciprocal relationships. Subthreshold stimuli applied at a slow rate in the septum and the suprachiasmatic nuclei (SCN) suppressed the rhythms without changing firing rates. On the other hand, stimulation of the optic nerve at a rate of 5 to 10/sec increased firing rates in 1/3 of neurons of SCN. Iontophoretically applied acetylcholine increased 80% of tested neurons of SCN, whereas norepinephrine, dopamine and 5 HT inhibited 64, 60 and 75% of SCN neurons respectively. These inhibitions were much stronger in neurons, the activity of which was increased by optic nerve stimulation. Stimulation of the SCN inhibited the tonic activity in cervical sympathetic nerves.

Nishino, H.

1977-01-01

81

A Plastic Clock: How Circadian Rhythms Respond to Environmental Cues in Drosophila  

Microsoft Academic Search

Circadian clocks synchronize the physiology and behavior of most animals with the day to night cycle. A fundamental property\\u000a of the molecular pacemakers generating circadian rhythms is their self-sustained nature: they keep oscillating even under\\u000a constant conditions, with a period close to, but not exactly, 24 h. However, circadian pacemakers have to be sensitive to\\u000a environmental cues to be beneficial. They

Raphaelle Dubruille; Patrick Emery

2008-01-01

82

The mammalian circadian timing system: organization and coordination of central and peripheral clocks.  

PubMed

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system. PMID:20148687

Dibner, Charna; Schibler, Ueli; Albrecht, Urs

2010-01-01

83

Daily Novel Wheel Running Reorganizes and Splits Hamster Circadian Activity Rhythms  

Microsoft Academic Search

The phenomenon of splitting of locomotor activity rhythms in constant light has implied that the mammalian circadian pacemaker is composed of multiple interacting circadian oscillators. Exposure of male Syrian hamsters to novel running wheels also induces splitting in some reports, although novel wheel running (NWR) is better known for its effects on altering circadian phase and the length of the

Michael R. Gorman; Theresa M. Lee

2001-01-01

84

[Circadian rhythm sleep disorder].  

PubMed

Primary pathophysiology of circadian rhythm sleep disorders(CRSDs) is a misalignment between the endogenous circadian rhythm phase and the desired or socially required sleep-wake schedule, or dysfunction of the circadian pacemaker and its afferent/efferent pathways. CRSDs consist of delayed sleep phase type, advanced sleep phase type, free-running type, irregular sleep-wake type, shift work type and jet lag type. Chronotherapy using strong zeitgebers (time cues), such as bright light and melatonin/ melatonin type 2 receptor agonist, is effective when administered with proper timing. Bright light is the strongest entraining agent of circadian rhythms. Bright light therapy (appropriately-timed exposure to bright light) for CRSDs is an effective treatment option, and can shift the sleep-wake cycle to earlier or later times, in order to correct for misalignment between the circadian system and the desired sleep-wake schedule. Timed administration of melatonin, either alone or in combination with light therapy has also been shown to be useful in the treatment of CRSDs. PMID:24437262

Mishima, Kazuo

2013-12-01

85

CIRCADIAN RHYTHMS Circadian Photoreception  

NSDL National Science Digital Library

The circadian rhythms of physiology and behavior are driven by autonomous cellular clocks. To be useful, these clocks must be synchronized to the day-night cycles of the real world. This article provides a review of research on circadian photoreceptors in mammals.

Michael Menaker (University of Virginia;Department of Biology)

2003-01-10

86

Glucocorticoids as entraining signals for peripheral circadian oscillators.  

PubMed

Mammalian circadian organization is governed by pacemaker neurons in the brain that communicate with oscillators in peripheral tissues. Adrenal glucocorticoids are important time-giving signals to peripheral circadian oscillators. We investigated the rhythm of Per1-luc expression in pineal, pituitary, salivary glands, liver, lung, kidney, cornea as well as suprachiasmatic nucleus from adrenalectomized and sham-operated rats kept under light-dark cycles, or exposed to single 6-h phase delays or advances of their light cycles. Adrenalectomy shifted the phases of Per1-luc in liver, kidney, and cornea and caused phase desynchrony and significant dampening in the rhythmicity of cornea. Treatment with hydrocortisone shifted the phases of Per1-luc in most of the tissues examined, even those that were not affected by adrenalectomy. The rhythm in cornea recovered in animals given hydrocortisone in vivo or when corneas were treated with dexamethasone in vitro. Adrenalectomy increased the rate of reentrainment after phase shifts in liver, kidney, cornea, pineal, lung, and suprachiasmatic nucleus but not in pituitary and salivary glands. Our data show that glucocorticoids act as strong entraining signals for peripheral circadian oscillators and may feed back on central oscillators as well. PMID:22893723

Pezük, Pinar; Mohawk, Jennifer A; Wang, Laura A; Menaker, Michael

2012-10-01

87

DISRUPTION OF CIRCADIAN RHYTHMICITY AND SUPRACHIASMATIC ACTION POTENTIAL FREQUENCY IN A MOUSE MODEL WITH CONSTITUTIVE ACTIVATION OF GLYCOGEN SYNTHASE KINASE-3  

PubMed Central

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in psychiatric diseases, neurodevelopment, and circadian regulation. Both GSK3 isoforms, ? and ?, exhibit a 24-hour variation of inhibitory phosphorylation within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker. We examined the hypothesis that rhythmic GSK3 activity is critical for robust circadian rhythmicity using GSK3?21A/21A/?9A/9A knock-in mice with serine-alanine substitutions at the inhibitory phosphorylation sites, making both forms constitutively active. We monitored wheel-running locomotor activity of GSK3 knock-in mice and used loose-patch electrophysiology to examine the effect of chronic GSK3 activity on circadian behavior and SCN neuronal activity. Double transgenic GSK3?/? knock-in mice exhibit disrupted behavioral rhythmicity, including significantly decreased rhythmic amplitude, lengthened active period, and increased activity bouts per day. This behavioral disruption was dependent on chronic activation of both GSK3 isoforms and was not seen in single transgenic GSK3? or GSK3? knock-in mice. Underlying the behavioral changes, SCN neurons from double transgenic GSK3?/? knock-in mice exhibited significantly higher spike rates during the subjective night compared to those from WT controls, with no differences detected during the subjective day. These results suggest that constitutive activation of GSK3 results in loss of the typical day/night variation of SCN neuronal activity. Together, these results implicate GSK3 activity as a critical regulator of circadian behavior and neurophysiological rhythms. Because GSK3 has been implicated in numerous pathologies, understanding how GSK3 modulates circadian rhythms and neurophysiological activity may lead to novel therapeutics for pathological disorders and circadian rhythm dysfunction. PMID:22986169

Paul, Jodi R.; Johnson, Russell L.; Jope, Richard S.; Gamble, Karen L.

2012-01-01

88

Mammalian circadian signaling networks and therapeutic targets  

Microsoft Academic Search

Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is

Andrew C Liu; Warren G Lewis; Steve A Kay

2007-01-01

89

Circadian Rhythms  

MedlinePLUS

... are found in most living things, including animals, plants and many tiny microbes. The study of circadian rhythms is called chronobiology. Are circadian rhythms the same thing as biological clocks? No, but they are related. Our biological clocks ...

90

Effects of altitude on circadian rhythm of adult locomotor activity in Himalayan strains of Drosophila helvetica  

Microsoft Academic Search

BACKGROUND: We recently reported that the altitude of origin altered the photic and thermal sensitivity of the circadian pacemaker controlling eclosion and oviposition rhythms of high altitude Himalayan strains of Drosophila ananassae. The present study was aimed at investigating the effects of altitude of origin on the pacemaker controlling the adult locomotor activity rhythm of D. helvetica. METHODS: Locomotor activity

Keny Vanlalhriatpuia; Vanlalnghaka Chhakchhuak; Satralkar K Moses; SB Iyyer; Kasture; AJ Shivagaje; Barnabas J Rajneesh; Dilip S Joshi

2007-01-01

91

Getting through to circadian oscillators: why use constant routines?  

NASA Technical Reports Server (NTRS)

Overt 24-h rhythmicity is composed of both exogenous and endogenous components, reflecting the product of multiple (periodic) feedback loops with a core pacemaker at their center. Researchers attempting to reveal the endogenous circadian (near 24-h) component of rhythms commonly conduct their experiments under constant environmental conditions. However, even under constant environmental conditions, rhythmic changes in behavior, such as food intake or the sleep-wake cycle, can contribute to observed rhythmicity in many physiological and endocrine variables. Assessment of characteristics of the core circadian pacemaker and its direct contribution to rhythmicity in different variables, including rhythmicity in gene expression, may be more reliable when such periodic behaviors are eliminated or kept constant across all circadian phases. This is relevant for the assessment of the status of the circadian pacemaker in situations in which the sleep-wake cycle or food intake regimes are altered because of external conditions, such as in shift work or jet lag. It is also relevant for situations in which differences in overt rhythmicity could be due to changes in either sleep oscillatory processes or circadian rhythmicity, such as advanced or delayed sleep phase syndromes, in aging, or in particular clinical conditions. Researchers studying human circadian rhythms have developed constant routine protocols to assess the status of the circadian pacemaker in constant behavioral and environmental conditions, whereas this technique is often thought to be unnecessary in the study of animal rhythms. In this short review, the authors summarize constant routine methodology and what has been learned from constant routines and argue that animal and human circadian rhythm researchers should (continue to) use constant routines as a step on the road to getting through to central and peripheral circadian oscillators in the intact organism.

Duffy, Jeanne F.; Dijk, Derk-Jan

2002-01-01

92

Isolating Neural Correlates of the Pacemaker for Food Anticipation  

PubMed Central

Mice fed a single daily meal at intervals within the circadian range exhibit food anticipatory activity. Previous investigations strongly suggest that this behaviour is regulated by a circadian pacemaker entrained to the timing of fasting/refeeding. The neural correlate(s) of this pacemaker, the food entrainable oscillator (FEO), whether found in a neural network or a single locus, remain unknown. This study used a canonical property of circadian pacemakers, the ability to continue oscillating after removal of the entraining stimulus, to isolate activation within the neural correlates of food entrainable oscillator from all other mechanisms driving food anticipatory activity. It was hypothesized that continued anticipatory activation of central nuclei, after restricted feeding and a return to ad libitum feeding, would elucidate a neural representation of the signaling circuits responsible for the timekeeping component of the food entrainable oscillator. Animals were entrained to a temporally constrained meal then placed back on ad libitum feeding for several days until food anticipatory activity was abolished. Activation of nuclei throughout the brain was quantified using stereological analysis of c-FOS expressing cells and compared against both ad libitum fed and food entrained controls. Several hypothalamic and brainstem nuclei remained activated at the previous time of food anticipation, implicating them in the timekeeping mechanism necessary to track previous meal presentation. This study also provides a proof of concept for an experimental paradigm useful to further investigate the anatomical and molecular substrates of the FEO. PMID:22558352

Blum, Ian David; Waddington Lamont, Elaine; Rodrigues, Trevor; Abizaid, Alfonso

2012-01-01

93

The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks  

Microsoft Academic Search

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeep- ing system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic

Charna Dibner; Ueli Schibler; Urs Albrecht

2010-01-01

94

Neonatal monosodium glutamate treatment prevents effects of constant light on circadian temperature rhythms of adult rats  

Microsoft Academic Search

Housing rats under continuous illumination (LL) disrupts circadian rhythms controlled by a pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The neural mechanisms underlying this effect are not well understood. The present study examined the effects of LL on circadian rhythms and on light-induced expression of Fos protein in the SCN, intergeniculate leaflet (IGL), and ventrolateral geniculate nucleus (vLGN) in

K. Edelstein; J. G. Pfaus; B. Rusak; S. Amir

1995-01-01

95

Engineered Biological Pacemakers  

Cancer.gov

The National Institute on Aging's Cellular Biophysics Section is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize biological pacemakers.

96

Heart pacemaker - discharge  

MedlinePLUS

... pacemaker is placed under your skin. These include: Battery powered cordless tools (such as screwdrivers and drills) Plug-in power tools (such as drills and table saws) Electric lawn mowers and leaf blowers Slot machines Stereo ...

97

Effects of circadian disruption on cardiometabolic system  

PubMed Central

The presence of day-night variations in cardiovascular and metabolic functioning is well known. However, only recently it has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep/wake cycle but are partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac autonomic activity, glucose metabolism and leptin —involved in appetite control—all show circadian variation (i.e., under constant behavioral and environmental conditions). This knowledge of behavioral vs. circadian modulation of cardiometabolic function is of clinical relevance given the morning peak in adverse cardiovascular incidents observed in epidemiological studies and given the increased risk for the development of diabetes, obesity, and cardiovascular disease in shift workers. We will review the evidence for circadian control of cardiometabolic functioning, as well its sensitivity to light and melatonin, and discuss potential implication for therapy. PMID:19784781

Rüger, Melanie; Scheer, Frank A.J.L.

2011-01-01

98

Cannabinoids and hamster circadian activity rhythms.  

PubMed

Circadian activity rhythms in hamsters are entrained to the daily light:dark cycle by photic information arriving from the retina to the suprachiasmatic nucleus, the site of the master circadian pacemaker in mammals. The effects of light on adjusting the timing of the circadian pacemaker is modified, both positively and negatively, by a variety of transmitter systems, but the effects of endocannabinoids have not been reported. Therefore, in this study we evaluated cannabinoids specific for the cannabinoid type 1 receptor (CB(1)) for their ability to modulate light-induced phase advances in hamster circadian activity rhythms. All compounds were administered intraperitoneally. The CB(1) agonist CP55940 potently inhibited light-induced phase shifts with near 90% inhibition achieved with a dose of 0.125 mg/kg. The inhibitory effect of CP55940 was partially reversed by the CB(1) antagonist LY320135 and completely reversed with 1 mg/kg of the CB(1) antagonist AM 251. Neither LY320135 nor AM 251 had any effect on light-induced phase shifts when administered alone. Further evidence for CB(1) involvement in hamster circadian rhythms was provided by immunohistochemical detection of CB(1) receptors in four separate nuclei comprising the principal components of the hamster circadian system: the suprachiasmatic nucleus, intergeniculate leaflet of the thalamus, and dorsal and median raphe nuclei. Altogether these data indicate that the endocannabinoid system has the capability to modulate circadian rhythms in the hamster and cannabis use should be evaluated for adverse effects on circadian rhythms in humans. PMID:18582849

Sanford, Anna E; Castillo, Elizabeth; Gannon, Robert L

2008-07-30

99

Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators  

PubMed Central

The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles. PMID:22379191

Saini, Camille; Morf, Jörg; Stratmann, Markus; Gos, Pascal; Schibler, Ueli

2012-01-01

100

Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction  

PubMed Central

Previously, we investigated the role of neuropeptide Y and leptin-sensitive networks in the mediobasal hypothalamus in sleep and feeding and found profound homeostatic and circadian deficits with an intact suprachiasmatic nucleus. We propose that the arcuate nuclei (Arc) are required for the integration of homeostatic circadian systems, including temperature and activity. We tested this hypothesis using saporin toxin conjugated to leptin (Lep-SAP) injected into Arc in rats. Lep-SAP rats became obese and hyperphagic and progressed through a dynamic phase to a static phase of growth. Circadian rhythms were examined over 49 days during the static phase. Rats were maintained on a 12:12-h light-dark (LD) schedule for 13 days and, thereafter, maintained in continuous dark (DD). After the first 13 days of DD, food was restricted to 4 h/day for 10 days. We found that the activity of Lep-SAP rats was arrhythmic in DD, but that food anticipatory activity was, nevertheless, entrainable to the restricted feeding schedule, and the entrained rhythm persisted during the subsequent 3-day fast in DD. Thus, for activity, the circuitry for the light-entrainable oscillator, but not for the food-entrainable oscillator, was disabled by the Arc lesion. In contrast, temperature remained rhythmic in DD in the Lep-SAP rats and did not entrain to restricted feeding. We conclude that the leptin-sensitive network that includes the Arc is required for entrainment of activity by photic cues and entrainment of temperature by food, but is not required for entrainment of activity by food or temperature by photic cues. PMID:23986359

Li, Ai-Jun; Dinh, Thu T.; Jansen, Heiko T.; Ritter, Sue

2013-01-01

101

Integration of human sleep-wake regulation and circadian rhythmicity  

NASA Technical Reports Server (NTRS)

The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.

Dijk, Derk-Jan; Lockley, Steven W.

2002-01-01

102

The Circadian Clock Starts Ticking at a Developmentally Early Stage  

Microsoft Academic Search

Although overt diurnal rhythms of behavior do not begin until well after birth, molecular studies suggest that the circadian clock may begin much earlier at a cellular level: mouse embryonic fibroblasts, for example, already possess robust clocks. By multiple criteria, we found no circadian clock present in mouse embryonic stem cells. Nevertheless, upon their differentiation into neurons, circadian gene expression

Elzbieta Kowalska; Ermanno Moriggi; Christoph Bauer; Charna Dibner; Steven A. Brown

2010-01-01

103

Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators  

PubMed Central

The circadian timing system in mammals is composed of a master pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and slave clocks in most peripheral cell types. The phase of peripheral clocks can be completely uncoupled from the SCN pacemaker by restricted feeding. Thus, feeding time, while not affecting the phase of the SCN pacemaker, is a dominant Zeitgeber for peripheral circadian oscillators. Here we show that the phase resetting in peripheral clocks of nocturnal mice is slow when feeding time is changed from night to day and rapid when switched back from day to night. Unexpectedly, the inertia in daytime feeding-induced phase resetting of circadian gene expression in liver and kidney is not an intrinsic property of peripheral oscillators, but is caused by glucocorticoid signaling. Thus, glucocorticoid hormones inhibit the uncoupling of peripheral and central circadian oscillators by altered feeding time. PMID:11742989

Le Minh, Nguyet; Damiola, Francesca; Tronche, François; Schütz, Günther; Schibler, Ueli

2001-01-01

104

[Molecular mechanisms of circadian clock functioning].  

PubMed

Most physiological processes of all organisms are rhythmic with a period of about 24 h and are generated by an endogenous biological CLOCK present in all cells. However, there is also a central CLOCK--the primary circadian pacemaker which is localized in the suprachiasmatic nuclei of the mammalian hypothalamus. Factors of groups Period (PER1, PER2 and PER3), BMAL (BMAL1 and BMAL2), CRYptochromes (CRY1 and CRY2) as well as some other factors are the components of this circadian CLOCK system. Some of these genes contain E-box sequences and their expression is regulated by a transcription factor complex CLOCK-BMAL1. The enzymes responsible for the post-translational modification of circadian gene products are also the components of circadian CLOCK system. These enzymes define CLOCK's work and determine the duration of circadian biorhythm and functional state of the whole organism. The most important of these enzymes are casein kinase-1epsilon and -1delta. We have analysed data about the interconnection between the circadian CLOCK system, cell cycle, and cancerogenesis as well as about the sensitivity of circadian gene expression to the action of toxic agents and nanomaterials. PMID:21888051

Karbovsky?, L L; Minchenko, D O; Garmash, Ia A; Minchenko, O G

2011-01-01

105

The circadian clock starts ticking at a developmentally early stage.  

PubMed

Although overt diurnal rhythms of behavior do not begin until well after birth, molecular studies suggest that the circadian clock may begin much earlier at a cellular level: mouse embryonic fibroblasts, for example, already possess robust clocks. By multiple criteria, we found no circadian clock present in mouse embryonic stem cells. Nevertheless, upon their differentiation into neurons, circadian gene expression was observed. In the first steps along the pathway from ES cells to neurons, a neural precursor cell (NPC) line already showed robust circadian oscillations. Therefore, at a cellular level, the circadian clock likely begins at the very earliest stages of mammalian development. PMID:21135160

Kowalska, Elzbieta; Moriggi, Ermanno; Bauer, Christoph; Dibner, Charna; Brown, Steven A

2010-12-01

106

Glucocorticoids and the circadian clock.  

PubMed

Glucocorticoids, hormones produced by the adrenal gland cortex, perform numerous functions in body homeostasis and the response of the organism to external stressors. One striking feature of their regulation is a diurnal release pattern, with peak levels linked to the start of the activity phase. This release is under control of the circadian clock, an endogenous biological timekeeper that acts to prepare the organism for daily changes in its environment. Circadian control of glucocorticoid production and secretion involves a central pacemaker in the hypothalamus, the suprachiasmatic nucleus, as well as a circadian clock in the adrenal gland itself. Central circadian regulation is mediated via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, while the adrenal gland clock appears to control sensitivity of the gland to the adrenocorticopic hormone (ACTH). The rhythmically released glucocorticoids in turn might contribute to synchronisation of the cell-autonomous clocks in the body and interact with them to time physiological dynamics in their target tissues around the day. PMID:18971218

Dickmeis, Thomas

2009-01-01

107

Long-term Effects of Early Cocaine Exposure on the Light Responsiveness of the Adult Circadian Timing System 1 1 Reviewed through the Developmental Neurotoxicology section, Charles F. Mactutus, Ph.D., Guest Editor  

Microsoft Academic Search

Early cocaine exposure is associated with a wide variety of neurobehavioral and teratogenic effects. The current study was conducted to determine the long-term effects of such exposure on the hamster circadian timing system. The circadian system drives rhythms in a tremendous diversity of physiological, behavioral, and endocrine functions. The fetal circadian pacemaker has recently been shown to express a functional

Wendy N. Strother; Charles V. Vorhees; Michael N. Lehman

1998-01-01

108

A role for the circadian genes in drug addiction.  

PubMed

Diurnal and circadian rhythms are prominent in nearly all bodily functions. Chronic disruptions in normal sleep wake and social schedules can lead to serious health problems such as those seen in shift worker's syndrome. Moreover, genetic disruptions in normal circadian gene functions have recently been linked to a variety of psychiatric conditions including depression, bipolar disorder, seasonal affective disorder and alcoholism. Recent studies are beginning to determine how these circadian genes and rhythms are involved in the development of drug addiction. Several of these studies suggest an important role for these genes in limbic regions of the brain, outside of the central circadian pacemaker in the suprachiasmatic nucleus (SCN). This review summarizes some of the basic research into the importance of circadian genes in drug addiction. PMID:18644396

Falcón, Edgardo; McClung, Colleen A

2009-01-01

109

System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock  

PubMed Central

The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERB? represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs. PMID:17298173

Kornmann, Benoît; Schaad, Olivier; Bujard, Hermann; Takahashi, Joseph S; Schibler, Ueli

2007-01-01

110

Circadian Clock Proteins in Prokaryotes: Hidden Rhythms?  

PubMed Central

Circadian clock genes are vital features of eukaryotes that have evolved such that organisms can adapt to our planet's rotation in order to anticipate the coming day or night as well as unfavorable seasons. This circadian clock uses oscillation as a timekeeping element. However, circadian clock mechanisms exist also in prokaryotes. The circadian clock of Cyanobacteria is well studied. It is regulated by a cluster of three genes: kaiA, kaiB, and kaiC. In this review, we will discuss the circadian system in cyanobacteria, and provide an overview and updated phylogenetic analysis of prokaryotic organisms that contain the main circadian genes. It is evident that the evolution of the kai genes has been influenced by lateral transfers but further and deeper studies are needed to get an in depth understanding of the exact evolutionary history of these genes. Interestingly, Legionella pneumophila an environmental bacterium and opportunistic human pathogen that parasitizes protozoa in fresh water environments also contains kaiB and kaiC, but their functions are not known. All of the residues described for the biochemical functions of the main pacemaker KaiC in Synechococcus elongatus are also conserved in the L. pneumophila KaiC protein. PMID:21687756

Loza-Correa, Maria; Gomez-Valero, Laura; Buchrieser, Carmen

2010-01-01

111

The Logic of Circadian Organization in Drosophila  

PubMed Central

Summary Background In the fruit fly Drosophila melanogaster, interlocked negative transcription/translation feedback loops provide the core of the circadian clock that generates rhythmic phenotypes. Although the current molecular model portrays the oscillator as cell autonomous, cross-talk among clock neurons is essential for robust cycling behavior. Nevertheless, the functional organization of the neuronal network remains obscure. Results Here we show that shortening or lengthening of the circadian period of locomotor activity can be obtained either by targeting different groups of clock cells with the same genetic manipulation or by challenging the same group of cells with activators and repressors of neuronal excitability. Conclusions Based on these observations we interpret circadian rhythmicity as an emerging property of the circadian network and we propose an initial model for its architectural design. PMID:25220056

Dissel, Stephane; Hansen, Celia N.; Özkaya, Özge; Hemsley, Matthew; Kyriacou, Charalambos P.; Rosato, Ezio

2014-01-01

112

The Effects of Spaceflight on the Rat Circadian Timing System  

NASA Technical Reports Server (NTRS)

Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than in one-G. Compared with control rats, the flight rats exhibited no change in HR. Finally, the LD FD2 flight rats demonstrated a reduced sensitivity to light as shown by significantly reduced c-fos expression in the SCN in comparison with controls. These findings constitute the first demonstration that microgravity affects the fundamental properties of the mammalian circadian timing system, specifically by influencing the clock's period, and its ability to maintain temporal organization and phase angle of synchronization to an external LD cycle.

Fuller, Charles A.; Murakami, Dean M.; Hoban-Higgins, Tana M.; Fuller, Patrick M.; Robinson, Edward L.; Tang, I.-Hsiung

2003-01-01

113

The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data  

NASA Technical Reports Server (NTRS)

Accurate estimation of the phases and amplitude of the endogenous circadian pacemaker from constant-routine core-temperature series is crucial for making inferences about the properties of the human biological clock from data collected under this protocol. This paper presents a set of statistical methods based on a harmonic-regression-plus-correlated-noise model for estimating the phases and the amplitude of the endogenous circadian pacemaker from constant-routine core-temperature data. The methods include a Bayesian Monte Carlo procedure for computing the uncertainty in these circadian functions. We illustrate the techniques with a detailed study of a single subject's core-temperature series and describe their relationship to other statistical methods for circadian data analysis. In our laboratory, these methods have been successfully used to analyze more than 300 constant routines and provide a highly reliable means of extracting phase and amplitude information from core-temperature data.

Brown, E. N.; Czeisler, C. A.

1992-01-01

114

Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria  

PubMed Central

For a biological oscillator to function as a circadian pacemaker that confers a fitness advantage, its timing functions must be stable in response to environmental and metabolic fluctuations. One such stability enhancer, temperature compensation, has long been a defining characteristic of these timekeepers. However, an accurate biological timekeeper must also resist changes in metabolism, and this review suggests that temperature compensation is actually a subset of a larger phenomenon, namely metabolic compensation, which maintains the frequency of circadian oscillators in response to a host of factors that impinge on metabolism and would otherwise destabilize these clocks. The circadian system of prokaryotic cyanobacteria is an illustrative model because it is composed of transcriptional and nontranscriptional oscillators that are coupled to promote resilience. Moreover, the cyanobacterial circadian program regulates gene activity and metabolic pathways, and it can be manipulated to improve the expression of bioproducts that have practical value. PMID:24905782

Johnson, Carl Hirschie; Egli, Martin

2014-01-01

115

Circadian gene expression in cultured cells.  

PubMed

In mammals, circadian oscillators not only exist in specialized neurons of the suprachiasmatic nucleus, but in almost all peripheral cell types. These oscillators are operative even in established fibroblast cell lines, such as Rat-1 cells or NIH3T3 cells, and in primary fibroblasts from mouse embryos or adult animals. This can be demonstrated by treating such cells for a short time period with high concentrations of serum or chemicals that activate a large number of known signaling pathways. The possibility of studying circadian rhythms in cultured cells should facilitate the biochemical and genetic dissection of the circadian clockwork and should promote the discovery of new clock components. PMID:15817311

Nagoshi, Emi; Brown, Steven A; Dibner, Charna; Kornmann, Benoît; Schibler, Ueli

2005-01-01

116

Time-of-Day- and Light-Dependent Expression of Ubiquitin Protein Ligase E3 Component N-Recognin 4 (UBR4) in the Suprachiasmatic Nucleus Circadian Clock  

PubMed Central

Circadian rhythms of behavior and physiology are driven by the biological clock that operates endogenously but can also be entrained to the light-dark cycle of the environment. In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN), which is composed of individual cellular oscillators that are driven by a set of core clock genes interacting in transcriptional/translational feedback loops. Light signals can trigger molecular events in the SCN that ultimately impact on the phase of expression of core clock genes to reset the master pacemaker. While transcriptional regulation has received much attention in the field of circadian biology in the past, other mechanisms including targeted protein degradation likely contribute to the clock timing and entrainment process. In the present study, proteome-wide screens of the murine SCN led to the identification of ubiquitin protein ligase E3 component N-recognin 4 (UBR4), a novel E3 ubiquitin ligase component of the N-end rule pathway, as a time-of-day-dependent and light-inducible protein. The spatial and temporal expression pattern of UBR4 in the SCN was subsequently characterized by immunofluorescence microscopy. UBR4 is expressed across the entire rostrocaudal extent of the SCN in a time-of-day-dependent fashion. UBR4 is localized exclusively to arginine vasopressin (AVP)-expressing neurons of the SCN shell. Upon photic stimulation in the early subjective night, the number of UBR4-expressing cells within the SCN increases. This study is the first to identify a novel E3 ubiquitin ligase component, UBR4, in the murine SCN and to implicate the N-end rule degradation pathway as a potential player in regulating core clock mechanisms and photic entrainment. PMID:25084275

Ling, Harrod H.; Beaulé, Christian; Chiang, Cheng-Kang; Tian, Ruijun; Figeys, Daniel; Cheng, Hai-Ying M.

2014-01-01

117

Changes in pH and NADPH Regulate the DNA Binding Activity of Neuronal PAS Domain Protein 2, a Mammalian Circadian Transcription Factor.  

PubMed

Neuronal PAS domain protein 2 (NPAS2) is a core clock transcription factor that forms a heterodimer with BMAL1 to bind the E-box in the promoter of clock genes and is regulated by various environmental stimuli such as heme, carbon monoxide, and NAD(P)H. In this study, we investigated the effects of pH and NADPH on the DNA binding activity of NPAS2. In an electrophoretic mobility shift (EMS) assay, the pH of the reaction mixture affected the DNA binding activity of the NPAS2/BMAL1 heterodimer but not that of the BMAL1/BMAL1 homodimer. A change in pH from 7.0 to 7.5 resulted in a 1.7-fold increase in activity in the absence of NADPH, and NADPH additively enhanced the activity up to 2.7-fold at pH 7.5. The experiments using truncated mutants revealed that N-terminal amino acids 1-61 of NPAS2 were sufficient to sense the change in both pH and NADPH. We further analyzed the kinetics of formation and DNA binding of the NPAS2/BMAL1 heterodimer at various pH values. In the absence of NADPH, a change in pH from 6.5 to 8.0 decreased the KD(app) value of the E-box from 125 to 22 nM, with an 8-fold increase in the maximal level of DNA binding for the NPAS2/BMAL1 heterodimer. The addition of NADPH resulted in a further decrease in KD(app) to 9 nM at pH 8.0. Furthermore, NPAS2-dependent transcriptional activity in a luciferase assay using NIH3T3 cells also increased with the pH of the culture medium. These results suggest that NPAS2 has a role as a pH and metabolite sensor in regulating circadian rhythms. PMID:25526362

Yoshii, Katsuhiro; Tajima, Fumihisa; Ishijima, Sumio; Sagami, Ikuko

2015-01-20

118

Synchronisation mechanisms of circadian rhythms in the suprachiasmatic nucleus.  

PubMed

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered as the master circadian pacemaker. Each cell in the SCN contains an autonomous molecular clock, and the SCN is composed of multiple single-cell circadian oscillators. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to create an integrated pacemaker that can govern behavioural and physiological rhythmicity and be reset by environmental light. The key is that the heterogeneous network formed by the cellular clocks within the SCN must synchronise to maintain timekeeping activity. To study the synchronisation mechanisms and the circadian rhythm generation, we propose a model based on the structural and functional heterogeneity of the SCN. The model is a heterogeneous network of circadian oscillators in which individual oscillators are self-sustained. The authors show that the dorsomedial region can smooth the periodic light-dark (LD) signal curve and affect its wave form. The authors also study the rhythmic process of the circadian oscillators under the effect of the daily LD cycle, including three courses: information afferent inputs, oscillation and information efferent outputs. The numerical simulations are also given to demonstrate the theoretical results. PMID:19292564

Li, Y; Liu, Z; Zhang, J; Wang, R; Chen, L

2009-03-01

119

Interference with cardiac pacemaker function.  

PubMed

A survey is given of the factors affecting cardiac pacemaker function. Whereas it was earlier considered that external interference was a frequent cause of a pacemaker failure, more recent studies indicate that this is of minor importance. It would appear that failure of pacemaker function due to changes in the QRS-complex, i.e. voltage change, intraventricular conduction defects and frequency changes, intraventricular conduction defects and frequency changes, are more important. A lesser known cause of failure in demand function is the inhibition which arises from skeletal muscle postentials. This appears to be a major problem in some types of pacemaker. Manufacturing defects are unavoidable, and it can still be assumed that electronic component defects may develop in 1 of 1000 pulse generators. Cases with the problem of early run-away pacemaker are still being reported and two such cases are discussed. In one of the patients the run-away phenomenon was intermittent, and was accompanied by a variation in run-away frequency. This possibility should thus always be taken into consideration in a pacemaker patient presenting with snycope. In a patient with a QRS-inhibited pacemaker a double stimulation phenomanen has been observed. PMID:1070234

Ohm, O J

1976-01-01

120

Circadian clock and cardiac vulnerability: A time stamp on multi-scale neuroautonomic regulation  

NASA Astrophysics Data System (ADS)

Cardiovascular vulnerability displays a 24-hour pattern with a peak between 9AM and 11AM. This daily pattern in cardiac risk is traditionally attributed to external factors including activity levels and sleep-wake cycles. However,influences from the endogenous circadian pacemaker independent from behaviors may also affect cardiac control. We investigate heartbeat dynamics in healthy subjects recorded throughout a 10-day protocol wherein the sleep/wake and behavior cycles are desynchronized from the endogenous circadian cycle,enabling assessment of circadian factors while controlling for behavior-related factors. We demonstrate that the scaling exponent characterizing temporal correlations in heartbeat dynamics over multiple time scales does exhibit a significant circadian rhythm with a sharp peak at the circadian phase corresponding to the period 9-11AM, and that this rhythm is independent from scheduled behaviors and mean heart rate. Our findings of strong circadian rhythms in the multi-scale heartbeat dynamics of healthy young subjects indicate that the underlying mechanism of cardiac regulation is strongly influenced by the endogenous circadian pacemaker. A similar circadian effect in vulnerable individuals with underlying cardiovascular disease would contribute to the morning peak of adverse cardiac events observed in epidemiological studies.

Ivanov, Plamen Ch.

2005-03-01

121

A statistical model of the human core-temperature circadian rhythm  

NASA Technical Reports Server (NTRS)

We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.

Brown, E. N.; Choe, Y.; Luithardt, H.; Czeisler, C. A.

2000-01-01

122

Avian Circadian Organization: A Chorus of Clocks  

PubMed Central

In birds, biological clock function pervades all aspects of biology, controlling daily changes in sleep: wake, visual function, song, migratory patterns and orientation, as well as seasonal patterns of reproduction, song and migration. The molecular bases for circadian clocks are highly conserved, and it is likely the avian molecular mechanisms are similar to those expressed in mammals, including humans. The central pacemakers in the avian pineal gland, retinae and SCN dynamically interact to maintain stable phase relationships and then influence downstream rhythms through entrainment of peripheral oscillators in the brain controlling behavior and peripheral tissues. Birds represent an excellent model for the role played by biological clocks in human neurobiology; unlike most rodent models, they are diurnal, they exhibit cognitively complex social interactions, and their circadian clocks are more sensitive to the hormone melatonin than are those of nocturnal rodents. PMID:24157655

Cassone, Vincent M

2013-01-01

123

CULLIN-3 Controls TIMELESS Oscillations in the Drosophila Circadian Clock  

E-print Network

for the circadian degradation of phosphorylated PER. We show here that CULLIN-3 (CUL-3) is required for the circadian control of PER and TIM oscillations. Expression of either Cul-3 RNAi or dominant negative forms of CUL-3 in the clock neurons alters locomotor behavior and dampens PER and TIM oscillations in light

Rouyer, Francois

124

How Does a Pacemaker Work?  

MedlinePLUS

... A pacemaker consists of a battery, a computerized generator, and wires with sensors at their tips. (The sensors are called electrodes.) The battery powers the generator, and both are surrounded by a thin metal ...

125

VideoLab: Optogenetic Pacemaker  

NSDL National Science Digital Library

In mammals, the heart's primary pacemaker lies in a specialized group of cells -- but do non-mammalian vertebrates have a similar control system? To find out, Arrenberg et al. genetically engineered zebrafish to express light-sensitive proteins, and then used light beams generated with a digital micromirror device to locate and manipulate the function of the pacemaker cells in the hearts of zebrafish embryos -- capturing the action on high-speed video.

Aristides B. Arrenberg (University of California; University of Freiburg;Department of Physiology; Institute of Biology); Didier Y. R. Stainier (University of California;Department of Biochemistry and Biophysics and Cardiovascular Research Institute); Herwig Baier (University of California;Department of Physiology); Jan Huisken (University of California; Max Planck Institute of Molecular Cell Biology and Genetics;Department of Biochemistry and Biophysics and Cardiovascular Research Institute)

2010-11-12

126

Phase shifting the circadian rhythm of neuronal activity in the isolated Aplysia eye with puromycin and cycloheximide. Electrophysiological and biochemical studies  

Microsoft Academic Search

A B S X R A c x The effects of pulse application of puromycin (PURO) or cyclohexi- mide (CHX) were tested on the circadian rhythm (CR) of spontaneous compound action potential (CAP) activity in the isolated Aplysia eye. CAP activity was recorded from the optic nerve in constant darkness at 15°C. PURO pulses (6, 12 h; 12-134\\/~g\\/ ml) and

BARRY S. ROTHMAN; FELIX STRUMWASSER

1976-01-01

127

Circadian Rhythm Disruption in Cancer Biology  

PubMed Central

Circadian rhythms show universally a 24-h oscillation pattern in metabolic, physiological and behavioral functions of almost all species. This pattern is due to a fundamental adaptation to the rotation of Earth around its own axis. Molecular mechanisms of generation of circadian rhythms organize a biochemical network in suprachiasmatic nucleus and peripheral tissues, building cell autonomous clock pacemakers. Rhythmicity is observed in transcriptional expression of a wide range of clock-controlled genes that regulate a variety of normal cell functions, such as cell division and proliferation. Desynchrony of this rhythmicity seems to be implicated in several pathologic conditions, including tumorigenesis and progression of cancer. In 2007, the International Agency for Research on Cancer (IARC) categorized “shiftwork that involves circadian disruption [as] probably carcinogenic to humans” (Group 2A in the IARC classification system of carcinogenic potency of an agentagent) (Painting, Firefighting, and Shiftwork; IARC; 2007). This review discusses the potential relation between disruptions of normal circadian rhythms with genetic driving machinery of cancer. Elucidation of the role of clockwork disruption, such as exposure to light at night and sleep disruption, in cancer biology could be important in developing new targeted anticancer therapies, optimizing individualized chronotherapy and modifying lighting environment in workplaces or homes. PMID:22811066

Savvidis, Christos; Koutsilieris, Michael

2012-01-01

128

A Circadian Signal of Change of Season in Patients With Seasonal Affective Disorder  

Microsoft Academic Search

Background: In animals, the circadian pacemaker regu- lates seasonal changes in behavior by transmitting a signal of day length to other sites in the organism. The signal is expressed reciprocally in the duration of noc- turnal melatonin secretion, which is longer in winter than in summer. We investigated whether such a signal could mediate the effects of change of season

Thomas A. Wehr; Wallace C. Duncan; Leo Sher; Daniel Aeschbach; Paul J. Schwartz; Erick H. Turner; Teodor T. Postolache; Norman E. Rosenthal

2001-01-01

129

Circadian Clock Function in the Mammalian Ovary.  

PubMed

Rhythmic events in the female reproductive system depend on the coordinated and synchronized activity of multiple neuroendocrine and endocrine tissues. This coordination is facilitated by the timing of gene expression and cellular physiology at each level of the hypothalamo-pituitary-ovarian (HPO) axis, including the basal hypothalamus and forebrain, the pituitary gland, and the ovary. Central to this pathway is the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) that, through its myriad outputs, provides a temporal framework for gonadotropin release and ovulation. The heart of the timing system, a transcription-based oscillator, imparts SCN pacemaker cells and a company of peripheral tissues with the capacity for daily oscillations of gene expression and cellular physiology. Although the SCN sits comfortably at the helm, peripheral oscillators (such as the ovary) have undefined but potentially critical roles. Each cell type of the ovary, including theca cells, granulosa cells, and oocytes, harbor a molecular clock implicated in the processes of follicular growth, steroid hormone synthesis, and ovulation. The ovarian clock is influenced by the reproductive cycle and diseases that perturb the cycle and/or follicular growth can disrupt the timing of clock gene expression in the ovary. Chronodisruption is known to negatively affect reproductive function and fertility in both rodent models and women exposed to shiftwork schedules. Thus, influencing clock function in the HPO axis with chronobiotics may represent a novel avenue for the treatment of common fertility disorders, particularly those resulting from chronic circadian disruption. PMID:25367899

Sellix, Michael T

2014-11-01

130

The bird circadian clock: insights from a computational model.  

PubMed

The circadian timekeeping system appears more complex in birds than in mammals. In mammals, the main pacemaker is centralized in the suprachiasmatic nuclei, whereas in birds, the pacemaker involves the interplay between the pineal and hypothalamic oscillators. In order to investigate the consequence of this complex mechanism, we propose here a mathematical model for the bird circadian clock. The model is based on the internal resonance between the pineal and hypothalamic oscillators, each described by Goodwin-like equations. We show that, consistently with experimental observations, self-sustained oscillations can be generated by mutual inhibitory coupling of the 2 clocks, even if individual oscillators present damped oscillations. We study the effect of constant and periodic administrations of melatonin, which, in intact birds, acts as the coupling variable between the pineal and the hypothalamus, and compare the prediction of the model with the experiments performed in pinealectomized birds. We also assess the entrainment properties when the system is subject to light-dark cycles. Analyses of the entrainment range, resynchronization time after jet lag, and entrainment phase with respect to the photoperiod lead us to formulate hypotheses about the physiological advantage of the particular architecture of the avian circadian clock. Although minimal, our model opens promising perspectives in modeling and understanding the bird circadian clock. PMID:24336417

Woller, Aurore; Gonze, Didier

2013-12-01

131

How Will a Pacemaker Affect My Lifestyle?  

MedlinePLUS

... this page from the NHLBI on Twitter. How Will a Pacemaker Affect My Lifestyle? Once you have ... are safe for you. Ongoing Care Your doctor will want to check your pacemaker regularly (about every ...

132

Impaired Leukocyte Trafficking and Skin Inflammatory Responses in Hamsters Lacking a Functional Circadian System  

PubMed Central

The immune system is under strong circadian control, and circadian desynchrony is a risk factor for metabolic disorders, inflammatory responses and cancer. Signaling pathways that maintain circadian rhythms (CRs) in immune function in vivo, and the mechanisms by which circadian desynchrony impairs immune function, remain to be fully-identified. These experiments tested the hypothesis that the hypothalamic circadian pacemaker in the suprachiasmatic nucleus (SCN) drives CRs in the immune system, using a non-invasive model of SCN circadian arrhythmia. Robust CRs in blood leukocyte trafficking, with a peak during the early light phase (ZT4) and nadir in the early dark phase (ZT18), were absent in arrhythmic hamsters, as were CRs in spleen clock gene (per1, bmal1) expression, indicating that a functional pacemaker in the SCN is required for the generation of CRs in leukocyte trafficking and for driving peripheral clocks in secondary lymphoid organs. Pinealectomy was without effect on CRs in leukocyte trafficking, but abolished CRs in spleen clock gene expression, indicating that nocturnal melatonin secretion is necessary for communicating circadian time information to the spleen. CRs in trafficking of antigen presenting cells (CD11c+ dendritic cells) in the skin were abolished, and antigen-specific delayed-type hypersensitivity skin inflammatory responses were markedly impaired in arrhythmic hamsters. The SCN drives robust CRs in leukocyte trafficking and lymphoid clock gene expression; the latter of which is not expressed in the absence of melatonin. Robust entrainment of the circadian pacemaker provides a signal critical to diurnal rhythms in immunosurveilliance and optimal memory T-cell dependent immune responses. PMID:23474187

Prendergast, Brian J.; Cable, Erin J.; Patel, Priyesh N.; Pyter, Leah M.; Onishi, Kenneth G.; Stevenson, Tyler J.; Ruby, Norman F.; Bradley, Sean P.

2013-01-01

133

Interferon-? Alters Electrical Activity and Clock Gene Expression in Suprachiasmatic Nucleus Neurons  

Microsoft Academic Search

The proinflammatory cytokine interferon (IFN-?) is an immunomodulatory molecule released by immune cells. It was originally described as an antiviral agent but can also affect functions in the nervous system including circadian activity of the principal mammalian circadian pacemaker, the suprachiasmatic nucleus. IFN-? and the synergistically acting cytokine tumor necrosis factor-? acutely decrease spontaneous excitatory postsynaptic activity and alter spiking

Yongho Kwak; Gabriella B. Lundkvist; Johan Brask; Alec Davidson; Michael Menaker; Krister Kristensson; Gene D. Block

2008-01-01

134

Circadian regulation of ion channels and their functions  

PubMed Central

Ion channels are the gatekeepers to neuronal excitability. Retinal neurons of vertebrates and invertebrates, neurons of the suprachiasmatic nucleus (SCN) of vertebrates, and pinealocytes of non-mammalian vertebrates display daily rhythms in their activities. The interlocking transcription–translation feedback loops with specific post-translational modulations within individual cells form the molecular clock, the basic mechanism that maintains the autonomic ~24-h rhythm. The molecular clock regulates downstream output signaling pathways that further modulate activities of various ion channels. Ultimately, it is the circadian regulation of ion channel properties that govern excitability and behavior output of these neurons. In this review, we focus on the recent development of research in circadian neurobiology mainly from 1980 forward. We will emphasize the circadian regulation of various ion channels, including cGMP-gated cation channels, various voltage-gated calcium and potassium channels, Na+/K+-ATPase, and a long-opening cation channel. The cellular mechanisms underlying the circadian regulation of these ion channels and their functions in various tissues and organisms will also be discussed. Despite the magnitude of chronobiological studies in recent years, the circadian regulation of ion channels still remains largely unexplored. Through more investigation and understanding of the circadian regulation of ion channels, the future development of therapeutic strategies for the treatment of sleep disorders, cardiovascular diseases, and other illnesses linked to circadian misalignment will benefit. PMID:19549279

Ko, Gladys Y.-P.; Shi, Liheng; Ko, Michael L.

2010-01-01

135

Circadian Rhythm Sleep Disorders  

PubMed Central

There have been remarkable advances in our understanding of the molecular, cellular and physiological mechanisms underlying the regulation of circadian rhythms, as well as the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance and safety. CRSDs are caused by alterations of the central circadian time-keeping system, or a misalignment of the endogenous circadian rhythm and the external environment. In this section, we provide a review of circadian biology and discuss the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice. PMID:23099133

Zhu, Lirong; Zee, Phyllis C.

2012-01-01

136

Circadian Gene Expression in Cultured Cells  

Microsoft Academic Search

In mammals, circadian oscillators not only exist in specialized neurons of the suprachiasmatic nucleus, but in almost all peripheral cell types. These oscillators are operative even in established fibroblast cell lines, such as Rat-1 cells or NIH3T3 cells, and in primary fibroblasts from mouse embryos or adult animals. This can be demonstrated by treating such cells for a short time

Emi Nagoshi; Steven A. Brown; Charna Dibner; Benoît Kornmann; Ueli Schibler

2005-01-01

137

Circadian period integrates network information through activation of the BMP signaling pathway.  

PubMed

Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ?150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands. PMID:24339749

Beckwith, Esteban J; Gorostiza, E Axel; Berni, Jimena; Rezával, Carolina; Pérez-Santángelo, Agustín; Nadra, Alejandro D; Ceriani, María Fernanda

2013-12-01

138

Circadian Period Integrates Network Information Through Activation of the BMP Signaling Pathway  

PubMed Central

Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ?150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands. PMID:24339749

Beckwith, Esteban J.; Gorostiza, E. Axel; Berni, Jimena; Rezával, Carolina; Pérez-Santángelo, Agustín; Nadra, Alejandro D.; Ceriani, María Fernanda

2013-01-01

139

Circadian adaptations to meal timing: neuroendocrine mechanisms  

PubMed Central

Circadian rhythms of behavior and physiology are generated by central and peripheral circadian oscillators entrained by periodic environmental or physiological stimuli. A master circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) is directly entrained by daily light-dark (LD) cycles, and coordinates the timing of other oscillators by direct and indirect neural, hormonal and behavioral outputs. The daily rhythm of food intake provides stimuli that entrain most peripheral and central oscillators, some of which can drive a daily rhythm of food anticipatory activity if food is restricted to one daily mealtime. The location of food-entrainable oscillators (FEOs) that drive food anticipatory rhythms, and the food-related stimuli that entrain these oscillators, remain to be clarified. Here, we critically examine the role of peripheral metabolic hormones as potential internal entrainment stimuli or outputs for FEOs controlling food anticipatory rhythms in rats and mice. Hormones for which data are available include corticosterone, ghrelin, leptin, insulin, glucagon, and glucagon-like peptide 1. All of these hormones exhibit daily rhythms of synthesis and secretion that are synchronized by meal timing. There is some evidence that ghrelin and leptin modulate the expression of food anticipatory rhythms, but none of the hormones examined so far are necessary for entrainment. Ghrelin and leptin likely modulate food-entrained rhythms by actions in hypothalamic circuits utilizing melanocortin and orexin signaling, although again food-entrained behavioral rhythms can persist in lesion and gene knockout models in which these systems are disabled. Actions of these hormones on circadian oscillators in central reward circuits remain to be evaluated. Food-entrained activity rhythms are likely mediated by a distributed system of circadian oscillators sensitive to multiple feeding related inputs. Metabolic hormones appear to play a modulatory role within this system. PMID:24133410

Patton, Danica F.; Mistlberger, Ralph E.

2013-01-01

140

Electrical interference in non-competitive pacemakers.  

PubMed

Patients with 41 implanted non-competitive pacemakers were investigated. A variety of domestic electrical equipment, a motor-car, and a physiotherapy diathermy apparatus were each operated in turn at various ranges from the patient. Interference effects on pacemaker function were assessed on the electrocardiograph. Medtronic demand 5841 pacemakers were stopped by diathermy while Cordis Ectocor pacemakers developed a fast discharge rate. Cordis triggered pacemakers (both Atricor and Ectocor) were sensitive to interference from many items of domestic equipment and the motor car. The Elema EM153 ran at an increased rate when an electric razor was running close to the pacemaker. The Devices demand 2980 and the Medtronic demand 5841 were not affected by the domestic equipment tested. The significance of interference effects is discussed in relation to pacemaker design. PMID:5470044

Sowton, E; Gray, K; Preston, T

1970-09-01

141

Physiologically based modelling of circadian control on cell proliferation.  

PubMed

The molecular circadian clock which is present in almost all cells of animal organisms exerts a control on the cell division cycle in proliferating tissues by modulating the activity of cyclins and cyclin dependent kinases (CDKs), the proteins which determine transitions from one phase of the cell cycle to the following one, until effective division. Each peripheral cell circadian clock is under the synchronising control of a central hypothalamic pacemaker which itself receives inputs, synchronising or disruptive, from external light and from circulating molecules such as cytokines. Principles for modelling these interacting systems are exposed. They rely on age-structured partial differential equations for cell proliferation in a population of cells and ordinary differential equations for the control of cell cycle phase transitions and for the circadian system presented as a network of oscillators with synchronisation and desynchronisation. These physiological cellular systems are coupled together and subject to pharmacological inputs, e.g. from anticancer therapies, which may be synchronised with cell cycle timing by the knowledge of the body circadian clock status, investigated by noninvasive measurements. The output of the controlled cell proliferation is a population growth exponent identifiable by in vivo tissue measurements; it allows to assess the proliferative status of the tissues under investigation, as a function of the circadian clock status, well fit or disrupted, and of pharmacological inputs such as used in anticancer treatments. PMID:17946797

Clairambault, Jean

2006-01-01

142

Circadian rhythms of temperature and activity in obese and lean Zucker rats  

NASA Technical Reports Server (NTRS)

The circadian timing system is important in the regulation of feeding and metabolism, both of which are aberrant in the obese Zucker rat. This study tested the hypothesis that these abnormalities involve a deficit in circadian regulation by examining the circadian rhythms of body temperature and activity in lean and obese Zucker rats exposed to normal light-dark cycles, constant light, and constant dark. Significant deficits in both daily mean and circadian amplitude of temperature and activity were found in obese Zucker female rats relative to lean controls in all lighting conditions. However, the circadian period of obese Zucker rats did not exhibit differences relative to lean controls in either of the constant lighting conditions. These results indicate that although the circadian regulation of temperature and activity in obese Zucker female rats is in fact depressed, obese rats do exhibit normal entrainment and pacemaker functions in the circadian timing system. The results suggest a deficit in the process that generates the amplitude of the circadian rhythm.

Murakami, D. M.; Horwitz, B. A.; Fuller, C. A.

1995-01-01

143

Potent circadian effects of dim illumination at night in hamsters.  

PubMed

Conventional wisdom holds that the circadian pacemaker of rodents and humans is minimally responsive to light of the intensity provided by dim moonlight and starlight. However, dim illumination (<0.005 lux) provided during the daily dark periods markedly alters entrainment in hamsters. Under dimly lit scotophases, compared to completely dark ones phases, the upper range of entrainment is increased by approximately 4 h, and re-entrainment is accelerated following transfer from long to short day lengths. Moreover, the incidence of bimodal entrainment to 24 h light:dark:light:dark cycles is increased fourfold. Notably, the nocturnal illumination inducing these pronounced effects is equivalent in photic energy to that of a 2 sec, 100 lux light pulse. These effects may be parsimoniously interpreted as an action of dim light on the phase relations between multiple oscillators comprising the circadian pacemaker. An action of dim light distinct from that underlying bright-light phase-resetting may promote more effective entrainment. Together, the present results refute the view that scotopic illumination is environmental "noise" and indicate that clock function is conspicuously altered by nighttime illumination like that experienced under dim moonlight and starlight. We interpret our results as evidence for a novel action of dim light on the coupling of multiple circadian oscillators. PMID:16687298

Gorman, Michael R; Evans, Jennifer A; Elliott, Jeffrey A

2006-01-01

144

Synchronization and entrainment of coupled circadian oscillators  

E-print Network

Circadian rhythms in mammals are controlled by the neurons located in the suprachiasmatic nucleus of the hypothalamus. In physiological conditions, the system of neurons is very efficiently entrained by the 24-hour light-dark cycle. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light dark cycle in neuronal synchronization. Nevertheless, heterogeneity as a natural and permanent ingredient of these cellular interactions is seemingly to play a major role in these biochemical processes. In this paper we use a model that considers the neurons of the suprachiasmatic nucleus as chemically-coupled modified Goodwin oscillators, and introduce non-negligible heterogeneity in the periods of all neurons in the form of quenched noise. The system response to the light-dark cycle periodicity is studied as a function of the interneuronal coupling strength, external forcing amplitude and neuronal heterogeneity. Our results indicate that the right amount of heterogeneity hel...

Komin, Niko; Hernandez-Garcia, Emilio; Toral, Raul

2010-01-01

145

Reconstruction of Hyman's second pacemaker.  

PubMed

Though journal articles and newspaper reports suggest that three Hyman pacemakers existed or were intended; a patent, descriptive photographs and a written description of an earlier model and only a photograph of a later model exist. A replica of the earlier has been made based on the patent and description, and a new replica of the second based on a critical deconstruction and analysis of the photograph of the second with a modern circuit duplicating the function of the earlier circuit. Both replicas were "operational" in that stimuli were mimicked though not delivered and neither could under any circumstances actually resuscitate the heart. The design and construction of the second Hyman pacemaker are presented. PMID:15869680

Furman, Seymour; Szarka, George; Layvand, Dmitriy

2005-05-01

146

21 CFR 870.1750 - External programmable pacemaker pulse generator.  

...External programmable pacemaker pulse generator. 870.1750 Section 870.1750...External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be...

2014-04-01

147

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false Indirect pacemaker generator function analyzer. 870.3640...870.3640 Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker generator function analyzer is an...

2013-04-01

148

21 CFR 870.3610 - Implantable pacemaker pulse generator.  

Code of Federal Regulations, 2013 CFR

...false Implantable pacemaker pulse generator. 870.3610 Section 870.3610...3610 Implantable pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that has a...

2013-04-01

149

21 CFR 870.3630 - Pacemaker generator function analyzer.  

Code of Federal Regulations, 2011 CFR

... 2011-04-01 false Pacemaker generator function analyzer. 870.3630 ...Prosthetic Devices § 870.3630 Pacemaker generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device...

2011-04-01

150

21 CFR 870.3630 - Pacemaker generator function analyzer.  

Code of Federal Regulations, 2013 CFR

... 2013-04-01 false Pacemaker generator function analyzer. 870.3630 ...Prosthetic Devices § 870.3630 Pacemaker generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device...

2013-04-01

151

21 CFR 870.3630 - Pacemaker generator function analyzer.  

Code of Federal Regulations, 2012 CFR

... 2012-04-01 false Pacemaker generator function analyzer. 870.3630 ...Prosthetic Devices § 870.3630 Pacemaker generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device...

2012-04-01

152

21 CFR 870.1750 - External programmable pacemaker pulse generator.  

Code of Federal Regulations, 2013 CFR

...External programmable pacemaker pulse generator. 870.1750 Section 870.1750...External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be...

2013-04-01

153

21 CFR 870.3600 - External pacemaker pulse generator.  

...2014-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600...870.3600 External pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has a...

2014-04-01

154

21 CFR 870.3630 - Pacemaker generator function analyzer.  

... 2014-04-01 false Pacemaker generator function analyzer. 870.3630 ...Prosthetic Devices § 870.3630 Pacemaker generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device...

2014-04-01

155

21 CFR 870.3600 - External pacemaker pulse generator.  

Code of Federal Regulations, 2012 CFR

...2012-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600...870.3600 External pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has a...

2012-04-01

156

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

...2014-04-01 false Indirect pacemaker generator function analyzer. 870.3640...870.3640 Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker generator function analyzer is an...

2014-04-01

157

21 CFR 870.3600 - External pacemaker pulse generator.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600...870.3600 External pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has a...

2013-04-01

158

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650 Food... § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold a...

2010-04-01

159

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2011 CFR

...2011-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650 Food... § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold a...

2011-04-01

160

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650 Food... § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold a...

2013-04-01

161

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

...2014-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650 Food... § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold a...

2014-04-01

162

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2012 CFR

...2012-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650 Food... § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold a...

2012-04-01

163

21 CFR 870.3690 - Pacemaker test magnet.  

... 2014-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690 Food...Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an...

2014-04-01

164

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2012 CFR

... 2012-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690 Food...Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an...

2012-04-01

165

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2013 CFR

... 2013-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690 Food...Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an...

2013-04-01

166

Epithermal neutron beam interference with cardiac pacemakers.  

PubMed

In this paper, a phantom study was performed to evaluate the effect of an epithermal neutron beam irradiation on the cardiac pacemaker function. Severe malfunction occurred in the pacemakers after substantially lower dose from epithermal neutron irradiation than reported in the fast neutron or photon beams at the same dose rate level. In addition the pacemakers got activated, resulting in nuclides with half-lives from 25 min to 115 d. We suggest that BNCT should be administrated only after removal of the pacemaker from the vicinity of the tumor. PMID:21478029

Koivunoro, H; Serén, T; Hyvönen, H; Kotiluoto, P; Iivonen, P; Auterinen, I; Seppälä, T; Kankaanranta, L; Pakarinen, S; Tenhunen, M; Savolainen, S

2011-12-01

167

Space Derived Health Aids (Cardiac Pacemaker)  

NASA Technical Reports Server (NTRS)

St. Jude Medical's Cardiac Rhythm Management Division's (formerly known as Pacesetter Systems, Inc.) pacer is a rechargeable cardiac pacemaker that eliminates the recurring need for surgery to implant a new battery. The Programalith is an advanced cardiac pacing system which permits a physician to reprogram a patient's implanted pacemaker without surgery. System consists of a pacemaker, together with a physician's console containing the programmer and a data printer. Signals are transmitted by wireless telemetry. Two-way communications, originating from spacecraft electrical power systems technology, allows physician to interrogate the pacemaker as to the status of the heart, then to fine tune the device to best suit the patient's needs.

1981-01-01

168

21 CFR 870.3700 - Pacemaker programmers.  

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A...

2014-04-01

169

21 CFR 870.3700 - Pacemaker programmers.  

Code of Federal Regulations, 2013 CFR

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A...

2013-04-01

170

Serotonin 1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: Evaluation of potential interactions with serotonin 2A and serotonin 2C receptors  

Microsoft Academic Search

Mammalian circadian activity rhythms are generated by pacemaker cells in the suprachiasmatic nucleus (SCN). As revealed by the actions of diverse agonists, serotonergic input from raphe nuclei generally inhibits photic signaling in the suprachiasmatic nucleus. In contrast, the serotonin (5HT)1A partial agonist, 4-(benzodioxan-5-yl)1-(indan2-yl)piperazine (S 15535), was found to enhance the phase-shifting influence of light on hamster circadian rhythms [Gannon, Neuroscience

R. L. Gannon; M. J. Millan

2006-01-01

171

Effects of gravity on the circadian period in rats  

NASA Technical Reports Server (NTRS)

The effect of increased gravity force on the circadian period of body temperature and activity of rats was investigated using rats implanted with a small radio telemetry device and, after a 2-week recovery and a 3-week control period at 1G, rotated at for 4 weeks at a constant 2G field in a 18-ft-diam centrifuge. Measurements of the mean freerunning period of the temperature and activity rhythms after 10 days showed that the exposure to 2G led to a functional separation of the pacemakers that regulate the activity and the temperature in the animals. Each pacemaker reacted differently: the activity period increased and the temperature period decreased. By the third or the fourth week, the activity and the temperature periods have returned to 1G control levels.

Murakami, Dean M.; Demaria, Victor H.; Fuller, Charles A.

1991-01-01

172

Identification of the molecular components of a Tigriopus californicus (Crustacea, Copepoda) circadian clock.  

PubMed

Copepods of the genus Tigriopus have been proposed as marine models for investigations of environmental perturbation. One rapidly increasing anthropogenic stressor for intertidal organisms is light pollution. Given the sensitivity of circadian rhythms to exogenous light, the genes/proteins of a Tigriopus circadian pacemaker represent a potential system for investigating the influences of artificial light sources on circadian behavior in an intertidal species. Here, the molecular components of a putative Tigriopus californicus circadian clock were identified using publicly accessible transcriptome data; the recently deduced circadian proteins of the copepod Calanus finmarchicus were used as a reference. Transcripts encoding homologs of all commonly recognized ancestral arthropod core clock proteins were identified (i.e. CLOCK, CRYPTOCHROME 2, CYCLE, PERIOD and TIMELESS), as were ones encoding proteins likely to modulate the core clock (i.e. CASEIN KINASE II, CLOCKWORK ORANGE, DOUBLETIME, PROTEIN PHOSPHATASE 1, PROTEIN PHOSPHATASE 2A, SHAGGY, SUPERNUMERARY LIMBS and VRILLE) or to act as inputs to it (i.e. CRYPTOCHROME 1). PAR DOMAIN PROTEIN 1 was the only circadian-associated protein not identified in Tigriopus; it appears absent in Calanus too. These data represent just the third full set of molecular components for a crustacean circadian pacemaker (Daphnia pulex and C. finmarchicus previously), and only the second obtained from transcribed sequences (C. finmarchicus previously). Given Tigriopus' proposed status as a model for investigating the influences of anthropogenic stressors in the marine environment, these data provide the first suite of gene/protein targets for understanding how light pollution may influence circadian physiology and behavior in an intertidal organism. PMID:25310881

Nesbit, Katherine T; Christie, Andrew E

2014-12-01

173

Impact of behavior on central and peripheral circadian clocks in the common vole Microtus arvalis, a mammal with ultradian rhythms  

PubMed Central

In most mammals, daily rhythms in physiology are driven by a circadian timing system composed of a master pacemaker in the suprachiasmatic nucleus (SCN) and peripheral oscillators in most body cells. The SCN clock, which is phase-entrained by light–dark cycles, is thought to synchronize subsidiary oscillators in peripheral tissues, mainly by driving cyclic feeding behavior. Here, we examined the expression of circadian clock genes in the SCN and the liver of the common vole Microtus arvalis, a rodent with ultradian activity and feeding rhythms. In these animals, clock-gene mRNAs accumulate with high circadian amplitudes in the SCN but are present at nearly constant levels in the liver. Interestingly, high-amplitude circadian liver gene expression can be elicited by subjecting voles to a circadian feeding regimen. Moreover, voles with access to a running wheel display a composite pattern of circadian and ultradian behavior, which correlates with low-amplitude circadian gene expression in the liver. Our data indicate that, in M. arvalis, the amplitude of circadian liver gene expression depends on the contribution of circadian and ultradian components in activity and feeding rhythms. PMID:16481616

van der Veen, Daan R.; Minh, Nguyet Le; Gos, Pascal; Arneric, Milica; Gerkema, Menno P.; Schibler, Ueli

2006-01-01

174

Research on sleep, circadian rhythms and aging - Applications to manned spaceflight  

NASA Technical Reports Server (NTRS)

Disorders of sleep and circadian rhythmicity are characteristic of both advancing age and manned spaceflight. Sleep fragmentation, reduced nocturnal sleep tendency and sleep efficiency, reduced daytime alertness, and increased daytime napping are common to both of these conditions. Recent research on the pathophysiology and treatment of disrupted sleep in older people has led to a better understanding of how the human circadian pacemaker regulates the timing of the daily sleep-wake cycle and how it responds to the periodic changes in the light-dark cycle to which we are ordinarily exposed. These findings have led to new treatments for some of the sleep disorders common to older individuals, using carefully timed exposure to bright light and darkness to manipulate the phase and/or amplitude of the circadian timing system. These insights and treatment approaches have direct applications in the design of countermeasures allowing astronauts to overcome some of the challenges which manned spaceflight poses for the human circadian timing system. We have conducted an operational feasibility study on the use of scheduled exposure to bright light and darkness prior to launch in order to facilitate adaptation of the circadian system of a NASA Space Shuttle crew to the altered sleep-wake schedule required for their mission. The results of this study illustrate how an understanding of the properties of the human circadian timing system and the consequences of circadian disruption can be applied to manned spaceflight.

Czeisler, Charles A.; Chiasera, August J.; Duffy, Jeanne F.

1991-01-01

175

Biological Clocks & Circadian Rhythms  

ERIC Educational Resources Information Center

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

Robertson, Laura; Jones, M. Gail

2009-01-01

176

The Arabidopsis Circadian System  

PubMed Central

Rhythms with periods of approximately 24 hr are widespread in nature. Those that persist in constant conditions are termed circadian rhythms and reflect the activity of an endogenous biological clock. Plants, including Arabidopsis, are richly rhythmic. Expression analysis, most recently on a genomic scale, indicates that the Arabidopsis circadian clock regulates a number of key metabolic pathways and stress responses. A number of sensitive and high-throughput assays have been developed to monitor the Arabidopsis clock. These assays have facilitated the identification of components of plant circadian systems through genetic and molecular biological studies. Although much remains to be learned, the framework of the Arabidopsis circadian system is coming into focus. Dedication This review is dedicated to the memory of DeLill Nasser, a wonderful mentor and an unwavering advocate of both Arabidopsis and circadian rhythms research. PMID:22303209

McClung, C. Robertson; Salomé, Patrice A.; Michael, Todd P.

2002-01-01

177

Pacemaker Component Allergy: Case Report and Review of the Literature  

Microsoft Academic Search

Pacemaker component allergy is a relatively uncommon cause of erythema and pain at the site of an implanted pacemaker. Allergies to multiple pacemaker components have been well described. We present a case in which 2 component allergies were documented on separate occasions. Although attempts were made to protect the patient by “coating” the pacemaker, the protective coating was incomplete and

David L. Hayes; Kathy Loesl

2002-01-01

178

The role of the circadian system in fractal neurophysiological control  

PubMed Central

Many neurophysiological variables such as heart rate, motor activity, and neural activity are known to exhibit intrinsic fractal fluctuations - similar temporal fluctuation patterns at different time scales. These fractal patterns contain information about health, as many pathological conditions are accompanied by their alteration or absence. In physical systems, such fluctuations are characteristic of critical states on the border between randomness and order, frequently arising from nonlinear feedback interactions between mechanisms operating on multiple scales. Thus, the existence of fractal fluctuations in physiology challenges traditional conceptions of health and disease, suggesting that high levels of integrity and adaptability are marked by complex variability, not constancy, and are properties of a neurophysiological network, not individual components. Despite the subject's theoretical and clinical interest, the neurophysiological mechanisms underlying fractal regulation remain largely unknown. The recent discovery that the circadian pacemaker (suprachiasmatic nucleus) plays a crucial role in generating fractal patterns in motor activity and heart rate sheds an entirely new light on both fractal control networks and the function of this master circadian clock, and builds a bridge between the fields of circadian biology and fractal physiology. In this review, we sketch the emerging picture of the developing interdisciplinary field of fractal neurophysiology by examining the circadian system’s role in fractal regulation. PMID:23573942

Pittman-Polletta, Benjamin R.; Scheer, Frank A.J.L.; Butler, Matthew P.; Shea, Steven A.; Hu, Kun

2013-01-01

179

Pacemakers charging using body energy  

PubMed Central

Life-saving medical implants like pacemakers and defibrillators face a big drawback that their batteries eventually run out and patients require frequent surgery to have these batteries replaced. With the advent of technology, alternatives can be provided for such surgeries. To power these devices, body energy harvesting techniques may be employed. Some of the power sources are patient's heartbeat, blood flow inside the vessels, movement of the body parts, and the body temperature (heat). Different types of sensors are employed, such as for sensing the energy from the heartbeat the piezoelectric and semiconducting coupled nanowires are used that convert the mechanical energy into electricity. Similarly, for sensing the blood flow energy, nanogenerators driven by ultrasonic waves are used that have the ability to directly convert the hydraulic energy in human body to electrical energy. Another consideration is to use body heat employing biothermal battery to generate electricity using multiple arrays of thermoelectric generators built into an implantable chip. These generators exploit the well-known thermocouple effect. For the biothermal device to work, it needs a 2°C temperature difference across it. But there are many parts of the body where a temperature difference of 5°C exists – typically in the few millimeters just below the skin, where it is planned to place this device. This study focuses on using body heat as an alternative energy source to recharge pacemaker batteries and other medical devices and prevent the possibility of life-risk during repeated surgery. PMID:21814432

Bhatia, Dinesh; Bairagi, Sweeti; Goel, Sanat; Jangra, Manoj

2010-01-01

180

Circadian Rhythm Abnormalities  

PubMed Central

Purpose: This article reviews the recent advances in understanding of the fundamental properties of circadian rhythms and discusses the clinical features, diagnosis, and treatment of circadian rhythm sleep disorders (CRSDs). Recent Findings: Recent evidence strongly points to the ubiquitous influence of circadian timing in nearly all physiologic functions. Thus, in addition to the prominent sleep and wake disturbances, circadian rhythm disorders are associated with cognitive impairment, mood disturbances, and increased risk of cardiometabolic disorders. The recent availability of biomarkers of circadian timing in clinical practice has improved our ability to identify and treat these CRSDs. Summary: Circadian rhythms are endogenous rhythms with a periodicity of approximately 24 hours. These rhythms are synchronized to the physical environment by social and work schedules by various photic and nonphotic stimuli. CRSDs result from a misalignment between the timing of the circadian rhythm and the external environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, non–24-hour, and irregular sleep-wake rhythm disorders). The most common symptoms of these disorders are difficulties with sleep onset and/or sleep maintenance and excessive sleepiness that are associated with impaired social and occupational functioning. Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian realignment with timed exposure to light, avoidance of bright light at inappropriate times, and adherence to scheduled sleep and wake times. In addition, pharmacologic agents are recommended for some of the CRSDs. For delayed sleep-phase, non–24-hour, and shift work disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift work disorder, wake-enhancing agents such as caffeine, modafinil, and armodafinil are options for the management of excessive sleepiness. PMID:23385698

Zee, Phyllis C.; Attarian, Hrayr; Videnovic, Aleksandar

2013-01-01

181

Phase shifting the circadian rhythm of neuronal activity in the isolated Aplysia eye with puromycin and cycloheximide. Electrophysiological and biochemical studies  

PubMed Central

The effects of pulse application of puromycin (PURO) or cycloheximide (CHX) were tested on the circadian rhythm (CR) of spontaneous compound action potential (CAP) activity in the isolated Aplysia eye. CAP activity was recorded from the optic nerve in constant darkness at 15degreesC. PURO pulses (6, 12 h; 12--134 mug/ml) and CHX pulses (12 h, 500--2,000 mug/ml) caused dose-dependent phase delays in the CR when administered during projected night. PURO pulses (6 h, 125 mug/ml) caused phase advances when given during projected day and caused phase delays when given during projected night. In biochemical experiments PURO (12 h, 20 mug/ml) and CHX (12 h, 500 mug/ml) inhibited leucine incorporation into the eye by about 50%. PURO (12 h; 50, 125 mug/ml) also changed the molecular weight distribution of proteins synthesized by the eye during the pulse. The effect of PURO (12 h, 125 mug/ml) on the level of incorporation was almost completely reversible within the next 12 h but the phase-shifted eye showed an latered spectrum of proteins for up to 28 h after the pulse. In electrophysiological experiments spontaneous CAP activity and responses to light were measured before, during, and after drug treatments. In all, eight parameters in three periods were analyzed quantitatively. Of these 24 indices, only 3 showed significant changes. PURO increased spontaneous CAP frequency by 67% 0-7 h after the drug pulse and increased the CAP amplitude of the tonic light response by 23% greater than 7 h after the pulse. CHX increased the intraburst spontaneous CAP frequency by 33% during the pulse and CAP frequency of the tonic light response by 32% 0- 7 h after the pulse. The above data indicate that phase-shifting doses of PURO and CHX inhibit protein synthesis in the eye without causing adverse electrophysiological effects, and suggest that protein synthesis is involved in the production of the CR of the isolated Aplysia eye. PMID:993764

1976-01-01

182

Pacemakers  

MedlinePLUS Videos and Cool Tools

... for your specific condition. ©1995-2013, The Patient Education Institute, Inc. [www.X-Plain.com] ct150109 Last ... for your specific condition. ©1995-2013, The Patient Education Institute, Inc. [www.X-Plain.com] ct150109 Last ...

183

Biophotonics: Circadian photonics  

NASA Astrophysics Data System (ADS)

A growing body of medical evidence suggests that disrupting the body's biological clock can have adverse effects on health. Researchers are now creating the photonic tools to monitor, predict and influence the circadian rhythm.

Rea, Mark S.

2011-05-01

184

[Circadian oscillators and hormones].  

PubMed

Circadian mechanism of clock-genes proteins (clock-proteins) directly and through an activation of clock-controlled genes initiates and tides over circadian rhythms of many processes, including secretion of hormones. However, investigations of the hormonal control of circadian oscillators of different levels and functions of clock-proteins apply to "top of iceberg" only. In the review, we analyse the investigations of clock-proteins functions and the hormonal control of clock-genes transcription and posttranslational modifications of clock-proteins. The clock-proteins had been discussed as second messengers for hormonal actions. Besides, the hormonal system is regarded as a system of synchronization of different clock-oscillators with genesis of ultradian, circadian and circannual rhythms. PMID:25509132

Chernysheva, M P

2013-01-01

185

Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle.  

PubMed

MicroRNA-mediated post-transcriptional regulations are increasingly recognized as important components of the circadian rhythm. Here we identify microRNA let-7, part of the Drosophila let-7-Complex, as a regulator of circadian rhythms mediated by a circadian regulatory cycle. Overexpression of let-7 in clock neurons lengthens circadian period and its deletion attenuates the morning activity peak as well as molecular oscillation. Let-7 regulates the circadian rhythm via repression of CLOCKWORK ORANGE (CWO). Conversely, upregulated cwo in cwo-expressing cells can rescue the phenotype of let-7-Complex overexpression. Moreover, circadian prothoracicotropic hormone (PTTH) and CLOCK-regulated 20-OH ecdysteroid signalling contribute to the circadian expression of let-7 through the 20-OH ecdysteroid receptor. Thus, we find a regulatory cycle involving PTTH, a direct target of CLOCK, and PTTH-driven miRNA let-7. PMID:25417916

Chen, Wenfeng; Liu, Zhenxing; Li, Tianjiao; Zhang, Ruifeng; Xue, Yongbo; Zhong, Yang; Bai, Weiwei; Zhou, Dasen; Zhao, Zhangwu

2014-01-01

186

Neurospora WC-1 Recruits SWI/SNF to Remodel frequency and Initiate a Circadian Cycle  

PubMed Central

In the negative feedback loop comprising the Neurospora circadian oscillator, the White Collar Complex (WCC) formed from White Collar-1 (WC-1) and White Collar-2 (WC-2) drives transcription of the circadian pacemaker gene frequency (frq). Although FRQ-dependent repression of WCC has been extensively studied, the mechanism by which the WCC initiates a circadian cycle remains elusive. Structure/function analysis of WC-1 eliminated domains previously thought to transactivate frq expression but instead identified amino acids 100–200 as essential for frq circadian expression. A proteomics-based search for coactivators with WCC uncovered the SWI/SNF (SWItch/Sucrose NonFermentable) complex: SWI/SNF interacts with WCC in vivo and in vitro, binds to the Clock box in the frq promoter, and is required both for circadian remodeling of nucleosomes at frq and for rhythmic frq expression; interestingly, SWI/SNF is not required for light-induced frq expression. These data suggest a model in which WC-1 recruits SWI/SNF to remodel and loop chromatin at frq, thereby activating frq expression to initiate the circadian cycle. PMID:25254987

Wang, Bin; Kettenbach, Arminja N.; Gerber, Scott A.; Loros, Jennifer J.; Dunlap, Jay C.

2014-01-01

187

Neurospora WC-1 recruits SWI/SNF to remodel frequency and initiate a circadian cycle.  

PubMed

In the negative feedback loop comprising the Neurospora circadian oscillator, the White Collar Complex (WCC) formed from White Collar-1 (WC-1) and White Collar-2 (WC-2) drives transcription of the circadian pacemaker gene frequency (frq). Although FRQ-dependent repression of WCC has been extensively studied, the mechanism by which the WCC initiates a circadian cycle remains elusive. Structure/function analysis of WC-1 eliminated domains previously thought to transactivate frq expression but instead identified amino acids 100-200 as essential for frq circadian expression. A proteomics-based search for coactivators with WCC uncovered the SWI/SNF (SWItch/Sucrose NonFermentable) complex: SWI/SNF interacts with WCC in vivo and in vitro, binds to the Clock box in the frq promoter, and is required both for circadian remodeling of nucleosomes at frq and for rhythmic frq expression; interestingly, SWI/SNF is not required for light-induced frq expression. These data suggest a model in which WC-1 recruits SWI/SNF to remodel and loop chromatin at frq, thereby activating frq expression to initiate the circadian cycle. PMID:25254987

Wang, Bin; Kettenbach, Arminja N; Gerber, Scott A; Loros, Jennifer J; Dunlap, Jay C

2014-09-01

188

Mathematical Models of Cardiac Pacemaking Function  

NASA Astrophysics Data System (ADS)

Over the past half century, there has been intense and fruitful interaction between experimental and computational investigations of cardiac function. This interaction has, for example, led to deep understanding of cardiac excitation-contraction coupling; how it works, as well as how it fails. However, many lines of inquiry remain unresolved, among them the initiation of each heartbeat. The sinoatrial node, a cluster of specialized pacemaking cells in the right atrium of the heart, spontaneously generates an electro-chemical wave that spreads through the atria and through the cardiac conduction system to the ventricles, initiating the contraction of cardiac muscle essential for pumping blood to the body. Despite the fundamental importance of this primary pacemaker, this process is still not fully understood, and ionic mechanisms underlying cardiac pacemaking function are currently under heated debate. Several mathematical models of sinoatrial node cell membrane electrophysiology have been constructed as based on different experimental data sets and hypotheses. As could be expected, these differing models offer diverse predictions about cardiac pacemaking activities. This paper aims to present the current state of debate over the origins of the pacemaking function of the sinoatrial node. Here, we will specifically review the state-of-the-art of cardiac pacemaker modeling, with a special emphasis on current discrepancies, limitations, and future challenges.

Li, Pan; Lines, Glenn T.; Maleckar, Mary M.; Tveito, Aslak

2013-10-01

189

Synchronization and entrainment of coupled circadian oscillators.  

PubMed

Circadian rhythms in mammals are controlled by the neurons located in the suprachiasmatic nucleus of the hypothalamus. In physiological conditions, the system of neurons is very efficiently entrained by the 24 h light-dark cycle. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light-dark cycle in neuronal synchronization. Nevertheless, heterogeneity as a natural and permanent ingredient of these cellular interactions seemingly plays a major role in these biochemical processes. In this paper, we use a model that considers the neurons of the suprachiasmatic nucleus as chemically coupled modified Goodwin oscillators, and introduce non-negligible heterogeneity in the periods of all neurons in the form of quenched noise. The system response to the light-dark cycle periodicity is studied as a function of the interneuronal coupling strength, external forcing amplitude and neuronal heterogeneity. Our results indicate that the right amount of heterogeneity helps the extended system to respond globally in a more coherent way to the external forcing. Our proposed mechanism for neuronal synchronization under external periodic forcing is based on heterogeneity-induced oscillator death, damped oscillators being more entrainable by the external forcing than the self-oscillating neurons with different periods. PMID:22419982

Komin, N; Murza, A C; Hernández-García, E; Toral, R

2011-02-01

190

Circadian genomics of the chick pineal gland in vitro  

PubMed Central

Background Chick pinealocytes exhibit all the characteristics of a complete circadian system, comprising photoreceptive inputs, molecular clockworks and an easily measured rhythmic output, melatonin biosynthesis. These properties make the in vitro pineal a particularly useful model for exploring circadian control of gene transcription in a pacemaker tissue, as well as regulation of the transcriptome by primary inputs to the clock (both photic and noradrenergic). Results We used microarray analysis to investigate the expression of approximately 8000 genes within cultured pinealocytes subjected to both LD and DD. We report that a reduced subset of genes was rhythmically expressed in vitro compared to those previously published in vivo, and that gene expression rhythms were lower in amplitude, although the functional distribution of the rhythmic transcriptome was largely similar. We also investigated the effects of 6-hour pulses of light or of norepinephrine on gene expression in free-running cultures during both subjective day and night. As expected, both light and norepinephrine inhibited melatonin production; however, the two treatments differentially enhanced or suppressed specific sets of genes in a fashion that was dependent upon time of day. Conclusion Our combined approach of utilizing a temporal, photic and pharmacological microarray experiment allowed us to identify novel genes linking clock input to clock function within the pineal. We identified approximately 30 rhythmic, light-responsive, NE-insensitive genes with no previously known clock function, which may play a role in circadian regulation of the pineal. These are candidates for future functional genomics experiments to elucidate their potential role in circadian physiology. Further, we hypothesize that the pineal circadian transcriptome is reduced but functionally conserved in vitro, and supports an endogenous role for the pineal in regulating local rhythms in metabolism, immune function, and other conserved pathways. PMID:18454867

Karaganis, Stephen P; Kumar, Vinod; Beremand, Phillip D; Bailey, Michael J; Thomas, Terry L; Cassone, Vincent M

2008-01-01

191

Circadian Rhythms in the Mouse: A Connections Map  

NSDL National Science Digital Library

Genetic and biochemical experiments over the past decade have facilitated the construction of a viable working model for the molecular mechanisms that generate the circadian rhythm in Mus musculus. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One, the "positive loop," controls the rhythmic expression of a Per-Arnt-Sim (PAS)-domain-containing positive transcription factor, BMAL1 (also called MOP3). The other, the "negative loop," controls the transcription of mPeriod 1 and 2 and mCryptochrome 1 and 2, two families of genes that encode repressor proteins. The loops are intertwined because the proteins mPeriod and mCryptochrome directly repress transcription mediated by the CLOCK:BMAL1 heterodimer, whereas CLOCK:BMAL1 drives transcription of the mPeriod and mCryptochrome genes, as well as that of Rev-erb-alpha, a repressor of Bmal1 expression. Mutations, including the tau mutation in hamsters [encoding Casein kinase I ε (CkIε)], have identified essential functions for other proteins in the timekeeping mechanism. The master pacemaker for circadian rhythms in mice is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light cycles can synchronize molecular rhythms in the SCN by stimulating the release of glutamate and the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) from melanopsin-containing retinal ganglion cells. This results in increased transcription of mPeriod genes and a shift in the phase of the clock. This Pathway Map of the murine circadian mechanism describes the individual known components of the mouse circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text

Russell N. Van Gelder (Washington University Medical School;Department of Molecular Biology and Pharmacology REV)

2003-08-05

192

Slow and rapid responses to CW and pulsed microwave radiation by individual Aplysia pacemakers.  

PubMed

Specific absorption rates (SARs) of microwave energy that altered firing rates were determined for individual pacemaker neurons in the abdominal ganglion of Aplysia californica. A stripline apparatus provided both for artifact-free recording of transmembrane potentials and for precise determination of the rate of absorption of microwave energy. Exposure for two to three minutes at an SAR of only a few mW/g was capable of changing the firing rate of some pacemakers. Two types of responses were observed. The response that was seen in all neurons developed slowly, reaching a steady state in one to three minutes. The other response was seen in a few neurons and occurred within five seconds from the onset of irradiation. Similar responses were obtained for two microwave frequencies, 1.5 and 2.45 GHz. Pulsed radiation induced rapid changes of firing rate more readily than did CW radiation at the same SAR. A convective heating scheme was used to study the effects of temperature changes on the pacemakers' firing rates. Since all of the responses are not readily explained by general heating of the preparation, alternate mechanisms are suggested for the observed effects. PMID:213605

Seaman, R L; Wachtel, H

1978-03-01

193

Cell, Vol. 119, 693705, November 24, 2004, Copyright 2004 by Cell Press Circadian Gene Expression in Individual Fibroblasts  

E-print Network

and Weaver, 2002).dian gene expression in NIH3T3 mouse fibroblasts in real time and in individual cells expression with little if anySCN neurons. Circadian gene expression in fibroblasts continues during cellCell, Vol. 119, 693­705, November 24, 2004, Copyright 2004 by Cell Press Circadian Gene Expression

Halazonetis, Thanos

194

microRNA modulation of circadian clock period and entrainment  

PubMed Central

microRNAs (miRNAs) are a class of small, non-coding, RNAs that regulate the stability or translation of mRNA transcripts. Although recent work has implicated miRNAs in development and in disease, the expression and function of miRNAs in the adult mammalian nervous system has not been extensively characterized. Here, we examine the role of two brain-specific miRNAs, miR-219 and miR-132, in modulating the circadian clock located in the suprachiasmatic nucleus. miR-219 is a target of the CLOCK/BMAL1 complex, exhibits robust circadian rhythms of expression and the in vivo knockdown of miR-219 lengthens the circadian period. miR-132 is induced by photic entrainment cues via a MAPK/CREB-dependent mechanism, modulates clock gene expression, and attenuates the entraining effects of light. Collectively, these data reveal miRNAs as clock- and light-regulated genes and provide a mechanistic examination of their roles as effectors of pacemaker activity and entrainment. PMID:17553428

Cheng, Hai-Ying M.; Papp, Joseph W.; Varlamova, Olga; Dziema, Heather; Russell, Brandon; Curfman, John P.; Nakazawa, Takanobu; Shimizu, Kimiko; Okamura, Hitoshi; Impey, Soren; Obrietan, Karl

2007-01-01

195

Separation of circadian and wake duration-dependent modulation of EEG activation during wakefulness  

NASA Technical Reports Server (NTRS)

The separate contribution of circadian rhythmicity and elapsed time awake on electroencephalographic (EEG) activity during wakefulness was assessed. Seven men lived in an environmental scheduling facility for 4 weeks and completed fourteen 42.85-h 'days', each consisting of an extended (28.57-h) wake episode and a 14.28-h sleep opportunity. The circadian rhythm of plasma melatonin desynchronized from the 42.85-h day. This allowed quantification of the separate contribution of circadian phase and elapsed time awake to variation in EEG power spectra (1-32 Hz). EEG activity during standardized behavioral conditions was markedly affected by both circadian phase and elapsed time awake in an EEG frequency- and derivation-specific manner. The nadir of the circadian rhythm in alpha (8-12 Hz) activity in both fronto-central and occipito-parietal derivations occurred during the biological night, close to the crest of the melatonin rhythm. The nadir of the circadian rhythm of theta (4.5-8 Hz) and beta (20-32 Hz) activity in the fronto-central derivation was located close to the onset of melatonin secretion, i.e. during the wake maintenance zone. As time awake progressed, delta frequency (1-4.5 Hz) and beta (20-32 Hz) activity rose monotonically in frontal derivations. The interaction between the circadian and wake-dependent increase in frontal delta was such that the intrusion of delta was minimal when sustained wakefulness coincided with the biological day, but pronounced during the biological night. Our data imply that the circadian pacemaker facilitates frontal EEG activation during the wake maintenance zone, by generating an arousal signal that prevents the intrusion of low-frequency EEG components, the propensity for which increases progressively during wakefulness.

Cajochen, C.; Wyatt, J. K.; Czeisler, C. A.; Dijk, D. J.

2002-01-01

196

Socially synchronized circadian oscillators  

PubMed Central

Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian ‘clock’). The alternation of environmental light and darkness synchronizes (entrains) these rhythms to the natural day–night cycle, and underlying mechanisms have been investigated using singly housed animals in the laboratory. But, most species ordinarily would not live out their lives in such seclusion; in their natural habitats, they interact with other individuals, and some live in colonies with highly developed social structures requiring temporal synchronization. Social cues may thus be critical to the adaptive function of the circadian system, but elucidating their role and the responsible mechanisms has proven elusive. Here, we highlight three model systems that are now being applied to understanding the biology of socially synchronized circadian oscillators: the fruitfly, with its powerful array of molecular genetic tools; the honeybee, with its complex natural society and clear division of labour; and, at a different level of biological organization, the rodent suprachiasmatic nucleus, site of the brain's circadian clock, with its network of mutually coupled single-cell oscillators. Analyses at the ‘group’ level of circadian organization will likely generate a more complex, but ultimately more comprehensive, view of clocks and rhythms and their contribution to fitness in nature. PMID:23825203

Bloch, Guy; Herzog, Erik D.; Levine, Joel D.; Schwartz, William J.

2013-01-01

197

Role of membrane conductances and protein synthesis in subjective day phase advances of the hamster circadian clock by neuropeptide Y.  

PubMed

Neurons of the mammalian circadian pacemaker in the hypothalamic suprachiasmatic nuclei exhibit a rhythm in firing rate that can be reset by neuropeptide Y. We recorded the effects of neuropeptide Y on Na+ and K+ conductances of hamster suprachiasmatic nuclei neurons using whole-cell, perforated-patch and cell-attached patch-clamp recordings, both in dissociated and brain slice preparations. While neuropeptide Y had no effect on voltage-gated Na+ currents, neuropeptide Y activated a leak K+ current. Neuropeptide Y phase advances in the suprachiasmatic nuclei brain slice preparation were blocked by a number of K+ channel blockers (tetraethylammonium chloride, dendrotoxin-I, glybenclamide). However, a K+ ionophore, valinomycin, did not shift the rhythm. The inhibition by tetraethylammonium chloride did not persist in the presence of glutamatergic receptor blockers. We have previously shown that glutamate can oppose neuropeptide Y phase-shifting actions, suggesting that K+ channel inhibition acts by inducing glutamate release. Protein synthesis inhibitors had no effect on clock phase when applied during the subjective day, and had no influence on neuropeptide Y-induced phase shifts. On the other hand, glutamate's ability to inhibit neuropeptide Y shifts was abolished by protein synthesis inhibition. Thus, while neuropeptide Y phase shifts do not require protein synthesis, glutamate blocks neuropeptide Y shifts via increased gene expression during the subjective day, at a time when it does not reset the clock. These results indicate that neuropeptide Y phase shifts via a mechanism that does not involve changes in membrane conductance or protein synthesis. PMID:10564350

Hall, A C; Earle-Cruikshanks, G; Harrington, M E

1999-10-01

198

Measuring stem cell circadian rhythm.  

PubMed

Circadian rhythms are biological rhythms that occur within a 24-h time cycle. Sleep is a prime example of a circadian rhythm and with it melatonin production. Stem cell systems also demonstrate circadian rhythms. This is particularly the case for the proliferating cells within the system. In fact, all proliferating cell populations exhibit their own circadian rhythm, which has important implications for disease and the treatment of disease. Stem cell chronobiology is particularly important because the treatment of cancer can be significantly affected by the time of day a drug is administered. This protocol provides a basis for measuring hematopoietic stem cell circadian rhythm for future stem cell chronotherapeutic applications. PMID:25388388

Hrushesky, William; Rich, Ivan N

2015-01-01

199

Effects of Gravity on Insect Circadian Rhythmicity  

NASA Technical Reports Server (NTRS)

Circadian rhythms - endogenous daily rhythmic fluctuations in virtually all characteristics of life - are generated and coordinated by the circadian timing system (CTS). The CTS is synchronized to the external 24-hour day by time cues such as the light/dark cycle. In an environment without time cues, the length of an animal's day is determined by the period of its internal pacemaker (tau) and the animal is said to be free-running. All life on earth evolved under the solar day; the CTS exists as an adaptation that allows organisms to anticipate and to prepare for rhythmic environmental fluctuations. All life on earth also evolved under the force of earth's gravitational environment. While it is therefore not surprising that changes in the lighting environment affect the CTS, it is surprising that changes in the gravitational environment would do so. However, recent data from one of our laboratories using the brn-3.1 knockout mouse revealed that this model, which lacks the sensory receptor hair cells within the neurovestibular system, does not respond to exposure to a hyperdynamic environment in the same fashion as normal mice. The brn-3.1 mice did not show the expected suppression of circadian rhythmicity shown by control mice exposed to 2G. Exposure to altered ambient force environments affects the amplitude, mean and timing of circadian rhythms in species from unicellular organisms to man. In addition, there is a circadian influence on the homeostatic response to acute 2G acceleration and pulses of 2G can act as a time cue, synchronizing the CTS. This is of significance because maintenance of internal and external temporal coordination is critical for normal physiological and psychological function. Typically, during adaptation to an increased gravitational environment (+G), an initial acute reaction is followed by adaptation and, eventually, a new steady state (14-16), which can take weeks to months to establish. Until the development of space stations, exposure to microgravity was, of necessity, relatively short in duration. In early spaceflight experiments an organism's internal rhythms often expressed periods that were different from each other, even in the presence of a 24.0 hour light-dark cycle, suggesting that the organism was experiencing internal desynchronization (17, 18). In (micro)G, the body temperature rhythm was delayed with respect to other body rhythms and to the light-dark cycle in rhesus macaques (19) and man (20, 21). In the absence of a light-dark cycle, the circadian rhythm of spore formation persisted in Neurospora crassa, however, both the variability and average period of the rhythm increased (22). The beetle Trigonoscelis gigas, exhibited changes in period during and following 11-13 days in (micro)G (23, 24). Resynchronization of the urinary calcium rhythm following a 1800 phase shift of the LID cycle was retarded in rats exposed to (micro)G compared to 1G controls (25). With the development of the Russian Mir Space Station, long-term controlled microgravity exposure became possible. We recorded activity rhythms from black-bodied Tenebrionid beetles, Trigonoscelis gigas, in (micro)G (spaceflight). Each insect was housed individually within an activity monitor (26) and data (activity counts) were collected and stored in five-minute bins. Thirty-two individual activity monitors were housed within each of 2 experimental kits. The beetles within each kit were divided into two groups and the lighting was controlled separately for each group.

Hoban-Higgins, Tana M.

2000-01-01

200

On Quantitative Software Quality Assurance Methodologies for Cardiac Pacemakers  

E-print Network

On Quantitative Software Quality Assurance Methodologies for Cardiac Pacemakers Marta Kwiatkowska an overview of ongoing research aimed at providing software quality as- surance methodologies for pacemakers with a variety of heart and pacemaker models. The framework supports a range of quantitative verification

Oxford, University of

201

Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock  

PubMed Central

Circadian and homeostatic neural circuits organize the temporal architecture of physiology and behavior, but knowledge of their interactions is imperfect. For example, neurons containing the neuropeptide orexin homeostatically control arousal and appetitive states, while neurons in the suprachiasmatic nuclei (SCN) function as the brain's master circadian clock. The SCN regulates orexin neurons so that they are much more active during the circadian night than the circadian day, but it is unclear whether the orexin neurons reciprocally regulate the SCN clock. Here we show both orexinergic innervation and expression of genes encoding orexin receptors (OX1 and OX2) in the mouse SCN, with OX1 being upregulated at dusk. Remarkably, we find through in vitro physiological recordings that orexin predominantly suppresses mouse SCN Period1 (Per1)-EGFP-expressing clock cells. The mechanisms underpinning these suppressions vary across the circadian cycle, from presynaptic modulation of inhibitory GABAergic signaling during the day to directly activating leak K+ currents at night. Orexin also augments the SCN clock-resetting effects of neuropeptide Y (NPY), another neurochemical correlate of arousal, and potentiates NPY's inhibition of SCN Per1-EGFP cells. These results build on emerging literature that challenge the widely held view that orexin signaling is exclusively excitatory and suggest new mechanisms for avoiding conflicts between circadian clock signals and homeostatic cues in the brain. PMID:24599460

Belle, Mino D.C.; Hughes, Alun T.L.; Bechtold, David A.; Cunningham, Peter; Pierucci, Massimo; Burdakov, Denis

2014-01-01

202

Sleep Syncope: Treatment with a Permanent Pacemaker  

PubMed Central

Vasovagal syncope usually occurs during upright posture, but Jardine et al. have described a variant that occurs at night. During “sleep syncope”, patients are awakened from sleep with nausea, abdominal cramping or a sense of impending diarrhea, get up, and faint in the bathroom. We report on a patient with recurrent sleep syncope (with physical injury) in whom an asystolic pause was documented during one of her “sleep syncope” spells. Implantation of a dual chamber pacemaker (5 year follow-up) “cured” her of further syncope. This is the 1st report of pacemaker use for this unusual form of reflex syncope. PMID:22433038

Rytlewski, Jason A.; Lee, John T.; Raj, Satish R.

2013-01-01

203

Improved automated monitoring and new analysis algorithm for circadian phototaxis rhythms in Chlamydomonas  

PubMed Central

Automated monitoring of circadian rhythms is an efficient way of gaining insight into oscillation parameters like period and phase for the underlying pacemaker of the circadian clock. Measurement of the circadian rhythm of phototaxis (swimming towards light) exhibited by the green alga Chlamydomonas reinhardtii has been automated by directing a narrow and dim light beam through a culture at regular intervals and determining the decrease in light transmittance due to the accumulation of cells in the beam. In this study, the monitoring process was optimized by constructing a new computer-controlled measuring machine that limits the test beam to wavelengths reported to be specific for phototaxis and by choosing an algal strain, which does not need background illumination between test light cycles for proper expression of the rhythm. As a result, period and phase of the rhythm are now unaffected by the time a culture is placed into the machine. Analysis of the rhythm data was also optimized through a new algorithm, whose robustness was demonstrated using virtual rhythms with various noises. The algorithm differs in particular from other reported algorithms by maximizing the fit of the data to a sinusoidal curve that dampens exponentially. The algorithm was also used to confirm the reproducibility of rhythm monitoring by the machine. Machine and algorithm can now be used for a multitude of circadian clock studies that require unambiguous period and phase determinations such as light pulse experiments to identify the photoreceptor(s) that reset the circadian clock in C. reinhardtii. PMID:20116270

Gaskill, Christa; Forbes-Stovall, Jennifer; Kessler, Bruce; Young, Mike; Rinehart, Claire A.; Jacobshagen, Sigrid

2010-01-01

204

Smooth-muscle BMAL1 participates in blood pressure circadian rhythm regulation.  

PubMed

As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood pressure without affecting SCN-controlled locomotor activity in murine models. In mesenteric arteries, BMAL1 bound to the promoter of and activated the transcription of Rho-kinase 2 (Rock2), and Bmal1 deletion abolished the time-of-day variations in response to agonist-induced vasoconstriction, myosin phosphorylation, and ROCK2 activation. Together, these data indicate that peripheral inputs contribute to the daily control of vasoconstriction and blood pressure and suggest that clock gene expression outside of the SCN should be further evaluated to elucidate pathogenic mechanisms of diseases involving blood pressure circadian rhythm disruption. PMID:25485682

Xie, Zhongwen; Su, Wen; Liu, Shu; Zhao, Guogang; Esser, Karyn; Schroder, Elizabeth A; Lefta, Mellani; Stauss, Harald M; Guo, Zhenheng; Gong, Ming Cui

2014-12-01

205

Gold-coated pacemaker implantation after allergic reactions to pacemaker compounds.  

PubMed

An 86-year-old man underwent pacemaker implantation for symptomatic atrio-ventricular block grade 2 Mobitz II. The patient suffered repeated admissions for iterative sterile wound necrosis, leading to two generator re-implantations. No bacterial infection was detected in the microbiological screening tests. The skin patch testing to titanium was negative. Nevertheless, we decided to remove the pacemaker system and to implant a gold-plated generator with polyurethane leads. Since then, there has been no recurrence of wound complications. Gold-plated generator and polyurethane leads are effective in treating allergic reactions to pacemaker system components in selected cases. Negative skin patch testing to titanium does not exclude allergic reaction to this pacemaker component. PMID:20022879

Syburra, Thomas; Schurr, Ulrich; Rahn, Mariette; Graves, Kirk; Genoni, Michele

2010-05-01

206

Melatonin Signaling Controls Circadian Swimming Behavior in Marine Zooplankton  

PubMed Central

Summary Melatonin, the “hormone of darkness,” is a key regulator of vertebrate circadian physiology and behavior. Despite its ubiquitous presence in Metazoa, the function of melatonin signaling outside vertebrates is poorly understood. Here, we investigate the effect of melatonin signaling on circadian swimming behavior in a zooplankton model, the marine annelid Platynereis dumerilii. We find that melatonin is produced in brain photoreceptors with a vertebrate-type opsin-based phototransduction cascade and a light-entrained clock. Melatonin released at night induces rhythmic burst firing of cholinergic neurons that innervate locomotor-ciliated cells. This establishes a nocturnal behavioral state by modulating the length and the frequency of ciliary arrests. Based on our findings, we propose that melatonin signaling plays a role in the circadian control of ciliary swimming to adjust the vertical position of zooplankton in response to ambient light. PMID:25259919

Tosches, Maria Antonietta; Bucher, Daniel; Vopalensky, Pavel; Arendt, Detlev

2014-01-01

207

Circadian rhythms regulate amelogenesis.  

PubMed

Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization. PMID:23486183

Zheng, Li; Seon, Yoon Ji; Mourão, Marcio A; Schnell, Santiago; Kim, Doohak; Harada, Hidemitsu; Papagerakis, Silvana; Papagerakis, Petros

2013-07-01

208

Drosophila GPCR Han is a receptor for the circadian clock neuropeptide PDF.  

PubMed

The pigment-dispersing factor (PDF) is a neuropeptide controlling circadian behavioral rhythms in Drosophila, but its receptor is not yet known. From a large-scale temperature preference behavior screen in Drosophila, we isolated a P insertion mutant that preferred different temperatures during the day and night. This mutation, which we named han, reduced the transcript level of CG13758. We found that Han was expressed specifically in 13 pairs of circadian clock neurons in the adult brain. han null flies showed arrhythmic circadian behavior in constant darkness. The behavioral characteristics of han null mutants were similar to those of pdf null mutants. We also found that PDF binds specifically to S2 cells expressing Han, which results in the elevation of cAMP synthesis. Therefore, we herein propose that Han is a PDF receptor regulating circadian behavioral rhythm through coordination of activities of clock neurons. PMID:16242407

Hyun, Seogang; Lee, Youngseok; Hong, Sung-Tae; Bang, Sunhoe; Paik, Donggi; Kang, Jongkyun; Shin, Jinwhan; Lee, Jaejung; Jeon, Keunhye; Hwang, Seungyoon; Bae, Eunkyung; Kim, Jaeseob

2005-10-20

209

[Heart pacemaker with lithium batteries. 2 years' clinical experience].  

PubMed

102 lithium-powered cardiac pacemakers manufactured by Cardiac Pacemakers Inc. (CPI 301 UD, 101 UA and 501 UD) were implanted in 94 patients. During the observation time (25 months) the following complications were registered: 2 pulse generator failures, 4 failures of the demand-function, anodic muscle-twitching in 2 patients, 2 erosions of the pacemaker-pocket and 1 hematoma of the pocket. 5 pulse generators were exchanged without malfunction of the pacemaker. In 4 patients reinterventions on the electrode had, to be performed. 4 deaths occurred, none of them related to malfunction of the pacemaker. 2 lithium-powered pacemakers were explanted in other hospitals, for reasons not known to us and 1 patient left the German Federal Republic. 83 patients are under control with well working lithium-powered pacemakers. PMID:964900

Präuer, H W; Lampadius, M; Wirtzfeld, A; Schmück, L

1976-03-11

210

Prevention of pacemaker-associated contact dermatitis by polytetrafluoroethylene sheet and conduit coating of the pacemaker system.  

PubMed

A 73-year-old female with sick sinus syndrome and atrial fibrillation was implanted with a ventricular demand inhibit pacemaker. She subsequently developed multiple episodes of skin irritation and necrosis. Skin patch testing revealed sensitivity to almost every component of the pacemaker system. The pacemaker was removed and replaced with a new pacemaker in which the generator was covered with a polytetrafluoroethylene (PTFE) sheet and the lead was covered with PTFE conduit. The patient suffered no further episodes of pacemaker-associated contact dermatitis. PMID:24899091

Taguchi, Takahiro; Maeba, Satoru; Sueda, Taijiro

2014-09-01

211

Protein localization during the cyanobacterial circadian cycle  

E-print Network

Circadian clocks are ubiquitous throughout the living world. Of these circadian clocks, the simplest one is found in cyanobacteria - unicellular, photosynthetic marine organisms. Studies of the circadian clock of Synechococcus ...

Luitel, Prashant

2008-01-01

212

Melatonin for Circadian Rhythm Disturbances in Dementia  

E-print Network

Melatonin for Circadian Rhythm Disturbances in Dementia Available from: http. Describe the pathophysiology of circadian rhythm disturbances in dementia 2. Evaluate current treatment options for circadian rhythm disturbances in dementia 3. Review available literature on the use

Pillow, Jonathan

213

MDMA alters the response of the circadian clock to a photic and non-photic stimulus  

Microsoft Academic Search

3,4-Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a widely used recreational drug that damages serotonin 5-HT neurons in animals and possibly humans. Published literature has shown that the serotonergic system is involved in photic and non-photic phase shifting of the circadian clock, which is located in the suprachiasmatic nuclei. Despite the dense innervation of the circadian system by 5-HT and the known

Suzanne Colbron; Mark Jones; Stephany M Biello

2002-01-01

214

Assaying Locomotor Activity to Study Circadian Rhythms and Sleep Parameters in Drosophila  

PubMed Central

Most life forms exhibit daily rhythms in cellular, physiological and behavioral phenomena that are driven by endogenous circadian (?24 hr) pacemakers or clocks. Malfunctions in the human circadian system are associated with numerous diseases or disorders. Much progress towards our understanding of the mechanisms underlying circadian rhythms has emerged from genetic screens whereby an easily measured behavioral rhythm is used as a read-out of clock function. Studies using Drosophila have made seminal contributions to our understanding of the cellular and biochemical bases underlying circadian rhythms. The standard circadian behavioral read-out measured in Drosophila is locomotor activity. In general, the monitoring system involves specially designed devices that can measure the locomotor movement of Drosophila. These devices are housed in environmentally controlled incubators located in a darkroom and are based on using the interruption of a beam of infrared light to record the locomotor activity of individual flies contained inside small tubes. When measured over many days, Drosophila exhibit daily cycles of activity and inactivity, a behavioral rhythm that is governed by the animal's endogenous circadian system. The overall procedure has been simplified with the advent of commercially available locomotor activity monitoring devices and the development of software programs for data analysis. We use the system from Trikinetics Inc., which is the procedure described here and is currently the most popular system used worldwide. More recently, the same monitoring devices have been used to study sleep behavior in Drosophila. Because the daily wake-sleep cycles of many flies can be measured simultaneously and only 1 to 2 weeks worth of continuous locomotor activity data is usually sufficient, this system is ideal for large-scale screens to identify Drosophila manifesting altered circadian or sleep properties. PMID:20972399

Chiu, Joanna C.; Low, Kwang Huei; Pike, Douglas H.; Yildirim, Evrim; Edery, Isaac

2010-01-01

215

Circadian Rhythm Disorders and Melatonin Production in 127 Blind Women with and without Light Perception.  

PubMed

Light is the major environmental time cue that synchronizes the endogenous central circadian pacemaker, located in the suprachiasmatic nuclei of the hypothalamus, and is detected exclusively by the eyes primarily via specialized non-rod, non-cone ganglion cell photoreceptors. Consequently, most blind people with no perception of light (NPL) have either nonentrained or abnormally phased circadian rhythms due to this inability to detect light. Conversely, most visually impaired participants with some degree of light perception (LP) exhibit normal entrainment, emphasizing the functional separation of visual and "nonvisual" photoreception. The aims of the study were to identify the prevalence of circadian disorders in blind women, with the further aim of examining how eye disease may relate to the type of circadian disorder. Participants (n = 127, age 50.8 ± 13.4 years) completed an 8-week field study including daily sleep diaries and sequential 4 to 8 hourly urine collections over 48 h on 2 to 3 occasions separated by at least 2 weeks. Circadian type was determined from the timing and time course of the melatonin rhythm measured by cosinor-derived urinary 6-sulfatoxymelatonin rhythm peak. Of the participants with NPL (n = 41), the majority were abnormally phased (24%) or nonentrained (39%), with 37% classified as normally entrained. Of the participants with LP (n = 86), the majority were normally entrained (69%). Eighteen LP participants (21%) were abnormally phased (8 advanced, 10 delayed). Nine LP participants (10%) were nonentrained. The eye conditions most associated with abnormal phase and/or nonentrained circadian rhythms were bilateral enucleation (67%) and retinopathy of prematurity (57%). By contrast, 84% of participants with retinitis pigmentosa and 83% of those with age-related macular degeneration were normally entrained. These findings suggest that the etiology of blindness in addition to LP status is related to an individual's ability to process the circadian light signal. PMID:24916394

Flynn-Evans, Erin E; Tabandeh, Homayoun; Skene, Debra J; Lockley, Steven W

2014-06-10

216

CREB Influences Timing and Entrainment of the SCN Circadian Clock  

PubMed Central

The transcriptional feedback circuit, which is at the core of the suprachiasmatic nucleus (SCN) circadian (i.e., 24 h) clock, is tightly coupled to both external entrainment cues, such as light, as well as rhythmic cues that arise on a system-wide level within the SCN. One potential signaling pathway by which these cues are conveyed to the molecular clock is the CREB/CRE transcriptional cascade. In this study, we employed a tetracycline-inducible CREB repressor mouse strain, in which approximately 60% of the SCN neurons express the transgene, to test CREB functionality in the clock and its effects on overt rhythmicity. We show that attenuated CREB signaling in the SCN led to a significant reduction in light-evoked clock entrainment. An examination of circadian timing revealed that CREB repressor mice exhibited normal free-running rhythms in the absence of external lighting cues. However, under conditions of constant light, which typically leads to a lengthening of the circadian period, CREB repressor mice exhibited a dramatic arrhythmic phenotype, which could be reversed with doxycycline. At a cellular level, the repression of CREB led to a significant reduction in both the expression of the circadian clock proteins PERIOD1 and PERIOD2 and the clock output hormones AVP and VIP. Together, these data support the idea that the CRE transcriptional pathway orchestrates transcriptional events that are essential for both the maintenance of SCN timing and light entrainment of the circadian clock. PMID:21135157

Lee, Boyoung; Li, Aiqing; Hansen, Katelin F.; Cao, Ruifeng; Yoon, Jae Hwa; Obrietan, Karl

2011-01-01

217

N-nitrosomelatonin enhances photic synchronization of mammalian circadian rhythms.  

PubMed

Most physiological processes in mammals are synchronized to the daily light:dark cycle by a circadian clock located in the hypothalamic suprachiasmatic nucleus. Signal transduction of light-induced phase advances of the clock is mediated through a neuronal nitric oxide synthase-guanilyl cyclase pathway. We have employed a novel nitric oxide-donor, N-nitrosomelatonin, to enhance the photic synchronization of circadian rhythms in hamsters. The intraperitoneal administration of this drug before a sub-saturating light pulse at circadian time 18 generated a twofold increase of locomotor rhythm phase-advances, having no effect over saturating light pulses. This potentiation was also obtained even when inhibiting suprachiasmatic nitric oxide synthase activity. However, N-nitrosomelatonin had no effect on light-induced phase delays at circadian time 14. The photic-enhancing effects were correlated with an increased suprachiasmatic immunoreactivity of FBJ murine osteosarcoma viral oncogene and period1. Moreover, in vivo nitric oxide release by N-nitrosomelatonin was verified by measuring nitrate and nitrite levels in suprachiasmatic nuclei homogenates. The compound also accelerated resynchronization to an abrupt 6-h advance in the light:dark cycle (but not resynchronization to a 6-h delay). Here, we demonstrate the chronobiotic properties of N-nitrosomelatonin, emphasizing the importance of nitric oxide-mediated transduction for circadian phase advances. PMID:24261470

Baidanoff, Fernando M; Plano, Santiago A; Doctorovich, Fabio; Suárez, Sebastián A; Golombek, Diego A; Chiesa, Juan J

2014-04-01

218

Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor  

PubMed Central

The circadian clock enables the anticipation of daily recurring environmental changes by presetting an organism’s physiology and behavior. Driven and synchronized by a central pacemaker in the brain, circadian output genes fine-tune a wide variety of physiological parameters in peripheral organs. However, only a subset of circadianly transcribed genes seems to be directly regulated by core clock proteins. Assuming that yet unidentified transcription factors may exist in the circadian transcriptional network, we set out to develop a novel technique, differential display of DNA-binding proteins (DDDP), which we used to screen mouse liver nuclear extracts. In addition to several established circadian transcription factors, we found DNA binding of heat-shock factor 1 (HSF1) to be highly rhythmic. HSF1 drives the expression of heat-shock proteins at the onset of the dark phase, when the animals start to be behaviorally active. Furthermore, Hsf1-deficient mice have a longer free-running period than wild-type littermates, suggesting a combined role for HSF1 in the mammalian timekeeping and cytoprotection systems. Our results also suggest that the new screening method DDDP is not limited to the identification of circadian transcription factors but can be applied to discover novel transcriptional regulators in various biological systems. PMID:18245447

Reinke, Hans; Saini, Camille; Fleury-Olela, Fabienne; Dibner, Charna; Benjamin, Ivor J.; Schibler, Ueli

2008-01-01

219

Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor.  

PubMed

The circadian clock enables the anticipation of daily recurring environmental changes by presetting an organism's physiology and behavior. Driven and synchronized by a central pacemaker in the brain, circadian output genes fine-tune a wide variety of physiological parameters in peripheral organs. However, only a subset of circadianly transcribed genes seems to be directly regulated by core clock proteins. Assuming that yet unidentified transcription factors may exist in the circadian transcriptional network, we set out to develop a novel technique, differential display of DNA-binding proteins (DDDP), which we used to screen mouse liver nuclear extracts. In addition to several established circadian transcription factors, we found DNA binding of heat-shock factor 1 (HSF1) to be highly rhythmic. HSF1 drives the expression of heat-shock proteins at the onset of the dark phase, when the animals start to be behaviorally active. Furthermore, Hsf1-deficient mice have a longer free-running period than wild-type littermates, suggesting a combined role for HSF1 in the mammalian timekeeping and cytoprotection systems. Our results also suggest that the new screening method DDDP is not limited to the identification of circadian transcription factors but can be applied to discover novel transcriptional regulators in various biological systems. PMID:18245447

Reinke, Hans; Saini, Camille; Fleury-Olela, Fabienne; Dibner, Charna; Benjamin, Ivor J; Schibler, Ueli

2008-02-01

220

A model for predicting electromagnetic interference of implanted cardiac pacemakers by mobile telephones  

Microsoft Academic Search

A prediction of the electromagnetic interference (EMI) of pacemakers due to mobile phones is significant in improving the immunity of pacemakers. The Pacemaker Committee of Japan recently conducted immunity tests of pacemakers for mobile phones, and consequently concluded that the connector between the pacemaker housing and the lead wire of the electrode plays a major role for the EMI due

Jianqing Wang; Osamu Fujiwara; Toshio Nojima

2000-01-01

221

Circadian rhythms. Decoupling circadian clock protein turnover from circadian period determination.  

PubMed

The mechanistic basis of eukaryotic circadian oscillators in model systems as diverse as Neurospora, Drosophila, and mammalian cells is thought to be a transcription-and-translation-based negative feedback loop, wherein progressive and controlled phosphorylation of one or more negative elements ultimately elicits their own proteasome-mediated degradation, thereby releasing negative feedback and determining circadian period length. The Neurospora crassa circadian negative element FREQUENCY (FRQ) exemplifies such proteins; it is progressively phosphorylated at more than 100 sites, and strains bearing alleles of frq with anomalous phosphorylation display abnormal stability of FRQ that is well correlated with altered periods or apparent arrhythmicity. Unexpectedly, we unveiled normal circadian oscillations that reflect the allelic state of frq but that persist in the absence of typical degradation of FRQ. This manifest uncoupling of negative element turnover from circadian period length determination is not consistent with the consensus eukaryotic circadian model. PMID:25635104

Larrondo, Luis F; Olivares-Yañez, Consuelo; Baker, Christopher L; Loros, Jennifer J; Dunlap, Jay C

2015-01-30

222

Uncovering the Proteome Response of the Master Circadian Clock to Light Using an AutoProteome System*  

PubMed Central

In mammals, the suprachiasmatic nucleus (SCN) is the central circadian pacemaker that governs rhythmic fluctuations in behavior and physiology in a 24-hr cycle and synchronizes them to the external environment by daily resetting in response to light. The bilateral SCN is comprised of a mere ?20,000 neurons serving as cellular oscillators, a fact that has, until now, hindered the systematic study of the SCN on a global proteome level. Here we developed a fully automated and integrated proteomics platform, termed AutoProteome system, for an in-depth analysis of the light-responsive proteome of the murine SCN. All requisite steps for a large-scale proteomic study, including preconcentration, buffer exchanging, reduction, alkylation, digestion and online two-dimensional liquid chromatography-tandem MS analysis, are performed automatically on a standard liquid chromatography-MS system. As low as 2 ng of model protein bovine serum albumin and up to 20 ?g and 200 ?g of SCN proteins can be readily processed and analyzed by this system. From the SCN tissue of a single mouse, we were able to confidently identify 2131 proteins, of which 387 were light-regulated based on a spectral counts quantification approach. Bioinformatics analysis of the light-inducible proteins reveals their diverse distribution in different canonical pathways and their heavy connection in 19 protein interaction networks. The AutoProteome system identified vasopressin-neurophysin 2-copeptin and casein kinase 1 delta, both of which had been previously implicated in clock timing processes, as light-inducible proteins in the SCN. Ras-specific guanine nucleotide-releasing factor 1, ubiquitin protein ligase E3A, and X-linked ubiquitin specific protease 9, none of which had previously been implicated in SCN clock timing processes, were also identified in this study as light-inducible proteins. The AutoProteome system opens a new avenue to systematically explore the proteome-wide events that occur in the SCN, either in response to light or other stimuli, or as a consequence of its intrinsic pacemaker capacity. PMID:21859948

Tian, Ruijun; Alvarez-Saavedra, Matias; Cheng, Hai-Ying M.; Figeys, Daniel

2011-01-01

223

Circadian and sleep-dependent regulation of hormone release in humans  

NASA Technical Reports Server (NTRS)

Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian rhythm sleep disorders, including the dyssomnia of shift work and visual impairment. Yet to be fully investigated are the interactions of these factors with age and gender. Characterization of the factors governing hormone secretion is critical to understanding the temporal regulation of endocrine systems and presents many exciting areas for future research.

Czeisler, C. A.; Klerman, E. B.

1999-01-01

224

77 FR 37573 - Effective Date of Requirement for Premarket Approval for an Implantable Pacemaker Pulse Generator  

Federal Register 2010, 2011, 2012, 2013

...Approval for an Implantable Pacemaker Pulse Generator AGENCY: Food and Drug Administration...PDP) for implantable pacemaker pulse generators. The Agency has summarized its findings...PDP for the implantable pacemaker pulse generator. In accordance with section...

2012-06-22

225

Pacemaker lead erosion simulating "Loch Ness Monster": conservative management.  

PubMed

The majority of pacemaker pocket or lead erosions are due to either mechanical erosion by the bulky pulse generator or secondary to pacemaker pocket infection. We describe an unusual case of delayed pacemaker lead erosion causing extrusion of a portion of the pacing lead, with separate entry and exit points, with the gap filled with new skin formation, simulating the "Loch Ness Monster", which was successfully managed conservatively by surgical reinsertion. PMID:23284119

Garg, Naveen; Moorthy, Nagaraja

2012-12-01

226

Common pitfalls in interpreting pacemaker electrocardiograms in the emergency department.  

PubMed

The number of patients receiving pacemakers and defibrillators has grown substantially over the last 20 years. In addition, the complexity and sophistication of these devices have increased, making diagnosis of pacemaker problems using the electrocardiogram (ECG) more difficult for clinicians in the emergency department. This article will focus on a few of the pitfalls to be avoided when interpreting paced ECGs. Pacemaker algorithms designed to minimize right ventricular pacing may be confused with pathologic failure to output. Automatic capture threshold detection schemes may be misinterpreted as failure to capture as well as undersensing due to the extra "backup" pacemaker spikes noted on rhythm strips. Device testing done in the emergency department may produce waveforms on monitor resembling ventricular tachycardia if pacemaker-mediated tachycardia is produced accidentally. Ventricular safety pacing algorithms may also be misinterpreted as failure to sense appropriately, triggering questions about pacemaker malfunction. Certain types of true undersensing may resemble morphologies consistent with pacemaker lead dislodgment. In addition, sophisticated programming features designed to mimic normal physiology could be misconstrued as pacemaker malfunction. These include pacemaker hysteresis and sleep mode. The presence of frequent premature ventricular complexes would cause a pacemaker to inhibit ventricular pacing appropriately. However, this could produce a palpated heart rate that is substantially lower than the programmed lower rate of the device due to reduced perfusion by the premature ventricular complexes, again raising questions about the appropriate functioning of the pacemaker. All of these situations will be discussed in detail along with approaches to systematically examining the paced ECGs to minimize the risk of misinterpretation. Pacemaker timing cycles as they relate to troubleshooting of the paced ECG will also be introduced. PMID:21907995

Venkatachalam, K L

2011-01-01

227

Proton Beam Therapy Interference With Implanted Cardiac Pacemakers  

Microsoft Academic Search

Purpose: To investigate the effect of proton beam therapy (PBT) on implanted cardiac pacemaker function. Methods and Materials: After a phantom study confirmed the safety of PBT in patients with cardiac pacemakers, we treated 8 patients with implanted pacemakers using PBT to a total tumor dose of 33-77 gray equivalents (GyE) in dose fractions of 2.2-6.6 GyE. The combined total

Yoshiko Oshiro; Shinji Sugahara; Mio Noma; Masato Sato; Yuzuru Sakakibara; Takeji Sakae; Yasutaka Hayashi; Hidetsugu Nakayama; Koji Tsuboi; Nobuyoshi Fukumitsu; Ayae Kanemoto; Takayuki Hashimoto; Koichi Tokuuye

2008-01-01

228

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity  

PubMed Central

Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA) allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons. PMID:23505510

Mordel, Jérôme; Karnas, Diana; Pévet, Paul; Isope, Philippe; Challet, Etienne; Meissl, Hilmar

2013-01-01

229

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2013 CFR

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a)...

2013-04-01

230

21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).  

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Therapeutic Devices § 870.5550 External transcutaneous cardiac pacemaker (noninvasive)....

2014-04-01

231

21 CFR 870.3620 - Pacemaker lead adaptor.  

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A...

2014-04-01

232

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2013 CFR

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A...

2013-04-01

233

21 CFR 870.3730 - Pacemaker service tools.  

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification....

2014-04-01

234

21 CFR 870.3720 - Pacemaker electrode function tester.  

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3720 Pacemaker electrode function tester. (a)...

2014-04-01

235

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2013 CFR

...FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification....

2013-04-01

236

SIRT1 regulates circadian clock gene expression through PER2 deacetylation.  

PubMed

The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus of the brain that synchronizes countless subsidiary oscillators in peripheral tissues. The rhythm-generating mechanism is thought to rely on a feedback loop involving positively and negatively acting transcription factors. BMAL1 and CLOCK activate the expression of Period (Per) and Cryptochrome (Cry) genes, and once PER and CRY proteins accumulate to a critical level they form complexes with BMAL1-CLOCK heterodimers and thereby repress the transcription of their own genes. Here, we show that SIRT1, an NAD(+)-dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorgamma, Per2, and Cry1. SIRT1 binds CLOCK-BMAL1 in a circadian manner and promotes the deacetylation and degradation of PER2. Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry. PMID:18662546

Asher, Gad; Gatfield, David; Stratmann, Markus; Reinke, Hans; Dibner, Charna; Kreppel, Florian; Mostoslavsky, Raul; Alt, Frederick W; Schibler, Ueli

2008-07-25

237

Animal activity around the clock with no overt circadian rhythms: patterns, mechanisms and adaptive value.  

PubMed

Circadian rhythms are ubiquitous in many organisms. Animals that are forced to be active around the clock typically show reduced performance, health and survival. Nevertheless, we review evidence of animals showing prolonged intervals of activity with attenuated or nil overt circadian rhythms and no apparent ill effects. We show that around-the-clock and ultradian activity patterns are more common than is generally appreciated, particularly in herbivores, in animals inhabiting polar regions and habitats with constant physical environments, in animals during specific life-history stages (such as migration or reproduction), and in highly social animals. The underlying mechanisms are diverse, but studies suggest that some circadian pacemakers continue to measure time in animals active around the clock. The prevalence of around-the-clock activity in diverse animals and habitats, and an apparent diversity of underlying mechanisms, are consistent with convergent evolution. We suggest that the basic organizational principles of the circadian system and its complexity encompass the potential for chronobiological plasticity. There may be trade-offs between benefits of persistent daily rhythms versus plasticity, which for reasons still poorly understood make overt daily arrhythmicity functionally adaptive only in selected habitats and for selected lifestyles. PMID:23825202

Bloch, Guy; Barnes, Brian M; Gerkema, Menno P; Helm, Barbara

2013-08-22

238

Animal activity around the clock with no overt circadian rhythms: patterns, mechanisms and adaptive value  

PubMed Central

Circadian rhythms are ubiquitous in many organisms. Animals that are forced to be active around the clock typically show reduced performance, health and survival. Nevertheless, we review evidence of animals showing prolonged intervals of activity with attenuated or nil overt circadian rhythms and no apparent ill effects. We show that around-the-clock and ultradian activity patterns are more common than is generally appreciated, particularly in herbivores, in animals inhabiting polar regions and habitats with constant physical environments, in animals during specific life-history stages (such as migration or reproduction), and in highly social animals. The underlying mechanisms are diverse, but studies suggest that some circadian pacemakers continue to measure time in animals active around the clock. The prevalence of around-the-clock activity in diverse animals and habitats, and an apparent diversity of underlying mechanisms, are consistent with convergent evolution. We suggest that the basic organizational principles of the circadian system and its complexity encompass the potential for chronobiological plasticity. There may be trade-offs between benefits of persistent daily rhythms versus plasticity, which for reasons still poorly understood make overt daily arrhythmicity functionally adaptive only in selected habitats and for selected lifestyles. PMID:23825202

Bloch, Guy; Barnes, Brian M.; Gerkema, Menno P.; Helm, Barbara

2013-01-01

239

Development of the Circadian Timing System in Rat Pups Exposed to Microgravity during Gestation  

NASA Technical Reports Server (NTRS)

Ten pregnant Sprague Dawley rat dams were exposed to spaceflight aboard the Space Shuttle (STS-70) for gestational days 11-20 (G 11-20; FILT group). Control dams were maintained in either a flight-like (FIDS group) or vivarium cage environment (VIV group) on earth. All dams had ad lib access to food and water and were exposed to a light-dark cycle consisting of 12 hours of light (- 30 lux) followed by 12 hours of darkness. The dams were closely monitored from G 22 until parturition. All pups were cross-fostered at birth; each foster dam had a litter of 10 pups. Pups remained with their foster dam until post-natal day 21 (PN 21). Pup body mass was measured twice weekly. At PN14 FILT pups had a smaller body mass than did the VIV pups (p < 0.01). Circadian rhythms of body temperature and activity of pups from two FILT dams (n = 8), two FIDS dams (n = 9) and two VIV dams (n = 7) were studied starting from age PN 21. All pups had circadian rhythms of temperature and activity at this age. There were no significant differences in rhythms between groups that could be attributed to microgravity exposure. We also examined the development of neural structures involved in circadian rhythmicity: the retina, the intergeniculate leaflet (IGL) and the circadian pacemaker, the suprachiasmatic nucleus (SCN). There were small differences between the flight and control groups at very early stages of development (G 20 and PN3) which indicated that the development of both the SCN and the IGL. These results indicate that exposure to the microgravity environment of spaceflight during this embryonic development period does not affect the development of the circadian rhythms of body temperature and activity, but may affect the early development of the neural structures involved in circadian timing.

Fuller, Charles A.

2000-01-01

240

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

PubMed

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. PMID:25160468

Ikeno, Tomoko; Nelson, Randy J

2015-02-01

241

GW182 controls Drosophila circadian behavior and PDF-receptor signaling.  

PubMed

The neuropeptide PDF is crucial for Drosophila circadian behavior: it keeps circadian neurons synchronized. Here, we identify GW182 as a key regulator of PDF signaling. Indeed, GW182 downregulation results in phenotypes similar to those of Pdf and Pdf-receptor (Pdfr) mutants. gw182 genetically interacts with Pdfr and cAMP signaling, which is essential for PDFR function. GW182 mediates miRNA-dependent gene silencing through its interaction with AGO1. Consistently, GW182's AGO1 interaction domain is required for GW182's circadian function. Moreover, our results indicate that GW182 modulates PDFR signaling by silencing the expression of the cAMP phosphodiesterase DUNCE. Importantly, this repression is under photic control, and GW182 activity level--which is limiting in circadian neurons--influences the responses of the circadian neural network to light. We propose that GW182's gene silencing activity functions as a rheostat for PDFR signaling and thus profoundly impacts the circadian neural network and its response to environmental inputs. PMID:23583112

Zhang, Yong; Emery, Patrick

2013-04-10

242

Circadian gene variants in cancer.  

PubMed

Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356

Kettner, Nicole M; Katchy, Chinenye A; Fu, Loning

2014-06-01

243

Circadian rhythms, melatonin and depression.  

PubMed

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression. PMID:21476953

Quera Salva, M A; Hartley, S; Barbot, F; Alvarez, J C; Lofaso, F; Guilleminault, C

2011-01-01

244

CaV3.1 is a tremor rhythm pacemaker in the inferior olive  

PubMed Central

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of CaV3.1 T-type Ca2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking CaV3.1 gene. Intracellular recordings in brain-stem slices revealed that the CaV3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of CaV3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate CaV3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, CaV3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor. PMID:20498062

Park, Young-Gyun; Park, Hye-Yeon; Lee, C. Justin; Choi, Soonwook; Jo, Seonmi; Choi, Hansol; Kim, Yang-Hann; Shin, Hee-Sup; Llinas, Rodolfo R.; Kim, Daesoo

2010-01-01

245

Casein kinase 1 promotes synchrony of the circadian clock network.  

PubMed

Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbt(EY02910) loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbt(EY02910) flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (?32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbt(EY02910) mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun; Sehgal, Amita

2014-07-01

246

Translational profiling of clock cells reveals circadianly synchronized protein synthesis.  

PubMed

Genome-wide studies of circadian transcription or mRNA translation have been hindered by the presence of heterogeneous cell populations in complex tissues such as the nervous system. We describe here the use of a Drosophila cell-specific translational profiling approach to document the rhythmic "translatome" of neural clock cells for the first time in any organism. Unexpectedly, translation of most clock-regulated transcripts--as assayed by mRNA ribosome association--occurs at one of two predominant circadian phases, midday or mid-night, times of behavioral quiescence; mRNAs encoding similar cellular functions are translated at the same time of day. Our analysis also indicates that fundamental cellular processes--metabolism, energy production, redox state (e.g., the thioredoxin system), cell growth, signaling and others--are rhythmically modulated within clock cells via synchronized protein synthesis. Our approach is validated by the identification of mRNAs known to exhibit circadian changes in abundance and the discovery of hundreds of novel mRNAs that show translational rhythms. This includes Tdc2, encoding a neurotransmitter synthetic enzyme, which we demonstrate is required within clock neurons for normal circadian locomotor activity. PMID:24348200

Huang, Yanmei; Ainsley, Joshua A; Reijmers, Leon G; Jackson, F Rob

2013-11-01

247

Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network  

PubMed Central

Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbtEY02910 loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbtEY02910 flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (?32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbtEY02910 mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun

2014-01-01

248

Role of cardiomyocyte circadian clock in myocardial metabolic adaptation  

Technology Transfer Automated Retrieval System (TEKTRAN)

Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential f...

249

Biological Clocks and Circadian Rhythms  

NSDL National Science Digital Library

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 rhythms, they are provided with opportunities to connect learning to experiences and observations from their own lives. This article describes how to reset the biological clock of a shamrock plant while shedding light on its circadian rhythms.

Laura Robertson

2009-02-01

250

Circadian rhythms and tumor growth.  

PubMed

Hormone secretion, metabolism, and the cell cycle are under rhythmic control. Lack of rhythmic control has been predicted to lead to uncontrolled proliferation and cancer. Consistent with this prediction are findings that circadian disruption by dim light at night or chronic jet lag accelerates tumor growth in desynchronized animals. Circadian controlled factors such as insulin/IGF-1, glucocorticoids, catecholamines, and melatonin have be implicated in controlling tumor growth in the desynchronized animals. Recent attention has focused on the signaling pathways activated by the circadian controlled factors because these pathways hold the potential for the development of novel strategies for cancer prevention and treatment. PMID:22252116

Greene, Michael W

2012-05-28

251

[A Corynebacterium striatum endocarditis on a carrier of pacemaker].  

PubMed

We report a new case of a Corynebacterium striatum endocarditis on a carrier of a pacemaker. Corynebacterium striatum was isolated from blood culture, the pulse generator and the pacing lead. A literature review of Corynebacterium striatum endocarditis on a carrier of pacemaker was conducted. PMID:22565181

Abi, Rachid; Ez-Zahraouii, Khalil; Ghazouani, Mohammed; Zohoun, Alban; Kheyi, Jamal; Chaib, Ali; Elouennass, Mostafa

2012-01-01

252

Pinealectomy shortens resynchronisation times of house sparrow ( Passer domesticus) circadian rhythms  

NASA Astrophysics Data System (ADS)

In many birds periodic melatonin secretion by the pineal organ is essential for the high-amplitude self-sustained output of the circadian pacemaker, and thus for the persistence of rhythmicity in 24 h oscillations controlled by it. The elimination of the pineal melatonin rhythm, or a reduction of its amplitude, renders the circadian pacemaker a less self-sustained, often highly damped, oscillatory system. A reduction in the degree of self-sustainment of a rhythm should not only increase its range of entrainment but also shorten the resynchronization times following phase-shifts of the zeitgeber. This hypothesis has not yet been directly tested. We therefore carried out the present study in which house sparrows (Passer domesticus) were subjected to both 6-h advance and 6-h delay phase-shifts of the light-dark cycle before and after the pinealectomy, and the rhythms in locomotion and feeding were recorded. The results indicate that following the delay, but not the advance, phase shift, resynchronization times were significantly shorter after pinealectomy. The dependence of resynchronization times on the presence or absence of the pineal organ is not only of theoretical interest but might also be of functional significance in the natural life of birds. A reduction or elimination of the amplitude of the melatonin secretion rhythm by the pineal organ might be responsible for faster adjustment to changes in zeitgeber conditions in nature.

Kumar, Vinod; Gwinner, Eberhard

2005-09-01

253

Daily variation in the electrophysiological activity of mouse medial habenula neurones  

PubMed Central

AbstractIntrinsic daily or circadian rhythms arise through the outputs of the master circadian clock in the brain's suprachiasmatic nuclei (SCN) as well as circadian oscillators in other brain sites and peripheral tissues. SCN neurones contain an intracellular molecular clock that drives these neurones to exhibit pronounced day–night differences in their electrical properties. The epithalamic medial habenula (MHb) expresses clock genes, but little is known about the bioelectric properties of mouse MHb neurones and their potential circadian characteristics. Therefore, in this study we used a brain slice preparation containing the MHb to determine the basic electrical properties of mouse MHb neurones with whole-cell patch clamp electrophysiology, and investigated whether these vary across the day–night cycle. MHb neurones (n = 230) showed heterogeneity in electrophysiological state, ranging from highly depolarised cells (? ?25 to ?30 mV) that are silent with no membrane activity or display depolarised low-amplitude membrane oscillations, to neurones that were moderately hyperpolarised (?40 mV) and spontaneously discharging action potentials. These electrical states were largely intrinsically regulated and were influenced by the activation of small-conductance calcium-activated potassium channels. When considered as one population, MHb neurones showed significant circadian variation in their spontaneous firing rate and resting membrane potential. However, in recordings of MHb neurones from mice lacking the core molecular circadian clock, these temporal differences in MHb activity were absent, indicating that circadian clock signals actively regulate the timing of MHb neuronal states. These observations add to the extracellularly recorded rhythms seen in other brain areas and establish that circadian mechanisms can influence the membrane properties of neurones in extra-SCN sites. Collectively, the results of this study indicate that the MHb may function as an intrinsic secondary circadian oscillator in the brain, which can shape daily information flow in key brain processes, such as reward and addiction. PMID:24247982

Sakhi, Kanwal; Belle, Mino D C; Gossan, Nicole; Delagrange, Philippe; Piggins, Hugh D

2014-01-01

254

Use of pacemaker programmers for disaster victim identification.  

PubMed

Disaster victim identification (DVI) presents a number of physical and legal challenges, involving the degeneration of human remains and legal obstacles to forensic examinations. One non-invasive method for positive identification may be the use of a pacemaker programmer to detect and obtain data from pacemakers recovered from unidentified remains. To test the usefulness of this method, this investigation examined the efficiency and utility of 5 different pacemaker programmers in the positive identification of victims of the March 2011 tsunami in Japan at 8 disaster sites in May 2011. On scanning 148 sets of remains, data were successfully obtained from 1 implant in 1 set of remains, allowing for the rapid positive identification of the individual. Scanning pacemakers with pacemaker programmers can be a non-invasive method of positive identification that meets Japanese legal and institutional requirements, but this method is ineffective without a preceding whole-body X-ray scan. PMID:23592022

Makinae, Haruka; Numata, Norio; Kitaoka, Hirofumi; Daimon, Masao; Yamamoto, Taira; Amano, Atsushi

2013-12-01

255

Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks  

PubMed Central

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase. PMID:23824542

Saini, Camille; Liani, André; Curie, Thomas; Gos, Pascal; Kreppel, Florian; Emmenegger, Yann; Bonacina, Luigi; Wolf, Jean-Pierre; Poget, Yves-Alain; Franken, Paul; Schibler, Ueli

2013-01-01

256

An Effect of Castration and Testosterone Replacement on a Circadian Pacemaker in Mice (Mus musculus)  

Microsoft Academic Search

Castration of mice in freerunning conditions (total darkness, DD) causes a reduction of running wheel activity in the beginning of the active period (alpha ) and stimulates activity at the end of alpha . Simultaneously, the period (tau ) of the freerunning rhythm is increased. Both effects are abolished by implantation of a Silastic capsule from which a physiological dose

Serge Daan; David Damassa; Colin S. Pittendrigh; Erla R. Smith

1975-01-01

257

The mammalian sympathetic prevertebral ganglia: Models for the study of neuronal networks and basic neuronal properties  

Microsoft Academic Search

The mammalian sympathetic prevertebral ganglia regulate various visceral functions and in particular the digestive tract motility. Several integrative properties of these ganglia have been described: convergence of central inputs, projection of visceral inputs at the pre- and post synaptic level and pacemaker activity of the neurones. This review presents the results obtained on another integrative property which has been widely

Caroline Fasano; Jean-Pierre Niel

2009-01-01

258

The circadian clock goes genomic  

PubMed Central

Large-scale biology among plant species, as well as comparative genomics of circadian clock architecture and clock-regulated output processes, have greatly advanced our understanding of the endogenous timing system in plants. PMID:23796230

2013-01-01

259

Circadian insights into dopamine mechanisms.  

PubMed

Almost every physiological or behavioral process in mammals follows rhythmic patterns, which depend mainly on a master circadian clock located in the hypothalamic suprachiasmatic nucleus (SCN). The dopaminergic (DAergic) system in the brain is principally implicated in motor functions, motivation and drug intake. Interestingly, DA-related parameters and behaviors linked to the motivational and arousal states, show daily rhythms that could be regulated by the SCN or by extra-SCN circadian oscillator(s) modulating DAergic systems. Here we examine what is currently understood about the anatomical and functional central multi-oscillatory circadian system, highlighting how the main SCN clock communicates timing information with other brain clocks to regulate the DAergic system and conversely, how DAergic cues may have feedback effects on the SCN. These studies give new insights into the role of the brain circadian system in DA-related neurologic pathologies, such as Parkinson's disease, attention deficit/hyperactive disorder and drug addiction. PMID:25281877

Mendoza, J; Challet, E

2014-10-01

260

[Circadian rhythm and mood disorder].  

PubMed

Mood disorders show a common feature of distorted cycling of biological systems, manifesting, for example, as diurnal mood variation in depression, phasic time course in bipolar disorder, and seasonal mood swing in seasonal affective disorder. Accordingly, circadian dysfunction has been supposed to play an etiological role in mood disorders. Increasing evidence indicates that circadian misalignment between neuroendocrinological rhythm and the timing of sleep correlates with the severity of symptoms. In addition, several genetic studies have suggested that certain clock gene variants play a role in vulnerability to these disorders, and especially bipolar disorders. However, the role of circadian phenotypes and circadian genes in mood spectrum disorders remains unclear, although currently seem to have a pathoplastic rather than a pathogenetic effect. PMID:24437274

Konno, Michiko

2013-12-01

261

[Depression and circadian rhythm].  

PubMed

Adverse changes in circadian rhythms are an integral part of the clinical features of endogenous depression, and particularly of seasonal depression. Alongside twenty-four variations in the major symptoms, these forms of depression can be characterised psychometrically, physiologically and biologically. The most classical adverse changes are amplitude modifications, fluctuations and periodicity of the hormonal secretory rhythms. Pathophysiological and psychopathological models have been proposed to combat these abnormalities. The leading models include free course, phase advance (or instability) and hypnic models, or those based on disturbances of the internal clock. The main psychopathological models are those of endokinesis and psychosocial desynchronisation. The therapeutic applications of the pathophysiological models use manipulation of the wake-sleep cycle, phototherapy and melatonin and its derivatives : those of the psychopathological models used time-space management and development of resynchronisation capacities. The question determining whether these adverse changes are a cause or effect of depressive behaviour is unresolved. PMID:19268174

Azorin, J M; Kaladjian, A

2009-01-01

262

Clinical experience of pacemaker treatment in children.  

PubMed

Pacemaker treatment is more complicated in children than in adults, mainly because of electrode problems. A pacemaker system was implanted in 23 children aged 2 days-14 years (mean 4.8 years, with 11 less than or equal to 3 years) at the Karolinska Hospital since 1983. The indications for pacing were peroperative atrioventricular block (AVB) in 13 cases, congenital AVB in five, sinoatrial disorder in four and slow ventricular arrhythmia in one case. The initially implanted electrode was epicardial in ten children (in the first 2 years of the study) and endocardial in the other 13. Eight of the ten epicardial electrodes had to be replaced by endocardial within a mean of 2.5 years. There were 18 reoperations, the reasons being increased threshold/exit block--all epicardial leads (8 cases), electrode failure (1), 'stretching' of the electrode secondary to body growth (4), local infection (3) and generator replacement (2). The reoperation rate was unacceptably high in children with epicardial electrodes. Endocardial pacing is the method of choice even for small infants. PMID:1529301

Nordlander, R; Pehrsson, S K; Böök, K; Zetterqvist, P; Fahlén-Vepsä, I L

1992-01-01

263

Urethral stromal tumor with pacemaker cell phenotype.  

PubMed

Penile malignancies are rare in developed countries. The authors present a case of a penile urethral mesenchymal tumor occurring in a 51-year-old Caucasian male and displaying light microscopic, immunohistochemical, and ultrastructural features suggestive of a pacemaker cell type, combined with a lack of diagnostic features of any other established tumor category. The immunohistochemical profile was intensely positive for vimentin, PKC theta, and NSE and weakly positive to nonreactive for CD34 and smooth muscle actin, and entirely negative for CD117 (c-kit), S-100, and other markers. C-kit and PDGFRA gene analysis showed no mutations. Electron microscopy revealed tumor cells with plentiful cytoplasm and cytoplasmic processes/filopodia, both filled with intermediate filaments and occasional solitary focal densities. There were also prominent smooth endoplasmic reticulum cisternae, caveolae, neurosecretory granules, particularly concentrated in cytoplasmic processes, and synaptic-type structures. Poorly formed basal lamina, gap junctions, and intercellular collagen aggregates, consistent with skeinoid-type fibers, were also noted. Interstitial cells with potential pacemaker function have been recently described in the lower urinary tract, including the urethra, and this tumor may be related to this cellular phenotype. PMID:17455099

Kanner, William A; Drachenberg, Cinthia B; Papadimitriou, John C; Wang, Suna; Meltzer, Stephen J; Sklar, Geoffrey N

2007-01-01

264

Bimodal oscillations of cyclic nucleotide concentrations in the circadian system of the Madeira cockroach Rhyparobia maderae.  

PubMed

Pigment-dispersing factor (PDF) is the most important coupling factor of the circadian system in insects, comparable to its functional ortholog vasoactive intestinal polypeptide of the mammalian circadian clock. In Drosophila melanogaster, PDF signals via activation of adenylyl cyclases, controlling circadian locomotor activity rhythms at dusk and dawn. In addition, PDF mediates circadian rhythms of the visual system and is involved in entrainment to different photoperiods. We examined whether PDF daytime-dependently elevates cAMP levels in the Madeira cockroach Rhyparobia maderae and whether cAMP mimics PDF effects on locomotor activity rhythms. To determine time windows of PDF release, we searched for circadian rhythms in concentrations of cAMP and its functional opponent cGMP in the accessory medulla (AMe), the insect circadian pacemaker controlling locomotor activity rhythms, and in the optic lobes, as the major input and output area of the circadian clock. Enzyme-linked immunosorbent assays detected PDF-dependent increases of cAMP in optic lobes and daytime-dependent oscillations of cAMP and cGMP baseline levels in the AMe, both with maxima at dusk and dawn. Although these rhythms disappeared at the first day in constant conditions (DD1), cAMP but not cGMP oscillations returned at the second day in constant conditions (DD2). Whereas in light-dark cycles the cAMP baseline level remained constant in other optic lobe neuropils, it oscillated in phase with the AMe at DD2. To determine whether cAMP and cGMP mimic PDF-dependent control of locomotor activity rhythms, both cyclic nucleotides were injected at different times of the circadian day using running-wheel assays. Whereas cAMP injections generated delays at dusk and advances at dawn, cGMP only delayed locomotor activity at dusk. For the first time we found PDF-dependent phase advances at dawn in addition to previously described phase delays at dusk. Thus, we hypothesize that PDF release at dusk and dawn controls locomotor activity rhythms and visual system processing cAMP-dependently. PMID:25231947

Schendzielorz, Julia; Schendzielorz, Thomas; Arendt, Andreas; Stengl, Monika

2014-10-01

265

Circadian molecular clocks and cancer.  

PubMed

Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors; Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular examples exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock. PMID:24099911

Kelleher, Fergal C; Rao, Aparna; Maguire, Anne

2014-01-01

266

ROLES OF LIGHT AND SEROTONIN IN THE REGULATION OF GASTRIN-RELEASING PEPTIDE AND ARGININE VASOPRESSIN OUTPUT IN THE SCN CIRCADIAN CLOCK  

PubMed Central

Daily timing of the mammalian circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic input from the retina via the retinohypothalamic tract. This signaling is mediated by glutamate which activates SCN retinorecipient units communicating to pacemaker cells in part through the release of gastrin-releasing peptide (GRP). Efferent signaling from the SCN involves another SCN-containing peptide, arginine vasopressin (AVP). It is notable that little is known concerning the mechanisms regulating these peptides, as literature on in vivo peptide release in the SCN is sparse. Here, microdialysis-radioimmunoassay procedures were used to characterize mechanisms controlling GRP and AVP release in the hamster SCN. In animals housed under a 14hr:10hr 24hr LD cycle both peptides exhibited daily fluctuations of release, with levels increasing during the morning to peak around midday. Under constant darkness, this pattern persisted for AVP, but rhythmicity was altered for GRP, characterized by a broad plateau throughout the subjective night and early subjective day. Neuronal release of the peptides was confirmed by their suppression with reverse-microdialysis perfusion of calcium blockers and stimulation with depolarizing agents. Reverse-microdialysis perfusion with the 5-HT1A,7 agonist, 8-OH-DPAT, during the day significantly suppressed GRP but had little effect on AVP. Also, perfusion with the glutamate agonist NMDA, or exposure to light at night, increased GRP but did not affect AVP. These analyses reveal distinct daily rhythms of SCN peptidergic activity, with GRP but not AVP release attenuated by serotonergic activation that inhibits photic phase-resetting, and activated by glutamatergic and photic stimulation that mediate this phase-resetting. PMID:20731711

Francl, Jessica M.; Kaur, Gagandeep; Glass, J. David

2010-01-01

267

Cognitive Performance as a Zeitgeber: Cognitive Oscillators and Cholinergic Modulation of the SCN Entrain Circadian Rhythms  

PubMed Central

The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals that can synchronize or entrain to environmental cues. Although light exerts powerful influences on SCN output, other non-photic stimuli can modulate the SCN as well. We recently demonstrated that daily performance of a cognitive task requiring sustained periods of attentional effort that relies upon basal forebrain (BF) cholinergic activity dramatically alters circadian rhythms in rats. In particular, normally nocturnal rats adopt a robust diurnal activity pattern that persists for several days in the absence of cognitive training. Although anatomical and pharmacological data from non-performing animals support a relationship between cholinergic signaling and circadian rhythms, little is known about how endogenous cholinergic signaling influences SCN function in behaving animals. Here we report that BF cholinergic projections to the SCN provide the principal signal allowing for the expression of cognitive entrainment in light-phase trained animals. We also reveal that oscillator(s) outside of the SCN drive cognitive entrainment as daily timed cognitive training robustly entrains SCN-lesioned arrhythmic animals. Ablation of the SCN, however, resulted in significant impairments in task acquisition, indicating that SCN-mediated timekeeping benefits new learning and cognitive performance. Taken together, we conclude that cognition entrains non-photic oscillators, and cholinergic signaling to the SCN serves as a temporal timestamp attenuating SCN photic-driven rhythms, thereby permitting cognitive demands to modulate behavior. PMID:23441168

Gritton, Howard J.; Stasiak, Ashley M.; Sarter, Martin; Lee, Theresa M.

2013-01-01

268

Circadian performance of suprachiasmatic nuclei (SCN)-lesioned antelope ground squirrels in a desert enclosure.  

PubMed

Circadian activity parameters of 53 white-tailed antelope ground squirrels, Ammospermophilus leucurus, were measured to determine the role of the suprachiasmatic nuclei (SCN) pacemaker in their health and survival. Wheel-running activity was monitored in the laboratory with 44 individuals to document the presence of free-running circadian rhythms and ability to entrain to light-dark cycles. Twenty-two individuals were returned to the desert site of origin, including 12 intact control animals and 10 animals whose circadian timing had been disrupted by SCN-lesioning. Time of activity was recorded continuously for 15 days in a large outdoor enclosure by a motion detector, a microchip transponder detector, and video surveillance. An unplanned nighttime attack by a feral cat resulted in the death of 60% of the SCN-lesioned animals and 29% of the control animals in the enclosure. Surface activity of SCN-lesioned animals at the food cache occurred both in daytime and at night, ranging from 16.0% nighttime activity for one partially lesioned individual to 52.1% for one completely lesioned animal. Controls were strongly day-active, with nighttime surface trips constituting only 0-1.3% of all excursions to the cache. Nine wild free-ranging individuals, including one with a radiotransmitter collar, were exclusively day-active. One of the functions of the SCN in mammals may be to reduce activity of animals during times that are unfavorable for activity. PMID:9333206

DeCoursey, P J; Krulas, J R; Mele, G; Holley, D C

1997-11-01

269

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.  

PubMed

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ?24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology. PMID:21220317

Karatsoreos, Ilia N; Bhagat, Sarah; Bloss, Erik B; Morrison, John H; McEwen, Bruce S

2011-01-25

270

Membranes as possible pacemakers of metabolism.  

PubMed

Basal metabolic rate (BMR) varies dramatically among vertebrate species, both (i) being several fold higher in the endothermic mammals and birds compared to the ectothermic reptiles, amphibians and fish, and (ii) being much greater, on a body mass basis, in small vertebrates compared to large vertebrates. These differences in whole animal BMR are also manifest at the cellular level with substantial contributions to basal metabolic activity from the maintenance of various trans-membrane gradients. The percentage contribution of various processes to basal metabolism is remarkably consistent between different vertebrates and when BMR varies, the components of metabolic activity vary in relative unison. Membrane composition also varies between vertebrates and the degree of polyunsaturation of membrane phospholipids is correlated with cellular metabolic activity. In general, the tissue phospholipids and thus membrane bilayers of endotherms are more polyunsaturated than those from similar-sized ectotherms. In mammals membrane polyunsaturation is allometrically related to body mass. We suggest that membranes can act as pacemakers for overall metabolic activity. We propose that such membrane polyunsaturation increases the molecular activity of many membrane-bound proteins and consequently some specific membrane leak-pump cycles and cellular metabolic activity. We hypothesize a possible mechanistic basis for this effect that is based on a greater transfer of energy during intermolecular collisions of membrane proteins with the unsaturated two carbon units (C=C) of polyunsaturates compared to the single carbon units of saturated acyl chains, as well as the more even distribution of such units throughout the depth of the bilayer when membranes contain polyunsaturated acyl chains compared to monounsaturated ones. The proposed pacemaker role of differences in membrane bilayer composition is briefly discussed with respect to the brain (and sensory cells), evolution of mammalian endothermic metabolism, and its clinical implications for humans. PMID:10433891

Hulbert, A J; Else, P L

1999-08-01

271

The Comparison between Circadian Oscillators in Mouse Liver and Pituitary Gland Reveals Different Integration of Feeding and Light Schedules  

E-print Network

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues.

Isabelle M. Bur; Sonia Zouaoui; Pierre Fontanaud; Nathalie Coutry; François Molino; Agnès O. Martin; Patrice Mollard; Xavier Bonnefont

2010-01-01

272

Pacemaker activity and ionic currents in mouse atrioventricular node cells  

PubMed Central

It is well established that pacemaker activity of the sino-atrial node (SAN) initiates the heartbeat. However, the atrioventricular node (AVN) can generate viable pacemaker activity in case of SAN failure, but we have limited knowledge of the ionic bases of AVN automaticity. We characterized pacemaker activity and ionic currents in automatic myocytes of the mouse AVN. Pacemaking of AVN cells (AVNCs) was lower than that of SAN pacemaker cells (SANCs), both in control conditions and upon perfusion of isoproterenol (ISO). Block of INa by tetrodotoxin (TTX) or of ICa,L by isradipine abolished AVNCs pacemaker activity. TTX-resistant (INar) and TTX-sensitive (INas) Na+ currents were recorded in mouse AVNCs, as well as T-(ICa,T) and L-type (ICa,L) Ca2+ currents. ICa,L density was lower than in SANCs (51%). The density of the hyperpolarization-activated current, (If) and that of the fast component of the delayed rectifier current (IKr) were, respectively, lower (52%) and higher (53%) in AVNCs than in SANCs. Pharmacological inhibition of If by 3 µM ZD-7228 reduced pacemaker activity by 16%, suggesting a relevant role for If in AVNCs automaticity. Some AVNCs expressed also moderate densities of the transient outward K+ current (Ito). In contrast, no detectable slow component of the delayed rectifier current (IKs) could be recorded in AVNCs. The lower densities of If and ICa,L, as well as higher expression of IKr in AVNCs than in SANCs may contribute to the intrinsically slower AVNCs pacemaking than that of SANCs. PMID:21406959

Marger, Laurine; Mesirca, Pietro; Alig, Jacqueline; Torrente, Angelo; Dubel, Stefan; Engeland, Birgit; Kanani, Sandra; Fontanaud, Pierre; Striessnig, Jörg; Shin, Hee-Sup; Isbrandt, Dirk; Ehmke, Heimo; Nargeot, Joël

2011-01-01

273

Metabolism and the Circadian Clock Converge  

PubMed Central

Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. PMID:23303907

Eckel-Mahan, Kristin

2013-01-01

274

Circadian Rhythms and Obesity in Mammals  

PubMed Central

Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabolism. Moreover, disruption of circadian rhythms leads to obesity and metabolic disorders. Therefore, it is plausible that resetting of the circadian clock can be used as a new approach to attenuate obesity. Feeding regimens, such as restricted feeding (RF), calorie restriction (CR), and intermittent fasting (IF), provide a time cue and reset the circadian clock and lead to better health. In contrast, high-fat (HF) diet leads to disrupted circadian expression of metabolic factors and obesity. This paper focuses on circadian rhythms and their link to obesity. PMID:24527263

Froy, Oren

2012-01-01

275

Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*  

PubMed Central

Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

2014-01-01

276

Arrhythmia resulting from sensing malfunction in a P wave triggered pacemaker.  

PubMed

P wave triggered pacemakers can produce complicated arrhythmias during normal function. A ventricular, R wave inhibited pacemaker and an atrial sensing pacemaker were both present and functioning normally in the patient reported here. A premature paced beat was observed every 12th beat which resulted from discharge of the atrial sensing pacemaker. This arrhythmia appeared because a "P" wave occurred during the noise sampling period of the atrial sensing pacemaker, disabling the demand function and resulting in generator discharge on or near the T wave of a preceding unsensed beat while the pacemaker was in the asynchronous mode. PMID:7430871

Curtis, G P; Lief, L H

1980-10-01

277

Light, circadian and circannual rhythms  

Microsoft Academic Search

Organisms use circadian and circannual rhythms in cells or cell complexes for time measurements, thus the term biological clocks. Properties and models of biological clocks are discussed. In mammals, the biological clock system perceives light signals via the retina. Signals are then led to the suprachiasmatic nucleus (SCN) of the brain, functioning as the central clock region. Via pathways -

Anders Johnsson

278

Circadian rhythm sleep disorders (CRSD)  

Microsoft Academic Search

Circadian Rhythm Sleep Disorders (CRSD) are a group of sleep disorders characterized by a malsynchronization between a person's biological clock and the environmental 24-h schedule. These disorders can lead to harmful psychological and functional difficulties and are often misdiagnosed and incorrectly treated due to the fact that doctors are unaware of their existence. In the following review we describe the

Yaron Dagan

2002-01-01

279

Circadian Clock Mutants of Cyanobacteria  

Microsoft Academic Search

A diverse set of circadian clock mutants was isolated in a cyanobacterial strain that carries a bacterial luciferase reporter gene attached to a clock-controlled promoter. Among 150,000 clones of chemically mutagenized bioluminescent cells, 12 mutants were isolated that exhibit a broad spectrum of periods (between 16 and 60 hours), and 5 mutants were found that show a variety of unusual

Takao Kondo; Nicholas F. Tsinoremas; Susan S. Golden; Carl Hirschie Johnson; Shinsuke Kutsuna; Masahiro Ishiura

1994-01-01

280

`Rejuvenation' protects neurons in mouse models of Parkinson's disease  

Microsoft Academic Search

Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Cav1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as

C. Savio Chan; Jaime N. Guzman; Ema Ilijic; Jeff N. Mercer; Caroline Rick; Tatiana Tkatch; Gloria E. Meredith; D. James Surmeier

2007-01-01

281

An Extremely Rare Reason for Failure of Left Sided Pacemaker Implantation  

PubMed Central

We reported a case of isolated anomaly of the left brachiocephalic vein which is diagnosed during a permanent pacemaker implantation. It is a very rare anomaly and makes the left sided pacemaker implantation impossible. PMID:25505996

Öztürk, Ali; Özcan, Emin Evren; Genç, Berhan

2014-01-01

282

An extremely rare reason for failure of left sided pacemaker implantation.  

PubMed

We reported a case of isolated anomaly of the left brachiocephalic vein which is diagnosed during a permanent pacemaker implantation. It is a very rare anomaly and makes the left sided pacemaker implantation impossible. PMID:25505996

Ozel, Erdem; Oztürk, Ali; Ozcan, Emin Evren; Genç, Berhan

2014-01-01

283

Entrainment of coupled oscillators on regular networks by pacemakers.  

PubMed

We study Kuramoto oscillators, driven by one pacemaker, on d-dimensional regular topologies with nearest neighbor interactions. We derive the analytical expressions for the common frequency in the case of phase-locked motion and for the critical frequency of the pacemaker, placed at an arbitrary position in the lattice, so that above the critical frequency no phase-locked motion is possible. We show that the mere change in topology from an open chain to a ring induces synchronization for a certain range of pacemaker frequencies and couplings, while keeping the other parameters fixed. Moreover, we demonstrate numerically that the critical frequency of the pacemaker decreases as a power of the linear size of the lattice with an exponent equal to the dimension of the system. This leads in particular to the conclusion that for infinite-dimensional topologies the critical frequency for having entrainment decreases exponentially with increasing size of the system, or, more generally, with increasing depth of the network, that is, the average distance of the oscillators from the pacemaker. PMID:16605642

Radicchi, Filippo; Meyer-Ortmanns, Hildegard

2006-03-01

284

Ribonucleoprotein Complexes That Control Circadian Clocks  

PubMed Central

Circadian clocks are internal molecular time-keeping mechanisms that enable organisms to adjust their physiology and behavior to the daily surroundings. Misalignment of circadian clocks leads to both physiological and health impairment. Post-transcriptional regulation and translational regulation of circadian clocks have been extensively investigated. In addition, accumulating evidence has shed new light on the involvement of ribonucleoprotein complexes (RNPs) in the post-transcriptional regulation of circadian clocks. Numerous RNA-binding proteins (RBPs) and RNPs have been implicated in the post-transcriptional modification of circadian clock proteins in different model organisms. Herein, we summarize the advances in the current knowledge on the role of RNP complexes in circadian clock regulation. PMID:23698761

Wang, Dongni; Liang, Xiaodi; Chen, Xianyun; Guo, Jinhu

2013-01-01

285

Surgical removal of a giant vegetation on permanent endocavitary pacemaker wire and lead.  

PubMed

Pacemaker lead infections are rare. There are only about 0.4%-1.1% of the patients who have been implanted permanent pacemakers suffering from serious infections which lead to endocarditis. Generally, removal of the infected pacemaker wire and lead, long-term anti-infection therapy, and implantation of a new pacemaker to another anatomic site are accepted approaches for these patients. PMID:22218056

Guo-tao, Ma; Qi, Miao; Chao-ji, Zhang; Li-hua, Cao

2011-12-01

286

The circadian basis of winter depression  

Microsoft Academic Search

The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon\\/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phase revealed a therapeutic window for optimal alignment of circadian rhythms that also appears to be

Alfred J. Lewy; Bryan J. Lefler; Jonathan S. Emens; Vance K. Bauer

2006-01-01

287

The Circadian Basis of Winter Depression  

Microsoft Academic Search

The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon\\/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phase revealed a therapeutic window for optimal alignment of circadian rhythms that also appears to be

Alfred J. Lewy; Bryan J. Lefler; Jonathan S. Emens; Vance K. Bauer

2006-01-01

288

Epigenetic Regulation of Axonal Growth of Drosophila Pacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep  

PubMed Central

Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60-mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed “small ventrolateral neurons” (sLNvs), and their production of the neuropeptide pigment-dispersing factor (PDF) that functions to stabilize Drosophila sleep–wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer’s disease-associated APP affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of the sleep–wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep–wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 in sLNv growth and function under APP-induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep–wake regulation via control of axonal growth and PDF levels within the sLNv-encompassing neural network and provide insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer’s disease. PMID:22982579

Pirooznia, Sheila K.; Chiu, Kellie; Chan, May T.; Zimmerman, John E.; Elefant, Felice

2012-01-01

289

Experimental observation of transition from chaotic bursting to chaotic spiking in a neural pacemaker  

NASA Astrophysics Data System (ADS)

The transition from chaotic bursting to chaotic spiking has been simulated and analyzed in theoretical neuronal models. In the present study, we report experimental observations in a neural pacemaker of a transition from chaotic bursting to chaotic spiking within a bifurcation scenario from period-1 bursting to period-1 spiking. This was induced by adjusting extracellular calcium or potassium concentrations. The bifurcation scenario began from period-doubling bifurcations or period-adding sequences of bursting pattern. This chaotic bursting is characterized by alternations between multiple continuous spikes and a long duration of quiescence, whereas chaotic spiking is comprised of fast, continuous spikes without periods of quiescence. Chaotic bursting changed to chaotic spiking as long interspike intervals (ISIs) of quiescence disappeared within bursting patterns, drastically decreasing both ISIs and the magnitude of the chaotic attractors. Deterministic structures of the chaotic bursting and spiking patterns are also identified by a short-term prediction. The experimental observations, which agree with published findings in theoretical neuronal models, demonstrate the existence and reveal the dynamics of a neuronal transition from chaotic bursting to chaotic spiking in the nervous system.

Gu, Huaguang

2013-06-01

290

Epigenetic regulation of axonal growth of Drosophila pacemaker cells by histone acetyltransferase tip60 controls sleep.  

PubMed

Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60-mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed "small ventrolateral neurons" (sLNvs), and their production of the neuropeptide pigment-dispersing factor (PDF) that functions to stabilize Drosophila sleep-wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer's disease-associated APP affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of the sleep-wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep-wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 in sLNv growth and function under APP-induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep-wake regulation via control of axonal growth and PDF levels within the sLNv-encompassing neural network and provide insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer's disease. PMID:22982579

Pirooznia, Sheila K; Chiu, Kellie; Chan, May T; Zimmerman, John E; Elefant, Felice

2012-12-01

291

Intrinsic and extrinsic cues regulate the daily profile of mouse lateral habenula neuronal activity.  

PubMed

The epithalamic lateral habenula (LHb) is implicated as part of the mammalian brain's circadian system. Anatomical evidence suggests that the LHb receives extrinsic circadian timing cues from retinal ganglion cells and the master clock in the suprachiasmatic nuclei (SCN). Intriguingly, some LHb neurones contain the molecular circadian clock, but it is unclear if and how intrinsic and extrinsic circadian processes influence neuronal activity in the mouse LHb. Here, using an in vitro brain slice preparation isolating the LHb from the SCN, we show through whole-cell patch-clamp recordings that LHb neurones exhibit heterogeneity in their resting state, but the majority spontaneously fire action potentials (APs). Discharge rate of APs varied from low firing in the early day to higher firing later in the day and was absent in LHb brain slices prepared from Cry1(-/-)Cry2(-/-) mice that lack a functional molecular clock. Low amplitude circadian oscillations in the molecular circadian clock were also monitored in LHb brain slices, but were absent in Cry1(-/-)Cry2(-/-) LHb brain tissue. A putative neurochemical output signal of the SCN, prokineticin 2 (PK2), inhibited some LHb neurones by elevating the frequency of GABA release in the LHb. Using multi-electrode recordings in vivo, we found that LHb neurones sluggishly respond to retinal illumination, suggesting that they receive such information through polysynaptic processes. In summary, our results show for the first time that intrinsic circadian signals are important for regulating LHb neuronal state, while the SCN-derived signal PK2 is less influential. Moreover, we demonstrate that mouse LHb neurones have access to and can respond to visual input, but such signals are unlikely to be directly communicated to the LHb. Broadly, these findings raise the possibility that intrinsic circadian signals are likely to be influential in shaping LHb contributions to cognition and emotionality. PMID:25194046

Sakhi, Kanwal; Wegner, Sven; Belle, Mino D C; Howarth, Michael; Delagrange, Philippe; Brown, Timothy M; Piggins, Hugh D

2014-11-15

292

Chronic Artificial Blue-Enriched White Light Is an Effective Countermeasure to Delayed Circadian Phase and Neurobehavioral Decrements  

PubMed Central

Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n?=?10) exposed to 100–300 lux of standard fluorescent white (SW) light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE) light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks), followed by a BE lighting (2 weeks) for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks). This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc.), and may help design lighting strategies to maintain health, productivity, and personnel safety. PMID:25072880

Najjar, Raymond P.; Wolf, Luzian; Taillard, Jacques; Schlangen, Luc J. M.; Salam, Alex

2014-01-01

293

Pacemaker patients' perception of unsafe activities: a survey  

PubMed Central

Background Cardiac pacing is a recognized and widely used treatment for patients presenting with bradycardia. Physicians expect patients to return to normal activities almost immediately post implantation. However, patients themselves may perceive interference to pacemaker function by various routine activities and devices, and hence continue to lead restricted, disabled lives. The aim of this study is to determine if routine activities are perceived by pacemaker patients to interfere with their device function. Methods A descriptive cross sectional survey was carried out on consecutive patients at the pacemaker clinic at a public hospital in Karachi, Pakistan. A 47-question tool was developed and tested. Patients' perceptions of safety of performing various routine activities, along with socio-demographic data were recorded. Results The final sample included 93 adult patients (45% males). 41% were illiterate. 77.4% recalled receiving counselling at implantation, predominantly from the implanting physician and house staff. A considerable proportion of patients considered many routine activities unsafe including driving automobiles (28%), passing through metal detectors (31%), bending over (37%), and sleeping on the side of the pacemaker (30%). Also considered unsafe were operation of household appliances- TV/VCR (television/video cassette recorders) (53%), irons (55%)) and electrical wall switches (56%). For nearly all variables neither literacy nor history of counselling improved incorrect perceptions. Conclusion This study shows that our pacemaker patients perceive many routine activities as unsafe, potentially leading to disabling life style modifications. The tremendous investment in pacemaker technology to improve patient performance is not going to pay dividends if patients continue to remain disabled due to incorrect perceptions. Further studies are required to determine the reasons for these misperceptions, and to determine if these problems also exist in, and hinder, other patient populations. PMID:19014563

Aqeel, Masooma; Shafquat, Azam; Salahuddin, Nawal

2008-01-01

294

Circadian Rhythm Control: Neurophysiological Investigations  

NASA Technical Reports Server (NTRS)

The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.

Glotzbach, S. F.

1985-01-01

295

A rare cause of pacemaker failure: interatrial block.  

PubMed

Pacemaker and implantable cardioverter defibrillators (ICD) systems are useful in detection and differentiation of many symptomatic and asymptomatic arrhythmias. In this report, we described a rare condition that caused by failure in detection of a clinical tachyarrhythmia by a dual chamber pacemaker that implanted because of intermittent atrioventricular (AV) block and sinus node disease in a 46-year-old patient. In our case, bidirectional interatrial block was demonstrated; and the symptoms associated with high ventricular rate caused by left atrial tachyarrhythmias relieved after AV node ablation. PMID:24047493

Demircan, Sabri; Yuksel, Serkan; Gulel, Okan

2013-09-01

296

Circadian misalignment in mood disturbances  

Microsoft Academic Search

Recent refinements in methodology allow chronobiological researchers to answer the following questions: is there circadian\\u000a misalignment in sleep and mood disturbances, and, if so, is it of the phase-advance or phase-delay type? Measurement of the\\u000a dim light melatonin onset-to-midsleep interval, or phase-angle difference, in sleep and mood disorders should answer these\\u000a questions. Although the phase-advance hypothesis of affective disorders was

Alfred J. Lewy

2009-01-01

297

Modeling the mammalian circadian clock  

NASA Astrophysics Data System (ADS)

In biology, important processes often depend on a temporal schedule. The 24-hour periodicity of solar illumination caused by the earth's rotation has consequences for environmental factors such as temperature and humidity as well as ecological factors such as the presence of food, predators, or potential mates. As a result, many organisms have evolved to develop a circadian clock that allows them to anticipate these environmental changes in the absence of direct temporal cues. In recent years, extensive efforts have been made to deconstruct the biological clockwork from various organisms, develop mathematical models of circadian function, and construct synthetic analogues to test our understanding. My present work has two major foci. First, we have used regulatory principles revealed by recent experimental work to construct a model of the core genetic oscillator of the mammalian circadian system that captures key system-level behaviors. Second, we are exploring the possibility of a post-translational phosphorylation-based oscillator that is coupled to the core oscillator, conferring enhanced robustness and stability on the complete system. A simple model of this post-translational oscillator reveals key design constraints that must be satisfied by any such oscillator.

Jolley, Craig; Ueda, Hiroki

2012-02-01

298

Aspergillus fumigatus pacemaker lead endocarditis: A case report and review of the literature  

PubMed Central

The diagnosis of fungal endocarditis requires a high index of clinical suspicion. Rarely, pacemaker implantation may be a risk factor for the development of fungal endocarditis. A 71-year-old man with a history of multiple transvenous pacemaker manipulations and fever of an uncertain source is described. A diagnosis of culture-negative pacemaker endocarditis was established only after repeat transthoracic echocardiography. Amphotericin B was instituted; however, the patient developed a cerebral infarct and died. Postmortem examination demonstrated Aspergillus fumigatus within a large pacemaker lead thrombus, tricuspid and aortic valve vegetations, and septic pulmonary and renal emboli. The present report describes the clinical and pathological features of a rare case of Aspergillus fumigatus pacemaker lead endocarditis and suggests that serial echocardiograms may be effective in the early detection of pacemaker lead vegetations. The diagnostic features and therapeutic management of pacemaker lead endocarditis are reviewed. PMID:16568159

Leong, Roger; Gannon, Brian R; Childs, Tim J; Isotalo, Phillip A; Abdollah, Hoshiar

2006-01-01

299

Circadian Rhythms: In the Loop at Last  

NSDL National Science Digital Library

This Viewpoint compares and contrasts the circadian clocks of mammals and of Drosophila, emphasizing how different players are used to create the same basic script. Both the general script and the specific details of the murine and Drosophila circadian pathways are available at Science's Signal Transduction Knowledge Environment Connections Maps.

Russell N. Van Gelder (Washington University;Department of Ophthalmology and Visual Sciences/Department of Molecular Biology and Pharmacology); Erik D. Herzog (Washington University;Department of Biology); William Schwartz (University of Massachusetts Medical School;Department of Neurology); Paul Taghert (Washington University;Department of Anatomy and Neurobiology)

2003-06-06

300

Circadian systems: different levels of complexity.  

PubMed Central

After approximately 50 years of circadian research, especially in selected circadian model systems (Drosophila, Neurospora, Gonyaulax and, more recently, cyanobacteria and mammals), we appreciate the enormous complexity of the circadian programme in organisms and cells, as well as in physiological and molecular circuits. Many of our insights into this complexity stem from experimental reductionism that goes as far as testing the interaction of molecular clock components in heterologous systems or in vitro. The results of this enormous endeavour show circadian systems that involve several oscillators, multiple input pathways and feedback loops that contribute to specific circadian qualities but not necessarily to the generation of circadian rhythmicity. For a full appreciation of the circadian programme, the results from different levels of the system eventually have to be put into the context of the organism as a whole and its specific temporal environment. This review summarizes some of the complexities found at the level of organisms, cells and molecules, and highlights similar strategies that apparently solve similar problems at the different levels of the circadian system. PMID:11710975

Roenneberg, T; Merrow, M

2001-01-01

301

THE INTRINSIC CIRCADIAN CLOCK WITHIN THE CARDIOMYOCYTE  

Technology Transfer Automated Retrieval System (TEKTRAN)

Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully...

302

[Relation between dementia and circadian rhythm disturbance].  

PubMed

Dementia and circadian rhythm disturbance are closely linked. First, dementia patient shows circadian rhythm disorders (e.g. insomnia, night wandering, daytime sleep). These symptoms are a burden for caregivers. Circadian rhythm disturbance of dementia relates ADL and cognitive impairment, and diurnal rhythm disorder of blood pressure and body temperature. Some study shows that circadian rhythm disorders in dementia are a disturbance of neural network between suprachiasmatic nucleus and cerebral white matter, and involvement of both frontal lobes, left parietal and occipital cortex, left temporoparietal region. The first-line treatment of circadian rhythm disturbance should be non-drug therapy (e.g. exercise, bright light exposure, reduce caffeine intake, etc.). If physician prescribe drugs, keep the rule of low-dose and short-term and avoid benzodiazepines. Atypical antipsychotic drugs like risperidone and some antidepressants are useful for treatment of insomnia in dementia. But this usage is off-label. So we must well inform to patient and caregiver, and get consent about treatment. Second, some study shows circadian rhythm disorder is a risk factor of dementia. However, we should discuss that circadian rhythm disturbance is "risk factor of dementia" or "prodromal symptom of dementia". If a clinician finds circadian rhythm disorder in elderly people, should be examined cognitive and ADL function, and careful about that patients have dementia or will develop dementia. PMID:24724422

Nakamura, Kei; Meguro, Kenichi

2014-03-01

303

INTRINSIC CIRCADIAN RHYTHMS IN THE CARDIOMYOCYTE  

Technology Transfer Automated Retrieval System (TEKTRAN)

The cardiomyocyte possesses a fully functional circadian clock. Circadian clocks are a set of proteins that generate self-sustained transcriptional positive and negative feedback loops with a free-running period of 24 hours. These intracellular molecular mechanisms confer the selective advantage of ...

304

Dynamics of a Multistage Circadian System  

Microsoft Academic Search

Tissues throughout the body exhibit circadian rhythms, forming a multioscillatory system whose disruption results in jet lag and other health problems in travelers and rotational shift workers. The authors’ simulations of the dynamics of a multistage circadian system (based on experimental results for nocturnal rodents) reveal the flexibility and stability inherent in a multistage system, as well as potential pitfalls.

Tanya Leise; Hava Siegelmann

2006-01-01

305

Circadian rhythms in myocardial metabolism and function  

Technology Transfer Automated Retrieval System (TEKTRAN)

Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral...

306

The Circadian Clock Modulates Renal Sodium Handling  

PubMed Central

The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clock-deficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling. PMID:22440902

Nikolaeva, Svetlana; Pradervand, Sylvain; Centeno, Gabriel; Zavadova, Vlasta; Tokonami, Natsuko; Maillard, Marc; Bonny, Olivier

2012-01-01

307

Clinical experience with a new multiprogrammable dual chamber pacemaker.  

PubMed

We evaluated the clinical performance of a new dual chamber pacemaker, ELA Chorus, in 35 patients. This device incorporates linear rate adaptive AV delay (AVDR), rate smoothing, fallback, impedance telemetry, pacemaker mediated tachycardia (PMT) recognition and reprogramming software, intracardiac electrogram displays, autothreshold testing, diagnostic data, battery depletion curves, and laptop computer programming. Mean patient age was 68 years; 18 patients had AV block, six had sinus node dysfunction (one with AV block), nine had carotid sinus hypersensitivity (three with AV block), and two had vagally mediated syncope. At hospital discharge, programming was DDD with a mean low rate of 60 (50-70) beats/min, mean high rate of 126 (120-154) beats/min; AVDR was ON in 21 patients, rate smoothing ON in six patients, fallback ON in six patients, and PMT reprogramming algorithm ON in 27 patients. Pacemaker follow-up involved 500 clinic visits over 14.3 months (1-36). Three patients developed atrial fibrillation, reprogrammed to DDI mode (two patients) or fallback (one patient). Fallback was used 617 times. PMT occurred 427 times in six patients; the PMT algorithm reprogrammed AV delay and postventricular atrial refractory period (PVARP) automatically, a function unique to the Chorus. Intracardiac electrograms and autothreshold testing improved follow-up efficiency. This new dual chamber pacemaker enhances programming flexibility and improves diagnostic accuracy at follow-up. PMID:1279556

Kutalek, S P; Schuster, M M; Hessen, S E; Sheppard, R; Maquilan, M; Nydegger, C

1992-11-01

308

Hydrogen-induced microelectronic capacitor failure in pacemakers.  

PubMed

Ceramic chip capacitors used in hybrid microelectronics for cardiac pacemakers are usually highly reliable. However, under certain conditions of capacitor construction, capacitor materials, mounting techniques, and environmental conditions, high failure rates may occur. A specific example is presented in which a ceramic capacitor used in an implanted pacemaker delaminated and failed approximately 30 days after being implanted. The failed capacitor caused a pulse rate rise, but due to circuit design techniques, the rate increase was limited to an acceptable value. The capacitor that failed was from an isolated lot of capacitors that was manufactured using pure palladium plates. The circuit containing this capacitor was hermetically sealed within a titanium case by welding. During the welding, a small amount of hydrogen was released from the titanium which, over a period of 2 to 4 weeks, was absorbed by the palladium plates in the capacitor. By absorbing the hydrogen, the palladium plates exhibit a volumetric expansion of sufficient magnitude to crack and delaminate the capacitor to the point of failure. Subsequently, the recurrence of this failure mode has been avoided by using capacitors containing special palladium alloys that cannot absorb hydrogen. This phenomenon is of interest to pacemaker designers since mercury batteries used in conventional pacemakers generate large amounts of hydrogen and potentially may be responsible for complications when used in conjunction with capacitors containing palladium. PMID:958043

Rainer, W G; Kolenik, S A; Whittaker, R E; Sadler, T R; Lapin, E S

1976-01-01

309

Extensive and divergent circadian gene expression in liver and heart  

Microsoft Academic Search

Many mammalian peripheral tissues have circadian clocks; endogenous oscillators that generate transcriptional rhythms thought to be important for the daily timing of physiological processes. The extent of circadian gene regulation in peripheral tissues is unclear, and to what degree circadian regulation in different tissues involves common or specialized pathways is unknown. Here we report a comparative analysis of circadian gene

Kai-Florian Storch; Ovidiu Lipan; Igor Leykin; N. Viswanathan; Fred C. Davis; Wing H. Wong; Charles J. Weitz

2002-01-01

310

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

PubMed Central

Summary 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. PMID:23213472

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

2012-01-01

311

Photic and nonphotic effects on the circadian activity rhythm in the diurnal rodent Arvicanthis ansorgei.  

PubMed

The main purpose of the study was to compare behavioural properties of entrainment to photic (30 min; 200lx) and nonphotic (melatonin: 1 h; 100 microg) stimuli in the diurnal rodent Arvicanthis ansorgei. Male animals (n=38) were used, and running wheel activity was recorded. Following entrainment to 12:12 h LD the animals were transferred to DD (dim red light) to freerun before treatment started. A phase response curve (PRC) to light was determined showing a phase delay region in the early subjective night (CT 8-16) and a phase advance region in the late subjective night (CT 18-4). Activity onset defined CT=0. Entrainment to daily phase advance and phase delay light pulses occurred at circadian phases corresponding to the respective phase shift regions of the PRC. Similarly, also entrainment to daily melatonin pulses occurred in two narrow time windows located near the beginning (CT 0) and the end of the subjective day (CT 10), but where light had a phase advance effect melatonin had a phase delay effect and vice versa. These results are consistent with the neurobiological model of Hastings et al. (Chronobiol Int 1998;15:425-445) on the differential effects of photic and nonphotic resetting cues on the circadian pacemaker. PMID:16157395

Slotten, Helge A; Krekling, Sturla; Pévet, Paul

2005-11-30

312

Time's arrow flies like a bird: two paradoxes for avian circadian biology.  

PubMed

Biological timekeeping in birds is a fundamental feature of avian physiology, behavior and ecology. The physiological basis for avian circadian rhythmicity has pointed to a multi-oscillator system of mutually coupled pacemakers in the pineal gland, eyes and hypothalamic suprachiasmatic nuclei (SCN). In passerines, the role of the pineal gland and its hormone melatonin is particularly important. More recent molecular biological studies have pointed to a highly conserved mechanism involving rhythmic transcription and translation of "clock genes". However, studies attempting to reconcile the physiological role of pineal melatonin with molecular studies have largely failed. Recent work in our laboratory has suggested that melatonin-sensitive physiological processes are only loosely coupled to transcriptional oscillations. Similarly, although the pineal gland has been shown to be critical for overt circadian behaviors, its role in annual cycles of reproductive function appears to be minimal. Recent work on the seasonal control of birdsong, however, suggests that, although the pineal gland does not directly affect gonadal cycles, it is important for seasonal changes in song. Experimental analyses that address these paradoxes will shed light on the roles the biological clock play in birds and in vertebrates in general. PMID:19523398

Cassone, Vincent M; Paulose, Jiffin K; Whitfield-Rucker, Melissa G; Peters, Jennifer L

2009-09-01

313

Cell clocks and neuronal networks: neuron ticking and synchronization in aging and aging-related neurodegenerative disease.  

PubMed

Body function rhythmicity has a key function for the regulation of internal timing and adaptation to the environment. A wealth of recent data has implicated endogenous biological rhythm generation and regulation in susceptibility to disease, longevity, cognitive performance. Concerning brain diseases, it has been established that many molecular pathways implicated in neurodegeneration are under circadian regulation. At the molecular level, this regulation relies on clock genes forming interconnected, self-sustained transcriptional/translational feedback loops. Cells of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, are endowed with this molecular clockwork. Brain cells in many other regions, including those which play a key role in learning and memory, as well as peripheral cells show a circadian oscillatory behavior regulated by the same molecular clockwork. We here address the question as to whether intracellular clockwork signaling and/or the intercellular dialogue between "brain clocks" are disrupted in aging-dependent neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. The potential implications of clock genes in cognitive functions in normal conditions, clinical disturbances of circadian rhythms, and especially the sleep-wake cycle, in aging-dependent neurodegenerative diseases and data in animal models are reviewed. The currently limited knowledge in this field is discussed in the context of the more extensive body of data available on cell clocks and molecular clockwork during normal aging. Hypotheses on implications of the synchronization between brain oscillators in information processing in neural networks lay ground for future studies on brain health and disease. PMID:23627753

Bonaconsa, Marta; Colavito, Valeria; Pifferi, Fabien; Aujard, Fabienne; Schenker, Esther; Dix, Sophie; Grassi-Zucconi, Gigliola; Bentivoglio, Marina; Bertini, Giuseppe

2013-07-01

314

Circadian rhythms and treatment implications in depression.  

PubMed

In humans almost all physiological and behavioural functions occur on a rhythmic basis. Therefore the possibility that delays, advances or desynchronizations of circadian rhythms may play a role in the pathophysiology of psychiatric disorders is an interesting field of research. In particular mood disorders such as seasonal affective disorder and major depression have been linked to circadian rhythms alterations. Furthermore, the antidepressant efficacy of both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms, such as new antidepressant medications, light-therapy and sleep deprivation, is consistent with the idea that circadian alterations may represent a core component of depression, at least in a subgroup of depressed patients. This paper briefly describes the molecular and genetic mechanisms regulating the endogenous clock system, and reviews the literature supporting the relationships between depression, antidepressant treatments and changes in circadian rhythms. PMID:20691746

Monteleone, Palmiero; Martiadis, Vassilis; Maj, Mario

2011-08-15

315

Cocaine modulates pathways for photic and nonphotic entrainment of the mammalian SCN circadian clock.  

PubMed

Cocaine abuse is highly disruptive to circadian physiological and behavioral rhythms. The present study was undertaken to determine whether such effects are manifest through actions on critical photic and nonphotic regulatory pathways in the master circadian clock of the mouse suprachiasmatic nucleus (SCN). Impairment of SCN photic signaling by systemic (intraperitoneal) cocaine injection was evidenced by strong (60%) attenuation of light-induced phase-delay shifts of circadian locomotor activity during the early night. A nonphotic action of cocaine was apparent from its induction of 1-h circadian phase-advance shifts at midday. The serotonin receptor antagonist, metergoline, blocked shifting by 80%, implicating a serotonergic mechanism. Reverse microdialysis perfusion of the SCN with cocaine at midday induced 3.7 h phase-advance shifts. Control perfusions with lidocaine and artificial cerebrospinal fluid had little shifting effect. In complementary in vitro experiments, photic-like phase-delay shifts of the SCN circadian neuronal activity rhythm induced by glutamate application to the SCN were completely blocked by cocaine. Cocaine treatment of SCN slices alone at subjective midday, but not the subjective night, induced 3-h phase-advance shifts. Lidocaine had no shifting effect. Cocaine-induced phase shifts were completely blocked by metergoline, but not by the dopamine receptor antagonist, fluphenazine. Finally, pretreatment of SCN slices for 2 h with a low concentration of serotonin agonist (to block subsequent serotonergic phase resetting) abolished cocaine-induced phase shifts at subjective midday. These results reveal multiple effects of cocaine on adult circadian clock regulation that are registered within the SCN and involve enhanced serotonergic transmission. PMID:22218419

Glass, J David; Brager, Allison J; Stowie, Adam C; Prosser, Rebecca A

2012-03-15

316

Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson's disease.  

PubMed

Although a wide range of physiological functions regulated by dopamine (DA) display circadian variations, the role of DA in the generation and/or modulation of these rhythms is unknown. In Parkinson's disease (PD) patients, in addition to the classical motor symptoms, disturbances of the pattern of daily rest/wake cycles are common non-motor symptoms. We investigated daily and circadian rhythms of rest/activity behaviors in a transgenic MitoPark mouse model with selective inactivation of mitochondrial transcription factor A (Tfam) resulting in a slow and progressive degeneration of DA neurons in midbrain structures. Correlated with this, MitoPark mice show a gradual reduction in locomotor activity beginning at about 20weeks of age. In a light-dark cycle, MitoPark mice exhibit a daily pattern of rest/activity rhythms that shows an age-dependent decline in both the amplitude and the stability of the rhythm, coupled with an increased fragmentation of day/night activities. When the circadian system is challenged by exposure to constant darkness or constant light conditions, control littermates retain a robust free-running circadian locomotor rhythm, whereas in MitoPark mice, locomotor rhythms are severely disturbed or completely abolished. Re-exposure to a light/dark cycle completely restores daily locomotor rhythms. MitoPark mice and control littermates express similar masking behaviors under a 1h light/1h dark regime, suggesting that the maintenance of a daily pattern of rest/activity in arrhythmic MitoPark mice can be attributed to the acute inhibitory and stimulatory effects of light and darkness. These results imply that, in addition to the classical motor abnormalities observed in PD, the loss of the midbrain DA neurons leads to impairments of the circadian control of rest/activity rhythms. PMID:25171792

Fifel, Karim; Cooper, Howard M

2014-11-01

317

Circadian rhythms synchronize mitosis in Neurospora crassa  

PubMed Central

The cell cycle and the circadian clock communicate with each other, resulting in circadian-gated cell division cycles. Alterations in this network may lead to diseases such as cancer. Therefore, it is critical to identify molecular components that connect these two oscillators. However, molecular mechanisms between the clock and the cell cycle remain largely unknown. A model filamentous fungus, Neurospora crassa, is a multinucleate system used to elucidate molecular mechanisms of circadian rhythms, but not used to investigate the molecular coupling between these two oscillators. In this report, we show that a conserved coupling between the circadian clock and the cell cycle exists via serine/threonine protein kinase-29 (STK-29), the Neurospora homolog of mammalian WEE1 kinase. Based on this finding, we established a mathematical model that predicts circadian oscillations of cell cycle components and circadian clock-dependent synchronized nuclear divisions. We experimentally demonstrate that G1 and G2 cyclins, CLN-1 and CLB-1, respectively, oscillate in a circadian manner with bioluminescence reporters. The oscillations of clb-1 and stk-29 gene expression are abolished in a circadian arrhythmic frqko mutant. Additionally, we show the light-induced phase shifts of a core circadian component, frq, as well as the gene expression of the cell cycle components clb-1 and stk-29, which may alter the timing of divisions. We then used a histone hH1-GFP reporter to observe nuclear divisions over time, and show that a large number of nuclear divisions occur in the evening. Our findings demonstrate the circadian clock-dependent molecular dynamics of cell cycle components that result in synchronized nuclear divisions in Neurospora. PMID:24474764

Hong, Christian I.; Zámborszky, Judit; Baek, Mokryun; Labiscsak, Laszlo; Ju, Kyungsu; Lee, Hyeyeong; Larrondo, Luis F.; Goity, Alejandra; Chong, Hin Siong; Belden, William J.; Csikász-Nagy, Attila

2014-01-01

318

Virtual Neuron  

NSDL National Science Digital Library

Neurons are able to communicate with each other using biochemicals called neurotransmitters. Use Virtual Neuron to explore neurotransmitter properties, make neurons fire, and manipulate neural circuits.

2009-04-14

319

Genetic Analysis of Ectopic Circadian Clock Induction in Drosophila  

PubMed Central

Cell-autonomous feedback loops underlie the molecular oscillations that define circadian clocks. In Drosophila the transcription factor Clk activates multiple clock components of feedback loops many of which feed back and regulate Clk expression or activity. Previously the authors evoked similar molecular oscillations in putatively naïve neurons in Drosophila by ectopic expression of a single gene, Clk, suggesting a master regulator function. Using molecular oscillations of the core clock component PERIOD (PER), the authors observed dramatic and widespread molecular oscillations throughout the brain in flies expressing ectopic Clk. Consistent with the master regulator hypothesis, they found that Clk is uniquely capable of inducing ectopic clocks as ectopic induction of other clock components fails to induce circadian rhythms. Clk also induces oscillations even when expression is adult restricted, suggesting that ectopic clocks can even be induced in differentiated cells. However, if transgene expression is discontinued, PER expression disappears, indicating that Clk must be continually active to sustain ectopic clock function. In some cases Clk-mediated PER induction was observed without apparent synchronous cycling, perhaps due to desynchronization of rhythms between clocks or truly cell autonomous arrhythmic PER expression, indicating that additional factors may be necessary for coherent rhythms in cells ectopically expressing Clk. To determine minimal requirements for circadian clock induction by Clk, the authors determined the genetic requirements of ectopic clocks. No ectopic clocks are induced in mutants of Clk’s heterodimeric partner cyc. In addition, noncycling PER is observed when ectopic Clk is induced in a cryb mutant background. While other factors may contribute, these results indicate that persistent Clock induction is uniquely capable of broadly inducing ectopic rhythms even in adults, consistent with a special role at the top of a clock gene hierarchy. PMID:19755582

Kilman, Valerie L.; Allada, Ravi

2011-01-01

320

Circadian regulation of adipose function  

PubMed Central

Adipose physiology shows prominent variation over the course of the day, responding to changing demands in energy metabolism. In the last years the tight interaction between the endogenous circadian timing system and metabolic function has been increasingly acknowledged. Recent work suggests that clock and adipose function go hand in hand, regulating each other to ensure optimal adaptation to environmental changes over the 24-h cycle. In this review we describe the current knowledge on the mechanistic basis of this interaction and summarize recent findings on the impact of clock dysfunction on adipose physiology and energy homeostasis. PMID:24052895

Shostak, Anton; Husse, Jana; Oster, Henrik

2013-01-01

321

Causes and Consequences of Hyperexcitation in Central Clock Neurons  

PubMed Central

Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (?24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus. PMID:23990770

Diekman, Casey O.; Belle, Mino D. C.; Irwin, Robert P.; Allen, Charles N.; Piggins, Hugh D.; Forger, Daniel B.

2013-01-01

322

ORL1 receptor-mediated down-regulation of mPER2 in the suprachiasmatic nucleus accelerates re-entrainment of the circadian clock following a shift in the environmental light/dark cycle.  

PubMed

The circadian pacemaker in the suprachiasmatic nucleus (SCN) generates the near 24-h period of the circadian rhythm and is entrained to the 24-h daily cycle by periodic environmental signals, such as the light/dark cycle (photic signal), and can be modulated by various drugs (non-photic signals). The mechanisms by which non-photic signals modulate the circadian clock are not well understood in mice. In mice, many reportedly non-photic stimuli have little effect on the circadian rhythm in vivo. Herein, we investigated the molecular mechanism in W-212393-induced phase advance using mice. W-212393 caused a significant phase advance of locomotor activity rhythm in mice at subjective day. Injection of W-212393 during subjective day elicited down-regulation of mPER2 protein in the SCN shell region, but not mPer2 mRNA. Administration of W-212393 during subjective day failed to produce phase advance in mPer2-mutant mice as well as in ORL1 receptor deficient mice. Furthermore, we show that such inhibition of mPER2 accelerates re-entrainment of the circadian clock following an abrupt shift in the environmental light/dark cycle, such as occurs with transmeridian flight. The present results suggest that post-translational down-regulation of mPER2 protein in the shell region of mouse SCN may be involved in W-212393-induced non-photic phase advance. PMID:17196226

Miyakawa, Kazuko; Uchida, Ayumi; Shiraki, Tomomi; Teshima, Koji; Takeshima, Hiroshi; Shibata, Shigenobu

2007-03-01

323

HCN Channelopathy in External Globus Pallidus Neurons in Models of Parkinson’s Disease  

PubMed Central

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined. Following the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking that normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that plays an essential role in its generation – the HCN channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, not a cause, of key network pathophysiology – a conclusion consistent with the ability of L-type channel antagonists to attenuate silencing following DA depletion. PMID:21076425

Chan, C. Savio; Glajch, Kelly E.; Gertler, Tracy S.; Guzman, Jaime N.; Mercer, Jeff N.; Lewis, Alan S.; Goldberg, Alan B.; Tkatch, Tatiana; Shigemoto, Ryuichi; Fleming, Sheila M.; Chetkovich, Dane M.; Osten, Pavel; Kita, Hitoshi; Surmeier, D. James

2010-01-01

324

Circadian clocks and mood-related behaviors.  

PubMed

Circadian clocks are present in nearly all tissues of an organism, including the brain. The brain is not only the site of the master coordinator of circadian rhythms located in the suprachiasmatic nuclei (SCN) but also contains SCN-independent oscillators that regulate various functions such as feeding and mood-related behavior. Understanding how clocks receive and integrate environmental information and in turn control physiology under normal conditions is of importance because chronic disturbance of circadian rhythmicity can lead to serious health problems. Genetic modifications leading to disruption of normal circadian gene functions have been linked to a variety of psychiatric conditions including depression, seasonal affective disorder, eating disorders, alcohol dependence, and addiction. It appears that clock genes play an important role in limbic regions of the brain and influence the development of drug addiction. Furthermore, analyses of clock gene polymorphisms in diseases of the central nervous system (CNS) suggest a direct or indirect influence of circadian clock genes on brain function. In this chapter, I will present evidence for a circadian basis of mood disorders and then discuss the involvement of clock genes in such disorders. The relationship between metabolism and mood disorders is highlighted followed by a discussion of how mood disorders may be treated by changing the circadian cycle. PMID:23604481

Albrecht, Urs

2013-01-01

325

Relaxin-3 null mutation mice display a circadian hypoactivity phenotype.  

PubMed

Characterizing the neurocircuits and neurotransmitters that underlie arousal and circadian sleep/wake patterns is an important goal of neuroscience research, with potential implications for understanding human mental illnesses, such as major depression. Recent anatomical and functional studies suggest that relaxin-3 neurons and their ascending projections contribute to these functions via actions on key cortical, limbic and hypothalamic circuits. This study reports the behavioral phenotype of C57BL/6J backcrossed relaxin-3 knockout (KO) mice. Cohorts of adult, male and female relaxin-3 KO and wild-type (WT) littermate mice were subjected to a battery of behavioral tests to assess sensorimotor function and complex behavior. No overt deficits were detected in motor-coordination, spatial memory, sensorimotor gating, anxiety-like behavior or locomotor behavior in novel environments; and no marked genotype differences were observed in response to a chronic stress protocol. Notably however, compared to WT mice, relaxin-3 KO mice displayed robust hypoactivity during the dark/active phase when provided with free home-cage access to voluntary running wheels. This circadian hypoactivity was reflected by reduced time spent and distance traveled on running wheels, coupled with an increase in the time spent immobile, possibly reflecting increased sleeping. Overall, these studies support a role for relaxin-3 signaling in the control of arousal and sleep/wakefulness, and identify the relaxin-3 KO mouse as a useful model to study this role further. PMID:21899720

Smith, C M; Hosken, I T; Sutton, S W; Lawrence, A J; Gundlach, A L

2012-02-01

326

Circadian Integration of Glutamatergic Signals by Little SAAS in Novel Suprachiasmatic Circuits  

PubMed Central

Background Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood. Methodology/Principal Findings Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS. Conclusions/Significance Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock. PMID:20830308

Atkins, Norman; Mitchell, Jennifer W.; Romanova, Elena V.; Morgan, Daniel J.; Cominski, Tara P.; Ecker, Jennifer L.; Pintar, John E.; Sweedler, Jonathan V.; Gillette, Martha U.

2010-01-01

327

Cellular dissection of circadian peptide signals using genetically encoded membrane-tethered ligands  

PubMed Central

Background Neuropeptides regulate a broad range of physiological and behavioral processes. Elucidation of neuropeptide function requires identifying the cells that respond to neuropeptide signals and determining the molecular, cellular, physiological, and behavioral consequences of activation of their cognate GPCRs in those cells. As a novel tool for answering these questions, we have developed genetically encoded neuropeptides covalently tethered to a glycosylphosphatidyl inositol (GPI) glycolipid anchor on the extracellular leaflet of the plasma membrane (“t-peptides”). Results We show that t-peptides cell-autonomously induce activation of their cognate GPCRs in cells that express both the t-peptide and its receptor. In the neural circuit controlling circadian rest-activity rhythms in Drosophila melanogaster, rhythmic secretion of the neuropeptide Pigment Dispersing Factor (PDF) and activation of its GPCR (PDFR) are important for intercellular communication of phase information and coordination of cellular oscillations of multiple circadian clock neurons. Broad expression of t-PDF in the circadian control circuit overcomes arrhythmicity induced by pdf01 null mutation, most likely due to activation of PDFR in PDFR-expressing clock neurons that do not themselves secrete PDF. More restricted cellular expression of t-PDF suggests that activation of PDFR accelerates cellular timekeeping in some clock neurons, while decelerating others. Conclusions The activation of PDFR in pdf01 null-mutant flies—and thus the absence of PDF-mediated intercellular transfer of phase information—induces strong rhythmicity in constant darkness, thus establishing a distinct role for PDF signaling in the circadian control circuit independent of the intercellular communication of temporal phase information. The t-peptide technology we have developed and validated should provide a useful tool for cellular dissection of bioactive peptide signaling in a variety of organisms and physiological contexts. PMID:19592252

Choi, Charles; Fortin, Jean-Philippe; McCarthy, Ellena v.; Oksman, Lea; Kopin, Alan S.; Nitabach, Michael N.

2009-01-01

328

The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock  

PubMed Central

All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ?24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential “clock kinase” phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways. PMID:25144774

Dusik, Verena; Senthilan, Pingkalai R.; Mentzel, Benjamin; Hartlieb, Heiko; Wülbeck, Corinna; Yoshii, Taishi; Raabe, Thomas; Helfrich-Förster, Charlotte

2014-01-01

329

Characterisation of circadian rhythms of various duckweeds.  

PubMed

The plant circadian clock controls various physiological phenomena that are important for adaptation to natural day-night cycles. Many components of the circadian clock have been identified in Arabidopsis thaliana, the model plant for molecular genetic studies. Recent studies revealed evolutionary conservation of clock components in green plants. Homologues of clock-related genes have been isolated from Lemna gibba and Lemna aequinoctialis, and it has been demonstrated that these homologues function in the clock system in a manner similar to their functioning in Arabidopsis. While clock components are widely conserved, circadian phenomena display diversity even within the Lemna genus. In order to survey the full extent of diversity in circadian rhythms among duckweed plants, we characterised the circadian rhythms of duckweed by employing a semi-transient bioluminescent reporter system. Using a particle bombardment method, circadian bioluminescent reporters were introduced into nine strains representing five duckweed species: Spirodela polyrhiza, Landoltia punctata, Lemna gibba, L. aequinoctialis and Wolffia columbiana. We then monitored luciferase (luc+) reporter activities driven by AtCCA1, ZmUBQ1 or CaMV35S promoters under entrainment and free-running conditions. Under entrainment, AtCCA1::luc+ showed similar diurnal rhythms in all strains. This suggests that the mechanism of biological timing under day-night cycles is conserved throughout the evolution of duckweeds. Under free-running conditions, we observed circadian rhythms of AtCCA1::luc+, ZmUBQ1::luc+ and CaMV35S::luc+. These circadian rhythms showed diversity in period length and sustainability, suggesting that circadian clock mechanisms are somewhat diversified among duckweeds. PMID:24942699

Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T

2015-01-01

330

The circadian timing system in clinical oncology.  

PubMed

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest- activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P=0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients. PMID:24915535

Innominato, Pasquale F; Roche, Véronique P; Palesh, Oxana G; Ulusakarya, Ayhan; Spiegel, David; Lévi, Francis A

2014-06-01

331

[Circadian clock disruption and diabetes mellitus].  

PubMed

Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of obesity and type 2 diabetes. In humans, both shift work and the genetic variations of clock genes increase the risk of these disorders. In mice, the light conditions which induce chronic jet lag and modifications of the clock genes cause obesity and/or type 2 diabetes. Moreover, circadian clocks in peripheral tissues are impaired in both patients with type 2 diabetes and genetically obese diabetic mice. Therefore, circadian clocks are important new therapeutic targets for preventing and treating obesity and type 2 diabetes. PMID:24437264

Ando, Hitoshi; Fujimura, Akio

2013-12-01

332

Circadian Integration of Metabolism and Energetics  

PubMed Central

Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity and diabetes, and implications for rational therapeutics for these conditions. PMID:21127246

Bass, Joseph; Takahashi, Joseph S.

2013-01-01

333

Effect of Different Spectral Transmittances through Tinted Animal Cages on Circadian Metabolism and Physiology in Sprague–Dawley Rats  

PubMed Central

The suprachiasmatic nucleus is synchronized by the light:dark cycle and is the master biologic clock that serves as a pacemaker to regulate circadian rhythms. We explored the hypothesis that spectral transmittance (tint) of light through caging alters circadian rhythms of endocrine and metabolic plasma constituents in nonpigmented Sprague–Dawley rats. Rats (Crl:SD; n = 12 per group) were housed in a 12:12-h light:dark environment (300 lx; 123.0 ?W/cm2; lights on, 0600) in either clear-, amber-, blue-, or red-tinted rodent cages. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and measured for melatonin, total fatty acids, pH, glucose, lactic acid, corticosterone, insulin, and leptin. As expected, plasma melatonin levels were low during the light phase but higher during the dark phase in all groups; however, when compared with the clear-cage group, rats in amber-, blue-, and red-tinted cages had 29%, 74%, and 48%, respectively, greater total daily melatonin levels due to an increased duration and, in some cases, amplitude of the nocturnal melatonin signal. No differences were found in dietary and water intake, body growth rates, total fatty acids, pH, or glucose among groups. Disruptions in circadian rhythms, manifesting as alterations in phase timing, amplitude, or duration, occurred in the melatonin, lactic acid, corticosterone, insulin, and leptin levels of rats in tinted compared with clear cages. Therefore, the use of variously tinted animal cages significantly alters circadian rhythms in plasma measures of metabolism and physiology in laboratory rats, thus potentially altering the outcomes of scientific investigations. PMID:24411779

Wren, Melissa A; Dauchy, Robert T; Hanifin, John P; Jablonski, Michael R; Warfield, Benjamin; Brainard, George C; Blask, David E; Hill, Steven M; Ooms, Tara G; Bohm, Rudolf P

2014-01-01

334

Involvement of the brain region containing pigment-dispersing factor-immunoreactive neurons in the photoperiodic response of the bean bug, Riptortus pedestris.  

PubMed

The concept of insect photoperiodism based on a circadian clock has been supported by many studies demonstrating that the behavioural circadian rhythm and the photoperiodic response are driven by the same circadian clock genes. However, the neuronal mechanism of the circadian clock underlying photoperiodism is poorly understood. To examine whether circadian rhythm and photoperiodism share a neuronal mechanism, we focused on the neurons that express neuropeptide pigment-dispersing factor (PDF) in the bean bug, Riptortus pedestris. PDF has been identified as an important regulator of the insect circadian rhythm and is expressed in circadian clock neurons of various insect species. In R. pedestris, PDF immunoreactivity was detected in some clusters of cells and their fibres in the optic lobe and the protocerebrum. cDNA encoding a PDF precursor protein was highly conserved between R. pedestris and many other insects. Differences between day and night were not observed in the immunolabelling intensity in cell bodies of PDF-immunoreactive neurons and pdf mRNA expression levels in the head. Surgical removal of the region containing PDF-immunoreactive cell bodies at the medulla disrupted the photoperiodic regulation of diapause. However, gene suppression of pdf by RNA interference did not affect the photoperiodic response. These results suggest that the region containing PDF-immunoreactive somata is important for the photoperiodic response in R. pedestris, but pdf mRNA expression is probably not required for the response. PMID:24198258

Ikeno, Tomoko; Numata, Hideharu; Goto, Shin G; Shiga, Sakiko

2014-02-01

335

Design and Testing of a Percutaneously Implantable Fetal Pacemaker  

PubMed Central

We are developing a cardiac pacemaker with a small, cylindrical shape that permits percutaneous implantation into a fetus to treat complete heart block and consequent hydrops fetalis, which can otherwise be fatal. The device uses off-the-shelf components including a rechargeable lithium cell and a highly efficient relaxation oscillator encapsulated in epoxy and glass. A corkscrew electrode made from activated iridium can be screwed into the myocardium, followed by release of the pacemaker and a short, flexible lead entirely within the chest of the fetus to avoid dislodgement from fetal movement. Acute tests in adult rabbits demonstrated the range of electrical parameters required for successful pacing and the feasibility of successfully implanting the device percutaneously under ultrasonic imaging guidance. The lithium cell can be recharged inductively as needed, as indicated by a small decline in the pulsing rate. PMID:22855119

Loeb, Gerald E.; Zhou, Li; Zheng, Kaihui; Nicholson, Adriana; Peck, Raymond A.; Krishnan, Anjana; Silka, Michael; Pruetz, Jay; Chmait, Ramen; Bar-Cohen, Yaniv

2012-01-01

336

Ventricular perforation by pacemaker lead repaired with two hemostatic devices  

PubMed Central

INTRODUCTION Cardiac perforation is a rare, but potentially serious, complication of pacemaker implantation that may develop days or weeks after implantation. PRESENTATION OF CASE In the current case, 92-year-old man underwent permanent pacemaker implantation, but he presented 3 weeks later with severe symptoms. Computed tomography showed protrusion of the tip of the ventricular electrode through the right ventricle and into the chest wall. During an urgent surgical intervention, the lead was disconnected and extracted. A sealing hemostatic device and an hemostatic patch were applied to repair the ventricle; the procedure was uneventfull. DISCUSSION This case demonstrates how the correct diagnosis of ventricular perforation is crucial, and should be followed immediately by surgical planning. CONCLUSION The hemostatic patch is a valuable alternative to sutures in patients with thin and fragile ventricular wall, unable to undergo stitching. PMID:25460433

Prestipino, Filippo; Nenna, Antonio; Casacalenda, Adele; Chello, Massimo

2014-01-01

337

Isoperiodic neuronal activity in suprachiasmatic nucleus of the rat  

NASA Technical Reports Server (NTRS)

A subpopulation of neurons in the suprachiasmatic nucleus (SCN) is shown here to exhibit isoperiodic bursting activity. The period of discharge in these cells may be lengthened or the periodicity may be transiently disrupted by photic stimulation. It is suggested that many, if not all, of these cells are vasoactive intestinal polypeptide (VIP) neurons. It is shown that the ultradian periodicity of these cells, estimates of the VIP neuron population size in the SCN, effects of partial lesions on tau (period), and estimates of the phase stability of SCN-driven circadian rhythms are consistent with a strongly coupled, multioscillator model of circadian rhythmicity, in which the oscillator population constitutes a restricted subset of the SCN neuronal population.

Miller, J. D.; Fuller, C. A.

1992-01-01

338

Endovascular extraction techniques for pacemaker and ICD lead extraction  

PubMed Central

In the last few years, comprehensive endovascular techniques have been developed to extract chronically implanted pacemaker and defibrillator leads. It is important that referring physician have knowledge of the advantages and limitations of the different techniques. In this paper we discuss the techniques and results of the currently used endovascular extraction techniques. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7

Bracke, F.A.; Meijer, A.; van Gelder, B.

2001-01-01

339

Permanent pacemaker-associated actinomycetemcomitans endocarditis: A case report  

PubMed Central

Aggregatibacter actinomycetemcomitans is a Gram-negative bacillus, member of the HACEK group of bacteria, and it is a very rare cause of endocarditis. It is also an extremely rare cause of device-associated infection of the heart. We describe the case of a 25 year-old man who presented with pacemaker-associated endocarditis due to Aggregatibacter actinomycetemcomitans and also discuss the implications and treatment of this organism. PMID:24432293

Li, Zhenhong; Madeo, Jennifer; Ahmed, Shadab; Vidal, Alex; Makaryus, Amgad; Mejia, Jose; Yasmin, Tabassum

2013-01-01

340

Changing trends in pacemaker and implantable cardioverter defibrillator generator advisories.  

PubMed

Pacemaker and implantable cardioverter defibrillator (ICD) generator recalls and safety alerts (advisories) occur frequently, affect many patients, and are increasing in number and rate. It is unknown if advances in device technology have been accompanied by changing patterns of device advisory type. Weekly FDA Enforcement Reports from January 1991 to December 2000 were analyzed to identify all advisories involving pacemaker and ICD generators. This article represents additional analysis of previously cited advisories and does not contain additional recalls or safety alerts over those that have been previously reported. The 29 advisories (affecting 159,061 devices) from the early 1990s (1991-1995) were compared to the 23 advisories (affecting 364,084 devices) from the late 1990s (1996-2000). While the annual number of device advisories did not change significantly, ICD advisories became more frequent and a three-fold increase in the number of devices affected per advisory was observed. The number of devices affected by hardware advisories increased three-fold, due primarily to a 700-fold increase in electrical/circuitry abnormalities and a 20-fold increase in potential battery/capacitor malfunctions. Other types of hardware abnormalities (defects in the device header, hermetic seal, etc.) became less common. The number of devices recalled due to firmware (computer programming) abnormalities more than doubled. The remarkable technological advances in pacemaker and ICD therapy have been accompanied by changing patterns of device advisory type. Accurate, timely physician and patient notification systems, and routine pacemaker and ICD patient follow-up continue to be of paramount importance. PMID:12520666

Maisel, William H; Stevenson, William G; Epstein, Laurence M

2002-12-01

341

Plethyzmography in assessment of hemodynamic results of pacemaker functions programming  

NASA Astrophysics Data System (ADS)

The paper presents potential role of plethyzmography in optimization of heart hemodynamic function during pacemaker programming. The assessment of optimal stroke volume in patients, with implanted dual chamber pacemaker (DDD), by plethyzmography was a goal of the study. The data were collected during pacing rhythm. 20 patients (8 female and 12 male, average 77.4+/-4.6 years) with dual chamber pacemaker (DDD) and with pacing rhythm during routine pacemaker control and study tests were incorporated in the study group. Hemodynamic parameters were assessed during modification of atrio-ventricular delay (AVD) for pacing rhythm of 70 bpm and 90 bpm. The time of atrioventricular was programmed with 20 ms steps within range 100-200 ms and data were recorded with two minutes delay between two consecutive measurements. Stroke volume (SV) and cardiac output (CO) were calculated from plethyzmographic signal by using Beatscope software (TNO Holand). Highest SV calculated for given pacing rhythm was named optimal stroke volume (OSV) and consequently highest cardiac output was named maximal cardiac output (MCO). The time of atrio-ventricular delay for OSV was named optimal atrioventricular delay (OAVD). The results have showed: mean values of OAVD for 70 bpm - 152+/-33 ms and for 90 bpm -149+/-35 ms, shortening of the mean OAVD time caused by increase of pacing rate from 70 bpm to 90 bpm what resulted in statistically significant decrease of OSV with not statistically significant increase of MCO. The analysis of consecutive patients revealed three types of response to increase of pacing rhythm: 1. typical-shortening of OAVD, 2. neutral-no change of OAVD and 3.atypical-lengthening of OAVD.

Wojciechowski, Dariusz; Sionek, Piotr; Peczalski, Kazimierz; Janusek, Dariusz

2011-01-01

342

Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors  

PubMed Central

Serotonin (5-hydroxytryptamine: 5-HT) affects numerous functions in the gut, such as secretion, muscle contraction, and enteric nervous activity, and therefore to clarify details of 5-HT's actions leads to good therapeutic strategies for gut functional disorders. The role of interstitial cells of Cajal (ICC), as pacemaker cells, has been recognised relatively recently. We thus investigated 5-HT actions on ICC pacemaker activity. Muscle preparations with myenteric plexus were isolated from the murine ileum. Spatio-temporal measurements of intracellular Ca2+ and electric activities in ICC were performed by employing fluorescent Ca2+ imaging and microelectrode array (MEA) systems, respectively. Dihydropyridine (DHP) Ca2+ antagonists and tetrodotoxin (TTX) were applied to suppress smooth muscle and nerve activities, respectively. 5-HT significantly enhanced spontaneous Ca2+ oscillations that are considered to underlie electric pacemaker activity in ICC. LY-278584, a 5-HT3 receptor antagonist suppressed spontaneous Ca2+ activity in ICC, while 2-methylserotonin (2-Me-5-HT), a 5-HT3 receptor agonist, restored it. GR113808, a selective antagonist for 5-HT4, and O-methyl-5-HT (O-Me-5-HT), a non-selective 5-HT receptor agonist lacking affinity for 5-HT3 receptors, had little effect on ICC Ca2+ activity. In MEA measurements of ICC electric activity, 5-HT and 2-Me-5-HT caused excitatory effects. RT-PCR and immunostaining confirmed expression of 5-HT3 receptors in ICC. The results indicate that 5-HT augments ICC pacemaker activity via 5-HT3 receptors. ICC appear to be a promising target for treatment of functional motility disorders of the gut, for example, irritable bowel syndrome. PMID:21949791

Liu, Hong-Nian; Ohya, Susumu; Nishizawa, Yuji; Sawamura, Kenta; Iino, Satoshi; Syed, Mohsin Md; Goto, Kazunori; Imaizumi, Yuji; Nakayama, Shinsuke

2011-01-01

343

CIRCADIAN RHYTHMS Marking Time for a Kingdom  

NSDL National Science Digital Library

The author provides perspective on a study reported on page 483 of this issue. Findings from this study identifying a crucial circadian gene in hamsters represents "a major breakthrough for time-conscious mammals".

Michael Young (The Rockefeller University;Laboratory of Genetics and National Science Foundation Center for Biological Timing)

2000-04-21

344

Interference between mobile phones and pacemakers: a look inside.  

PubMed

In this study we analyzed the problem of electromagnetic interference (EMI) between mobile telephones and cardiac pacemakers (PM), by looking at the mechanisms by which the radiated radio frequency (RF) GSM signal may affect the pacemaker function. From a literature review on this topic, we noticed that older pacemakers had a higher rate of being affected by mobile phones when compared to newer ones. This is probably due to the fact that new generation of PM are more protected against electromagnetic field, being equipped with RF feedthrough filters incorporated to the internal PM circuitry. In some experiments conducted by our group, we found that modulated RF signals are somehow demodulated by the PM internal non-linear circuit elements, if no feedthrough assembly is incorporated inside the PM. Such demodulation phenomenon poses a critical problem because digital cellular phones use extremely low-frequency modulation (as low as 2 Hz), that can be mistaken for normal heartbeat. The feedthrough assembly seems instead to prevents the RF signals from accessing the PM enclosure, thus attenuating EMI signals over a broad range of frequencies. PMID:17938456

Censi, Federica; Calcagnini, Giovanni; Triventi, Michele; Mattei, Eugenio; Bartolini, Pietro

2007-01-01

345

Modulation of Hippocampal Theta Oscillations and Spatial Memory by Relaxin-3 Neurons of the Nucleus Incertus  

ERIC Educational Resources Information Center

Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the…

Ma, Sherie; Olucha-Bordonau, Francisco E.; Hossain, M. Akhter; Lin, Feng; Kuei, Chester; Liu, Changlu; Wade, John D.; Sutton, Steven W.; Nunez, Angel; Gundlach, Andrew L.

2009-01-01

346

Circadian stress tolerance in adult Caenorhabditis elegans  

Microsoft Academic Search

Circadian rhythms control several behaviors through neural networks, hormones and gene expression. One of these outputs in\\u000a invertebrates, vertebrates and plants is the stress resistance behavior. In this work, we studied the circadian variation\\u000a in abiotic stress resistance of adult C. elegans as well as the genetic mechanisms that underlie such behavior. Measuring the stress resistance by tap response behavior

Sergio H. Simonetta; Andrés Romanowski; Alicia N. Minniti; Nibaldo C. Inestrosa; Diego A. Golombek

2008-01-01

347

Circadian Clock Proteins in Mood Regulation  

PubMed Central

Mood regulation is known to be affected by the change of seasons. Recent research findings have suggested that mood regulation may be influenced by the function of circadian clocks. In addition, the activity of brown adipocytes has been hypothesized to contribute to mood regulation. Here, the overarching link to mood disorders might be the circadian clock protein nuclear receptor subfamily 1, group D, member 1. PMID:25610405

Partonen, Timo

2015-01-01

348

The effects of nuclear magnetic resonance on patients with cardiac pacemakers  

SciTech Connect

The effect of nuclear magnetic resonance (NMR) imaging on six representative cardiac pacemakers was studied. The results indicate that the threshold for initiating the asynchronous mode of a pacemaker is 17 gauss. Radiofrequency levels are present in an NMR unit and may confuse or possibly inhibit demand pacemakers, although sensing circuitry is normally provided with electromagnetic interference discrimination. Time-varying magnetic fields can generate pulse amplitudes and frequencies to mimic cardiac activity. A serious limitation in the possibility of imaging a patient with a pacemaker would be the alteration of normal pulsing parameters due to time-varying magnetic fields.

Pavlicek, W. (Cleveland Clinic Foundation, OH); Geisinger, M.; Castle, L.; Borkowski, G.P.; Meaney, T.F.; Bream, B.L.; Gallagher, J.H.

1983-04-01

349

Testing of Common Electromagnetic Environments for Risk of Interference with Cardiac Pacemaker Function  

PubMed Central

Background Cardiac pacemakers are known to be susceptible to strong electromagnetic fields (EMFs). This in vivo study investigated occurrence of electromagnetic interference with pacemakers caused by common environmental sources of EMFs. Methods Eleven volunteers with a pacemaker were exposed to EMFs produced by two mobile phone base stations, an electrically powered commuter train, and an overhead high voltage transmission lines. All the pacemakers were programmed in normal clinically selected settings with bipolar sensing and pacing configurations. Results None of the pacemakers experienced interference in any of these exposure situations. However, often it is not clear whether or not strong EMFs exist in various work environments, and hence an individual risk assessment is needed. Conclusions Modern pacemakers are well shielded against external EMFs, and workers with a pacemaker can most often return to their previous work after having a pacemaker implanted. However, an appropriate risk assessment is still necessary after the implantation of a pacemaker, a change of its generator, or major modification of its programming settings. PMID:24106646

Tiikkaja, Maria; Aro, Aapo L.; Alanko, Tommi; Lindholm, Harri; Sistonen, Heli; Hartikainen, Juha E.K.; Toivonen, Lauri; Juutilainen, Jukka; Hietanen, Maila

2013-01-01

350

Successful implantation of a dual-chamber pacemaker in an ELBW infant for long QT syndrome.  

PubMed

Long QT syndromes encompass the most prevalent group of ion channelopathies. Long QT syndromes are predominantly familial and predispose the affected individual to ventricular arrhythmias and sudden death. Permanent pacemaker insertion for long QT syndrome is discouraged apart from younger patients exhibiting 2:1 atrioventricular block. However, permanent pacemaker insertion is a relatively common procedure in neonates with atrioventricular block, and dual-chamber permanent pacemaker insertion in low birth weight infants is challenging. We describe the management of long QT syndrome - type 2 - presenting in an extremely preterm neonate including epicardial, dual-chamber permanent pacemaker insertion. PMID:24905882

McCrossan, Brian; d'Udekem, Yves; Davis, Andrew Mark; Pflaumer, Andreas

2015-03-01

351

Circadian Synchrony in Networks of Protein Rhythm Driven Neurons  

E-print Network

islets [2]. Perhaps most important, the healthy human heart beats at regular intervals of about 60 to 100 fires as one mass [1]. Synchronicity of oscillators is crucial in the human body. Plasma insulin are also synchronized. The beta cells are organized into islets and synchronize both within and between

Siegelmann , Hava T

352

Pilot Fatigue and Circadian Desynchronosis  

NASA Technical Reports Server (NTRS)

Pilot fatigue and circadian desynchronosis, its significance to air transport safety, and research approaches, were examined. There is a need for better data on sleep, activity, and other pertinent factors from pilots flying a variety of demanding schedules. Simulation studies of flight crew performance should be utilized to determine the degree of fatigue induced by demanding schedules and to delineate more precisely the factors responsible for performance decrements in flight and to test solutions proposed to resolve problems induced by fatigue and desynchronosis. It was concluded that there is a safety problem of uncertain magnitude due to transmeridian flying and a potential problem due to fatigue associated with various factors found in air transport operations.

1981-01-01

353

Circadian rhythm of aromatic l-amino acid decarboxylase in the rat suprachiasmatic nucleus: gene expression and decarboxylating activity in clock oscillating cells  

Microsoft Academic Search

Background: Aromatic L -amino acid decarboxylase (AADC) is the enzyme responsible for the decar- boxylation step in both the catecholamine and indoleamine synthetic pathways. In the brain, how- ever, a group of AADC containing neurones is found outside the classical monoaminergic cell groups. Since such non-monoaminergic AADC is expressed abundantly in the suprachiasmatic nucleus (SCN), the mammalian circadian centre, we

Yoshiki Ishida; Chihiro Yokoyama; Tsutomu Inatomi; Kazuhiro Yagita; Xin Dong; Lily Yan; Shun Yamaguchi; Ikuko Nagatsu; Takahide Komori; Kunio Kitahama; Hitoshi Okamura

2002-01-01

354

Circadian Rhythms in Prokaryotes: Luciferase as a Reporter of Circadian Gene Expression in Cyanobacteria  

Microsoft Academic Search

We have used a luciferase reporter gene and continuous automated monitoring of bioluminescence to demonstrate unequivocally that cyanobacteria exhibit circadian behaviors that are fundamentally the same as circadian rhythms of eukaryotes. We also show that these rhythms can be studied by molecular methods in Synechococcus sp. PCC7942, a strain for which genetic transformation is well established. A promoterless segment of

Takao Kondo; Carl A. Strayer; Resham D. Kulkarni; Walter Taylor; Masahiro Ishiura; Susan S. Golden; Carl Hirschie Johnson

1993-01-01

355

MDMA alters the response of the circadian clock to a photic and non-photic stimulus.  

PubMed

3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a widely used recreational drug that damages serotonin 5-HT neurons in animals and possibly humans. Published literature has shown that the serotonergic system is involved in photic and non-photic phase shifting of the circadian clock, which is located in the suprachiasmatic nuclei. Despite the dense innervation of the circadian system by 5-HT and the known selective neurotoxicity of MDMA, little is known about the effects of MDMA on the circadian oscillator. This study investigated whether repeated exposure to the serotonin neurotoxin MDMA alters the behavioural response of the Syrian hamster to phase shift to the serotonin 5-HT1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT). This agonist was administered under an Aschoff Type I (CT8) and Aschoff Type II (ZT8) paradigm (5 mg/kg) and was given before and after treatment with MDMA (10, 15 and 20 mg/kg administered on successive days). Pre-treatment with MDMA significantly attenuated phase shifts to 8-OH-DPAT. We also tested the ability of the clock to phase shift to a photic stimulus after treatment with MDMA. A 15-min light pulse (mean lux 125 at CT14 or ZT14) was administered before and after treatment with MDMA. Phase shifts to a photic stimulus were significantly attenuated by pre-treatment with MDMA. Our study demonstrates that repeated exposure to MDMA may alter the ability of the circadian clock to phase shift to a photic and non-photic stimulus in the hamster. Disruption of circadian function has been linked with a variety of clinical conditions such as sleep disorders, mood, concentration difficulties and depression, consequently outlining the potential dangers of long-term ecstasy use. PMID:12426045

Colbron, Suzanne; Jones, Mark; Biello, Stephany M

2002-11-22

356

Circadian Rhythms of Crawling and Swimming in the Nudibranch Mollusc Melibe leonina.  

PubMed

Daily rhythms of activity driven by circadian clocks are expressed by many organisms, including molluscs. We initiated this study, with the nudibranch Melibe leonina, with four goals in mind: (1) determine which behaviors are expressed with a daily rhythm; (2) investigate which of these rhythmic behaviors are controlled by a circadian clock; (3) determine if a circadian clock is associated with the eyes or optic ganglia of Melibe, as it is in several other gastropods; and (4) test the hypothesis that Melibe can use extraocular photoreceptors to synchronize its daily rhythms to natural light-dark cycles. To address these goals, we analyzed the behavior of 55 animals exposed to either artificial or natural light-dark cycles, followed by constant darkness. We also repeated this experiment using 10 animals that had their eyes removed. Individuals did not express daily rhythms of feeding, but they swam and crawled more at night. This pattern of locomotion persisted in constant darkness, indicating the presence of a circadian clock. Eyeless animals also expressed a daily rhythm of locomotion, with more locomotion at night. The fact that eyeless animals synchronized their locomotion to the light-dark cycle suggests that they can detect light using extraocular photoreceptors. However, in constant darkness, these rhythms deteriorated, suggesting that the clock neurons that influence locomotion may be located in, or near, the eyes. Thus, locomotion in Melibe appears to be influenced by both ocular and extraocular photoreceptors, although the former appear to have a greater influence on the expression of circadian rhythms. PMID:25572214

Newcomb, James M; Kirouac, Lauren E; Naimie, Amanda A; Bixby, Kimberly A; Lee, Colin; Malanga, Stephanie; Raubach, Maureen; Watson, Winsor H

2014-12-01

357

Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans.  

PubMed

The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00-08.00 h) in near darkness. Eight healthy male volunteers (24.4 +/- 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time. PMID:15459246

Rajaratnam, Shantha M W; Middleton, Benita; Stone, Barbara M; Arendt, Josephine; Dijk, Derk-Jan

2004-11-15

358

Circadian phase, sleepiness, and light exposure assessment in night workers with and without shift work disorder.  

PubMed

Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean ± SD] age: 39.2 ± 12.5 yrs; mean yrs on shift = 9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6 ± 8.6 yrs; mean years on shift = 8.4) participated. All participants were admitted to the sleep center at 16:00 h, where they stayed in a dim light (<10 lux) private room for the study period of 25 consecutive hours. Saliva samples for melatonin assessment were collected at 30-min intervals. Circadian phase was determined from circadian rhythms of salivary melatonin onset (dim light melatonin onset, DLMO) calculated for each individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00 h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42 ± 3.25 h, whereas in the SWD group it was 20:42 ± 2.21 h (z = 2.4; p circadian pacemaker in asymptomatic night-shift workers. In contrast, individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule. PMID:22823876

Gumenyuk, Valentina; Roth, Thomas; Drake, Christopher L

2012-08-01

359

Circadian Rhythms in Anesthesia and Critical Care Medicine: Potential Importance of Circadian Disruptions.  

PubMed

The rotation of the earth and associated alternating cycles of light and dark-the basis of our circadian rhythms-are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts. PMID:25294583

Brainard, Jason; Gobel, Merit; Bartels, Karsten; Scott, Benjamin; Koeppen, Michael; Eckle, Tobias

2014-10-01

360

Interval timing in mice does not rely upon the circadian pacemaker P.A. Lewisa,b,c  

E-print Network

, upon interval timing behaviour. Fourteen house mice (Mus musculus) were trained to estimate a 10-mice (Mus musculus). Lesioned animals were tested first under entrained LD conditions and then while free animals should only show a deficit when maintained in DD. Fourteen male C57/Bl6 house-mice (M. musculus

Miall, Chris

361

Comparison of circadian gene expression among different oscillator models: identification of critical output signals of the SCN pacemaker  

E-print Network

occur at the appropriate time of day or night in relation to the environmental cycle and to other functionally-affiliated events. For mammals, endogenous oscillations in gene expression are a prevalent feature of oscillatory cells residing...

Menger, Gus John, III

2009-05-15

362

Cell Division Cycles and Circadian Clocks 123  

PubMed Central

The cell division rhythm in Euglena gracilis Klebs (Z strain) freeruns with a circadian period (30.2 ± 1.8 hours for 156 monitored oscillations) in aerated, magnetically stirred, 8-liter, axenic batch cultures grown photoautotrophically at 25°C in LD: 3,3, (7,500 lux, cool-white fluorescent) 6-hour light cycles from the moment of inoculation. Cell number was measured at 2-hour intervals with an automatic fraction collector and Coulter Electronic Particle Counter. At different circadian times throughout the 30-hour division cycle, 3-hour light perturbations were imposed on free-running cell populations by giving light during one of the intervals when dark would have fallen in the LD: 3,3 regimen. Using the onset of division as the phase reference point, the net steady-state phase advance or delay (±??) of the rhythm was determined after transients, if any, had subsided (usually in one or two days) relative to an unperturbed control culture. Both +?? and ??? were found, with maximum values of approximately ±11 to 12 hours being obtained at circadian time (CT) 20 to 22 (the `breakpoint'); little, if any phase shift occurred if the light signal was given between CT 6 and CT 12. The phase-resetting curve obtained by plotting new phase (??) versus old phase (?) was of the type 0 (`strong') variety. Light perturbations, no matter when imposed, engendered new phases which mapped to a relatively restricted portion (CT 6 to CT 13) of the circadian cycle. These data provide the first detailed phase-response curve for a circadian mitotic clock. The findings, therefore, not only further support the hypothesis that a circadian oscillator (perhaps exhibiting limit cycle behavior) can modulate cell division in eukaryotic cells, but also provide a useful basis for the dissection of the nature and extent of the coupling between cell division and circadian cycles. PMID:16662464

Edmunds, Leland N.; Tay, Doranne E.; Laval-Martin, Danielle L.

1982-01-01

363

Fatal cardiac thromboembolism in a patient with a pacemaker during ureteroscopic lithotripsy for ureter stone: a case report  

PubMed Central

Intracardiac thrombosis is an infrequent and fatal complication in patients with an inserted pacemaker. A patient with an inserted pacemaker scheduled for ureter stone removal experienced cardiac arrest and cardiopulmonary resuscitation under general anesthesia. Echocardiography showed multiple intracardiac thrombi. Preoperative diagnostic workup including echocardiography for the detection of pacemaker lead thrombus, and the need for anticoagulation should be considered in patients with an inserted pacemaker and high-risk factors for thrombosis.

Chung, Mee Young; Chae, Su Min

2015-01-01

364

Bead Neuron  

NSDL National Science Digital Library

Using string and beads of different colors, students will make bead neurons and use them as models to understand the specialized cellular structure and function of neurons and how neurons communicate with each other.

Dr. Janet M Dubinsky (University of Minnesota Neuroscience)

2008-11-06

365

Calbindin-D28k immunoreactivity in the suprachiasmatic nucleus and the circadian response to constant light in the rat  

Microsoft Academic Search

Recent studies in the hamster have led to the discovery that the expression of the calcium binding protein, calbindin-D28k, is a defining feature of neurons in the suprachiasmatic nucleus involved in the regulation of circadian rhythms by environmental light.2,18,19,32 To study further the involvement of calbindin-D28k, we examined the effect of exposure to constant light on calbindin-D28k immunoreactivity in the

A Arvanitogiannis; B Robinson; C Beaulé; S Amir

2000-01-01

366

Physiologically based modelling of circadian control on cell proliferation  

E-print Network

one, until effective division. Each peripheral cell circadian clock is under the synchronising control anticancer therapies, which may be synchronised with cell cycle timing by the knowledge of the body circadianPhysiologically based modelling of circadian control on cell proliferation Jean Clairambault INRIA

Clairambault, Jean

367

Circadian rhythms in Macaca mulatta monkeys during Bion 11 flight  

NASA Technical Reports Server (NTRS)

Circadian rhythms of primate brain temperature, head and ankle skin temperature, motor activity, and heart rate were studied during spaceflight and on the ground. In space, the circadian rhythms of all the parameters were synchronized with diurnal Zeitgebers. However, in space the brain temperature rhythm showed a significantly more delayed phase angle, which may be ascribed to an increase of the endogenous circadian period.

Alpatov, A. M.; Hoban-Higgins, T. M.; Klimovitsky, V. Y.; Tumurova, E. G.; Fuller, C. A.

2000-01-01

368

A novel animal model linking adiposity to altered circadian rhythms  

Technology Transfer Automated Retrieval System (TEKTRAN)

Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metab...

369

Bilateral extracorporeal shock wave lithotripsy in a spinal cord injury patient with a cardiac pacemaker  

Microsoft Academic Search

Objectives: To review the precautions to be observed before and during extracorporeal shock wave lithotripsy (ESWL) in spinal cord injury (SCI) patients with a cardiac pacemaker and the safety of bilateral ESWL performed on the same day.Design: A case report of bilateral ESWL in a SCI patient with a permanent cardiac pacemaker.Setting: The Regional Spinal Injuries Centre, Southport, the Lithotripsy

S Vaidyanathan; R Hirst; KF Parsons; G Singh; BM Soni; T Oo; A Zaidi; JWH Watt; P Sett

2001-01-01

370

Comparison of the normal sinus node with seven types of rate responsive pacemaker during everyday activity.  

PubMed Central

The heart rate response of 59 patients aged 17-79 years implanted with seven different types of rate responsive pacemakers was evaluated during graded exercise treadmill testing and during standardised daily activities. The heart rate response in patients with pacemakers was compared with the chronotropic response in 20 healthy controls of similar age and sex distribution who performed identical protocols. All pacemaker types adequately simulated the control heart rate response during the graded exercise treadmill test except during the early stages of exercise. However, during everyday activities, the response of ventricular rate responsive (VVIR) pacemakers was varied. Activity sensing systems rapidly overresponded to staircase descent, to changes in walking speed, and to suitcase lifting with the pacemaker arm, and these systems did not respond to mental stress. "Physiological" sensors (QT and minute ventilation units) responded slowly to rapid changes in physiological demand. The QT pacemaker patients did respond to mental stress but showed a paradoxical increase in rate during the recovery phases of burst exercise protocols such as staircase ascent/descent and walking deceleration. Dual chamber pacemakers in VDD, DDD, and DDDR modes most closely simulated the normal chronotropic response during everyday activities. Graded exercise treadmill testing, in isolation, may not be the best way to asses or program the heart rate response in patients with the heart rate adaptive pacemakers because changes in heart rate during everyday activities may deviate considerably from the normal sinus response despite satisfactory simulation of the normal chronotropic response during treadmill testing. PMID:2390399

Sulke, A N; Pipilis, A; Henderson, R A; Bucknall, C A; Sowton, E

1990-01-01

371

Circadian Rhythms in Drosophila: A Connections Map  

NSDL National Science Digital Library

Genetic and biochemical experiments over the past decade have allowed the construction of a viable working model for the molecular mechanisms underlying circadian rhythm generation in Drosophila. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the "positive loop"--controls the rhythmic expression of a Per-Arnt-Sim (PAS)-domain-containing positive transcription factor, Clock. The second loop--the "negative loop"--controls the transcription of period and timeless, two genes encoding repressor proteins. The loops are intertwined because Period and Timeless directly repress transcription mediated by the Clock:Cycle heterodimer, whereas Clock:Cycle drives transcription of period and timeless, as well as that of vrille, a repressor of Clock expression. Other proteins, including kinases encoded by doubletime, shaggy, Andante, and Timekeeper, also have essential functions in the timekeeping mechanism. Light cycles can synchronize the Drosophila circadian pathway by directly stimulating Cryptochrome-dependent degradation of Timeless. This Pathway Map of the Drosophila circadian mechanism describes the individual known components of the fly circadian clock and their mutual interactions. An accompanying animation schematizes the dynamic interactions of the different components. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text

Russell N. Van Gelder (Department of Molecular Biology and Pharmacology;Department of Ophthalmology and Visual Sciences REV)

2003-08-05

372

Pacemaker discomfort induced by the wearing of seat belts.  

PubMed

A survey was made of 100 consecutive pacemaker recipients to examine problems they may have experienced with seat belts whilst travelling by car, either as drivers (29 patients) or front seat passengers (50 patients). Twenty-one per cent of the drivers and 30% of the front seat passengers had experienced symptoms, usually of a mild nature. Re-siting of the generator was only necessary in 1 patient and no example of electrode displacement was observed. Suggestions are made as to how this problem might be overcome. PMID:4022858

Wallis, M; Todd, I; Aber, C P

1985-04-01

373

Second-, minute- and hour-metronomes of intestinal pacemakers.  

PubMed

1. Movements of the gastrointestinal tract are required for the digestion of food and the expulsion of waste products. 2. The present paper will discuss the nature of electrical rhythms underlying some intestinal motility patterns. 3. The rhythms are generated by pacemakers with cycle rates appropriate to controlling individual contractions, motor patternings or switching between different motor programmes. 4. Electrical rhythms are discussed with periods of the order of seconds, minutes and hours. 5. Particular discussion is centred on rhythms recorded from the small and large intestine of the mouse. PMID:9784929

Bywater, R A; Spencer, N J; Fida, R; Taylor, G S

1998-10-01

374

Short-Wavelength Light Sensitivity of Circadian, Pupillary, and Visual Awareness in Humans Lacking an Outer Retina  

PubMed Central

Summary As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight [1–11]. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength (?480 nm) blue light and remain functional in the absence of rods and cones [8–10]. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (?max) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus (?480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all “visual” responses to light. PMID:18082405

Zaidi, Farhan H.; Hull, Joseph T.; Peirson, Stuart N.; Wulff, Katharina; Aeschbach, Daniel; Gooley, Joshua J.; Brainard, George C.; Gregory-Evans, Kevin; Rizzo, Joseph F.; Czeisler, Charles A.; Foster, Russell G.; Moseley, Merrick J.; Lockley, Steven W.

2007-01-01

375

Circadian typology: a comprehensive review.  

PubMed

The interest in the systematic study of the circadian typology (CT) is relatively recent and has developed rapidly in the two last decades. All the existing data suggest that this individual difference affects our biological and psychological functioning, not only in health, but also in disease. In the present study, we review the current literature concerning the psychometric properties and validity of CT measures as well as individual, environmental and genetic factors that influence the CT. We present a brief overview of the biological markers that are used to define differences between CT groups (sleep-wake cycle, body temperature, cortisol and melatonin), and we assess the implications for CT and adjustment to shiftwork and jet lag. We also review the differences between CT in terms of cognitive abilities, personality traits and the incidence of psychiatric disorders. When necessary, we have emphasized the methodological limitations that exist today and suggested some future avenues of work in order to overcome these. This is a new field of interest to professionals in many different areas (research, labor, academic and clinical), and this review provides a state of the art discussion to allow professionals to integrate chronobiological aspects of human behavior into their daily practice. PMID:23004349

Adan, Ana; Archer, Simon N; Hidalgo, Maria Paz; Di Milia, Lee; Natale, Vincenzo; Randler, Christoph

2012-11-01

376

Molecular components of the mammalian circadian clock  

PubMed Central

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested. PMID:23604473

Buhr, Ethan D.; Takahashi, Joseph S.

2013-01-01

377

Structural Insights into a Circadian Oscillator  

NSDL National Science Digital Library

An endogenous circadian system in cyanobacteria exerts pervasive control over cellular processes, including global gene expression. Indeed, the entire chromosome undergoes daily cycles of topological changes and compaction. The biochemical machinery underlying a circadian oscillator can be reconstituted in vitro with just three cyanobacterial proteins, KaiA, KaiB, and KaiC. These proteins interact to promote conformational changes and phosphorylation events that determine the phase of the in vitro oscillation. The high-resolution structures of these proteins suggest a ratcheting mechanism by which the KaiABC oscillator ticks unidirectionally. This posttranslational oscillator may interact with transcriptional and translational feedback loops to generate the emergent circadian behavior in vivo. The conjunction of structural, biophysical, and biochemical approaches to this system reveals molecular mechanisms of biological timekeeping.

Carl Hirschie Johnson (Vanderbilt University; Department of Biological Sciences)

2008-10-31

378

Nutrient Sensing and the Circadian Clock  

PubMed Central

The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24hr oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals, and that high-fat diet influences the period of locomotor activity under free-running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relationship between metabolic and circadian pathways. Here, we highlight the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems. PMID:22424658

Peek, Clara B.; Ramsey, Kathryn M.; Marcheva, Biliana; Bass, Joseph

2012-01-01

379

Circadian rhythm dysregulation in bipolar disorder.  

PubMed

When circadian rhythms - the daily oscillations of various physiological and behavioral events that are controlled by a central timekeeping mechanism - become desynchronized with the prevailing light:dark cycle, a maladaptative response can result. Animal data based primarily on genetic manipulations and clinical data from biomarker and gene expression studies support the notion that circadian abnormalities underlie certain psychiatric disorders. In particular, bipolar disorder has an interesting link to rhythm-related disease biology; other mood disturbances, such as major depressive disorder, seasonal affective disorder and the agitation and aggression accompanying severe dementia (sundowning), are also linked to changes in circadian rhythm function. Possibilities for pharmacological intervention derive most readily from the molecular oscillator, the cellular machinery that drives daily rhythms. PMID:20571973

Westrich, Ligia; Sprouse, Jeffrey

2010-07-01

380

A neuropeptide speeds circadian entrainment by reducing intercellular synchrony  

PubMed Central

Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light–dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase- and the dose-dependent response to VIP and that the transient phase desynchronization, or “phase tumbling”, could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8-h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag. PMID:24167276

An, Sungwon; Harang, Rich; Meeker, Kirsten; Granados-Fuentes, Daniel; Tsai, Connie A.; Mazuski, Cristina; Kim, Jihee; Doyle, Francis J.; Petzold, Linda R.; Herzog, Erik D.

2013-01-01

381

Circadian oscillations of cytosolic and chloroplastic free calcium in plants  

NASA Technical Reports Server (NTRS)

Tobacco and Arabidopsis plants, expressing a transgene for the calcium-sensitive luminescent protein apoaequorin, revealed circadian oscillations in free cytosolic calcium that can be phase-shifted by light-dark signals. When apoaequorin was targeted to the chloroplast, circadian chloroplast calcium rhythms were likewise observed after transfer of the seedlings to constant darkness. Circadian oscillations in free calcium concentrations can be expected to control many calcium-dependent enzymes and processes accounting for circadian outputs. Regulation of calcium flux is therefore fundamental to the organization of circadian systems.

Johnson, C. H.; Knight, M. R.; Kondo, T.; Masson, P.; Sedbrook, J.; Haley, A.; Trewavas, A.

1995-01-01

382

Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling.  

PubMed

Evidence is accumulating regarding the importance of circadian core oscillators, several associated factors, and melatonin signaling in the maintenance of health. Dysfunction of endogenous clocks, melatonin receptor polymorphisms, age- and disease-associated declines of melatonin likely contribute to numerous diseases including cancer, metabolic syndrome, diabetes type 2, hypertension, and several mood and cognitive disorders. Consequences of gene silencing, overexpression, gene polymorphisms, and deviant expression levels in diseases are summarized. The circadian system is a complex network of central and peripheral oscillators, some of them being relatively independent of the pacemaker, the suprachiasmatic nucleus. Actions of melatonin on peripheral oscillators are poorly understood. Various lines of evidence indicate that these clocks are also influenced or phase-reset by melatonin. This includes phase differences of core oscillator gene expression under impaired melatonin signaling, effects of melatonin and melatonin receptor knockouts on oscillator mRNAs or proteins. Cross-connections between melatonin signaling pathways and oscillator proteins, including associated factors, are discussed in this review. The high complexity of the multioscillator system comprises alternate or parallel oscillators based on orthologs and paralogs of the core components and a high number of associated factors with varying tissue-specific importance, which offers numerous possibilities for interactions with melatonin. It is an aim of this review to stimulate research on melatonin signaling in peripheral tissues. This should not be restricted to primary signal molecules but rather include various secondarily connected pathways and discriminate between direct effects of the pineal indoleamine at the target organ and others mediated by modulation of oscillators. PMID:22034907

Hardeland, Rüdiger; Madrid, Juan Antonio; Tan, Dun-Xian; Reiter, Russel J

2012-03-01

383

PDF and cAMP enhance PER stability in Drosophila clock neurons.  

PubMed

The neuropeptide PDF is important for Drosophila circadian rhythms: pdf(01) (pdf-null) animals are mostly arrhythmic or short period in constant darkness and have an advanced activity peak in light-dark conditions. PDF contributes to the amplitude, synchrony, as well as the pace of circadian rhythms within clock neurons. PDF is known to increase cAMP levels in PDR receptor (PDFR)-containing neurons. However, there is no known connection of PDF or of cAMP with the Drosophila molecular clockworks. We discovered that the mutant period gene per(S) ameliorates the phenotypes of pdf-null flies. The period protein (PER) is a well-studied repressor of clock gene transcription, and the per(S) protein (PERS) has a markedly short half-life. The result therefore suggests that the PDF-mediated increase in cAMP might lengthen circadian period by directly enhancing PER stability. Indeed, increasing cAMP levels and cAMP-mediated protein kinase A (PKA) activity stabilizes PER, in S2 tissue culture cells and in fly circadian neurons. Adding PDF to fly brains in vitro has a similar effect. Consistent with these relationships, a light pulse causes more prominent PER degradation in pdf(01) circadian neurons than in wild-type neurons. The results indicate that PDF contributes to clock neuron synchrony by increasing cAMP and PKA, which enhance PER stability and decrease clock speed in intrinsically fast-paced PDFR-containing clock neurons. We further suggest that the more rapid degradation of PERS bypasses PKA regulation and makes the pace of clock neurons more uniform, allowing them to avoid much of the asynchrony caused by the absence of PDF. PMID:24707054

Li, Yue; Guo, Fang; Shen, James; Rosbash, Michael

2014-04-01

384

Circadian rhythms in the green sunfish retina  

PubMed Central

We investigated the occurrence of circadian rhythms in retinomotor movements and retinal sensitivity in the green sunfish, Lepomis cyanellus. When green sunfish were kept in constant darkness, cone photoreceptors exhibited circadian retinomotor movements; rod photoreceptors and retinal pigment epithelium (RPE) pigment granules did not. Cones elongated during subjective night and contracted during subjective day. These results corroborate those of Burnside and Ackland (1984. Investigative Ophthalmology and Visual Science. 25:539-545). Electroretinograms (ERGs) recorded in constant darkness in response to dim flashes (lambda = 640 nm) exhibited a greater amplitude during subjective night than during subjective day. The nighttime increase in the ERG amplitude corresponded to a 3-10-fold increase in retinal sensitivity. The rhythmic changes in the ERG amplitude continued in constant darkness with a period of approximately 24 h, which indicates that the rhythm is generated by a circadian oscillator. The spectral sensitivity of the ERG recorded in constant darkness suggests that cones contribute to retinal responses during both day and night. Thus, the elongation of cone myoids during the night does not abolish the response of the cones. To examine the role of retinal efferents in generating retinal circadian rhythms, we cut the optic nerve. This procedure did not abolish the rhythms of retinomotor movement or of the ERG amplitude, but it did reduce the magnitude of the nighttime phases of both rhythms. Our results suggest that more than one endogenous oscillator regulates the retinal circadian rhythms in green sunfish. Circadian signals controlling the rhythms may be either generated within the eye or transferred to the eye via a humoral pathway. PMID:3598559

1987-01-01

385

Circadian rhythms in the green sunfish retina.  

PubMed

We investigated the occurrence of circadian rhythms in retinomotor movements and retinal sensitivity in the green sunfish, Lepomis cyanellus. When green sunfish were kept in constant darkness, cone photoreceptors exhibited circadian retinomotor movements; rod photoreceptors and retinal pigment epithelium (RPE) pigment granules did not. Cones elongated during subjective night and contracted during subjective day. These results corroborate those of Burnside and Ackland (1984. Investigative Ophthalmology and Visual Science. 25:539-545). Electroretinograms (ERGs) recorded in constant darkness in response to dim flashes (lambda = 640 nm) exhibited a greater amplitude during subjective night than during subjective day. The nighttime increase in the ERG amplitude corresponded to a 3-10-fold increase in retinal sensitivity. The rhythmic changes in the ERG amplitude continued in constant darkness with a period of approximately 24 h, which indicates that the rhythm is generated by a circadian oscillator. The spectral sensitivity of the ERG recorded in constant darkness suggests that cones contribute to retinal responses during both day and night. Thus, the elongation of cone myoids during the night does not abolish the response of the cones. To examine the role of retinal efferents in generating retinal circadian rhythms, we cut the optic nerve. This procedure did not abolish the rhythms of retinomotor movement or of the ERG amplitude, but it did reduce the magnitude of the nighttime phases of both rhythms. Our results suggest that more than one endogenous oscillator regulates the retinal circadian rhythms in green sunfish. Circadian signals controlling the rhythms may be either generated within the eye or transferred to the eye via a humoral pathway. PMID:3598559

Dearry, A; Barlow, R B

1987-05-01

386

Does the circadian system regulate lactation?  

PubMed

Environmental variables such as photoperiod, heat, stress, nutrition and other external factors have profound effects on quality and quantity of a dairy cow's milk. The way in which the environment interacts with genotype to impact milk production is unknown; however, evidence from our laboratory suggests that circadian clocks play a role. Daily and seasonal endocrine rhythms are coordinated in mammals by the master circadian clock in the hypothalamus. Peripheral clocks are distributed in every organ and coordinated by signals from the master clock. We and others have shown that there is a circadian clock in the mammary gland. Approximately 7% of the genes expressed during lactation had circadian patterns including core clock and metabolic genes. Amplitude changes occurred in the core mammary clock genes during the transition from pregnancy to lactation and were coordinated with changes in molecular clocks among multiple tissues. In vitro studies using a bovine mammary cell line showed that external stimulation synchronized mammary clocks, and expression of the core clock gene, BMAL1, was induced by lactogens. Female clock/clock mutant mice, which have disrupted circadian rhythms, have impaired mammary development and their offspring failed to thrive suggesting that the dam's milk production was not adequate enough to nourish their young. We envision that, in mammals, during the transition from pregnancy to lactation the master clock is modified by environmental and physiological cues that it receives, including photoperiod length. In turn, the master clock coordinates changes in endocrine milieu that signals peripheral tissues. In dairy cows, it is clear that changes in photoperiod during the dry period and/or during lactation influences milk production. We believe that the photoperiod effect on milk production is mediated, in part by the 'setting' of the master clock with light, which modifies peripheral circadian clocks including the mammary core clock and subsequently impacts milk yield and may impact milk composition. PMID:22436218

Plaut, K; Casey, T

2012-03-01

387

Precision of the Gonyaulax circadian clock.  

PubMed

Under constant conditions, the circadian bioluminescent glow rhythm in populations (10(5) cells) of Gonyaulax polyedra is accurate to within 2 min/day. On successive days following the transfer to constant conditions, however, the glow exhibits a progressively broader waveform, implying that individual clocks in the population are drifting out of synchrony. Analysis of the glow waveform suggests that the standard deviation in circadian period among individual clocks is about 18 min and that the period of a given clock varies by less than this from one day to the next. PMID:6170441

Njus, D; Gooch, V D; Hastings, J W

1981-09-01

388

Regulation of Circadian Clocks by Redox Homeostasis*  

PubMed Central

Living organisms possess biological clocks that resonate with environmental cycles in light, temperature, and food availability. Recently, circadian oscillations in the redox state of peroxiredoxin have been described as an additional non-transcriptional timekeeping mechanism. Of note, this redox cycle is conserved in both prokaryotes and eukaryotes. How the classical “transcription-translation feedback loop” model and this redox oscillation are related is still poorly understood. In this minireview, we describe the most recent evidence pointing to cross-talk between the circadian clock and the redox status of the cell. PMID:23861436

Stangherlin, Alessandra; Reddy, Akhilesh B.

2013-01-01

389

Circadian polymorphisms associated with affective disorders  

PubMed Central

Background Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies. Methods Four groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples. Results In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample. Conclusion Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders. PMID:19166596

Kripke, Daniel F; Nievergelt, Caroline M; Joo, EJ; Shekhtman, Tatyana; Kelsoe, John R

2009-01-01

390

Molecular Mechanisms Underlying the Arabidopsis Circadian Clock  

PubMed Central

A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day–night cycle. This rhythm is generated by the so-called ‘circadian clock’. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. This progress has provided mechanistic insights into how key clock-associated proteins are integrated, and may help in understanding the essence of the clock's molecular mechanisms. PMID:21873329

Nakamichi, Norihito

2011-01-01

391

Ecological measurements of light exposure, activity, and circadian disruption  

PubMed Central

Circadian rhythms are biological rhythms that repeat at approximately 24 hours. In humans, circadian rhythms have an average period of 24.2 hours. The 24-hour patterns of light and dark on the retina synchronize circadian rhythms to the local time on earth. Lighting characteristics affecting circadian rhythms are very different than those affecting visual responses. Lack of synchronization between the endogenous clock and the local time has been associated with a host of maladies. Therefore, it is important to measure circadian light exposures over the course of the 24-hour day and to be able to assess circadian entrainment and disruption in actual living environments. Presented is an overview of the recently developed Daysimeter, a personal measurement device for recording activity and circadian light-exposure. When the Daysimeter is worn on the head, two light sensors near the eye are used to estimate circadian light (CLA) exposures over extended periods of time. Phasor analysis combines the measured periodic activity-rest patterns with the measured periodic light-dark patterns to assess behavioural circadian entrainment/disruption. As shown, day-shift and rotating-shift nurses exhibit remarkably different levels of behavioural circadian entrainment/disruption. These new ecological measurement and analysis techniques may provide important insights into the relationship between circadian disruption and well-being. PMID:23504497

Miller, D; Bierman, A; Figueiro, MG; Schernhammer, ES; Rea, MS

2013-01-01

392

Pacemaker failures characterized by continuous direct current leakage.  

PubMed

Pulse generator failure caused by continuous leakage of direct current through an output capacitor has not previously been appreciated. Routine post-explant electronic evaluation has identified the defect in six implanted and one external pulse generator. The constant direct current in the implantable units, 0.14 to 0.26 milliamperes, is in the range that produces ventricular arrhythmias in dogs although this did not occur in our patients. Evidence of local myocardial damage existed in four cases and of electrode deterioration in three. The implant failures occurred without warning and in four cases within 2 weeks of demonstrated normal function, blunting the predictive benefits of pacemaker monitoring programs. Capacitor discharge circuits used in many pacers are inherently capable of developing direct current leakage in the event of output capacitor short circuit. In one model of pacemakers such continuous direct current leakage caused 8.3 percent (3 of 36) of pulse generator failures, widely scattered in time at 23, 27 and 46 months after implant. Capacitor short circuit causing constant direct current leakage can masquerade as primary battery failure and should be suspected when cessation of pacer function is associated with increased threshold or poor myocardial electrogram without evidence of wire break or displacement. PMID:1274862

Fisher, J D; Furman, S; Parker, B; Escher, D J

1976-06-01

393

The genetics of mammalian circadian order and disorder: implications for physiology and disease  

Microsoft Academic Search

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates

Hee-Kyung Hong; Caroline H. Ko; Erin L. McDearmon; Joseph S. Takahashi

2008-01-01

394

Comparison of Fontan Survivors with and without Pacemakers: A Report from the Pediatric Heart Network Fontan Cross Sectional Study  

PubMed Central

Objective Although many Fontan patients undergo pacemaker placement, there are few studies characterizing this population. Our purpose was to compare clinical characteristics, functional status and measures of ventricular performance in Fontan patients with and without a pacemaker. Patients and Design The NHLBI funded Pediatric Heart Network (PHN) Fontan Cross Sectional Study characterized 546 Fontan survivors. Clinical characteristics, medical history and study outcomes (Child Health Questionnaire (CHQ), echocardiographic evaluation of ventricular function, and exercise testing) were compared between subjects with and without pacemakers. Results Of 71 subjects with pacemakers (13%), 43/71 (61%) were in a paced rhythm at the time of study enrollment (age 11.9±3.4 years). Pacemaker subjects were older at study enrollment, more likely to have single left ventricles, and taking more medications. There were no differences in age at Fontan or Fontan type between the pacemaker and no pacemaker groups. There were no differences in exercise performance between groups. CHQ physical summary scores were lower in the pacemaker subjects (39.7±14.3 vs. 46.1±11.2, p = 0.001). Ventricular ejection fraction z-score was also lower (?1.4±1.9 vs. ?0.8±2.0, p = 0.05) in pacemaker subjects. Conclusions In our cohort of Fontan survivors, those with a pacemaker have poorer functional status and evidence of decreased ventricular systolic function compared to Fontan survivors without a pacemaker. PMID:22762157

Williams, Richard V.; Travison, Thomas; Kaltman, Jonathan R.; Cecchin, Frank; Colan, Steven D.; Idriss, Salim F.; Lu, Minmin; Margossian, Renee; Reed, John H.; Silver, Eric S.; Stephenson, Elizabeth A.; Vetter, Victoria L.

2012-01-01

395

Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment  

PubMed Central

SUMMARY The retina consists of ordered arrays of individual types of neurons for processing vision. Here we show that such order is necessary for intrinsically photosensitive retinal ganglion cells (ipRGCs) to function as irradiance detectors. We found that during development, ipRGCs undergo proximity-dependent Bax-mediated apoptosis. Bax mutant mice exhibit disrupted ipRGC spacing and dendritic stratification with an increase in abnormally localized synapses. ipRGCs are the sole conduit for light input to circadian photoentrainment, and either their melanopsin-based photosensitivity or ability to relay rod-cone input is sufficient for circadian photoentrainment. Remarkably, the disrupted ipRGC spacing does not affect melanopsin-based circadian photoentrainment, but severely impairs rod/cone-driven photoentrainment. We demonstrate reduced rod-cone driven cFos activation and electrophysiological responses in ipRGCs, suggesting that impaired synaptic input to ipRGCs underlies the photoentrainment deficits. Thus, for irradiance detection, developmental apoptosis is necessary for the spacing and connectivity of ipRGCs that underlie their functioning within a neural network. PMID:23395376

Chen, Shih-Kuo; Chew, Kylie S.; McNeill, David S.; Keeley, Patrick W.; Ecker, Jennifer L.; Mao, Buqing Q.; Pahlberg, Johan; Kim, Bright; Lee, Sammy C. S.; Fox, Michael; Guido, William; Wong, Kwoon Y.; Sampath, Alapakkam P.; Reese, Benjamin E.; Kuruvilla, Rejji; Hattar, Samer

2012-01-01

396

Sinus venosus atrial septal defect: a rare cause of misplacement of pacemaker leads  

PubMed Central

Routine implantation of pacemakers and implantable cardioverter defibrillators is not commonly associated with complications. However, in some cases we see misplacement of pacemaker leads which is most often related to the presence of underlying cardiac anomalies. We report the case of misplacement of a pacemaker lead into the left ventricle of a 56-year-old patient paced in VVI/R mode and with a tined type pacemaker lead because of a symptomatic complete atrioventricular block. Electrocardiogram showed a pacemaker-generated rhythm with a right bundle branch block pattern. Chest X-ray showed the pacemaker lead located relatively high in relation to the diaphragm. Echocardiography visualized the pacemaker lead in the left heart chambers (atrium and ventricle), hence confirming its aberrant course. Further, the defect causing its passage to the left heart chambers was a sinus venosus atrial septal defect. The patient reported no complication related to the misplacement of the lead. After a brief period of oral anticoagulation, the lead was inserted into the right ventricle by percutaneous technique. PMID:23847433

Bodian, Malick; Aw, Fatou; Bamba, Mouhamadou Ndiaye; Kane, Adama; Jobe, Modou; Tabane, Alioune; Mbaye, Alassane; Sarr, Simon Antoine; Diao, Maboury; Sarr, Moustapha; Bâ, Serigne Abdou

2013-01-01

397

ACUTE ETHANOL DISRUPTS PHOTIC AND SEROTONERGIC CIRCADIAN CLOCK PHASE-RESETTING IN THE MOUSE  

PubMed Central

Background Alcohol abuse is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: 1) characterize the SCN pharmacokinetics of acute systemic ethanol administration; 2) explore the effects of acute ethanol on photic and non-photic phase-resetting; and 2) determine if the SCN is a direct target for photic effects. Methods First, microdialysis was used to characterize the pharmacokinetics of acute i.p. injections of 3 doses of ethanol (0.5, 1.0 and 2.0 g/kg) in the mouse suprachiasmatic (SCN) circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase-delays and serotonergic ([+]8-OH-DPAT-induced) phase-advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20–40 min post-injection with half-lives for clearance ranging from 0.6–1.8 hr. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase-delays. Conclusions These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and non-photic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism. PMID:21463340

Brager, Allison J.; Ruby, Christina L.; Prosser, Rebecca A.; Glass, J. David

2011-01-01

398

Temperature compensation and entrainment in circadian rhythms  

NASA Astrophysics Data System (ADS)

To anticipate daily variations in the environment and coordinate biological activities into a daily cycle many organisms possess a circadian clock. In the absence of external time cues the circadian rhythm persists with a period of approximately 24?h. The clock phase can be shifted by single pulses of light, darkness, chemicals, or temperature and this allows entrainment of the clock to exactly 24 h by cycles of these zeitgebers. On the other hand, the period of the circadian rhythm is kept relatively constant within a physiological range of constant temperatures, which means that the oscillator is temperature compensated. The mechanisms behind temperature compensation and temperature entrainment are not fully understood, neither biochemically nor mathematically. Here, we theoretically investigate the interplay of temperature compensation and entrainment in general oscillatory systems. We first give an analytical treatment for small temperature shifts and derive that every temperature-compensated oscillator is entrainable to external small-amplitude temperature cycles. Temperature compensation ensures that this entrainment region is always centered at the endogenous period regardless of possible seasonal temperature differences. Moreover, for small temperature cycles the entrainment region of the oscillator is potentially larger for rectangular pulses. For large temperature shifts we numerically analyze different circadian clock models proposed in the literature with respect to these properties. We observe that for such large temperature shifts sinusoidal or gradual temperature cycles allow a larger entrainment region than rectangular cycles.

Bodenstein, C.; Heiland, I.; Schuster, S.

2012-06-01

399

Coordination of circadian timing in mammals  

Microsoft Academic Search

Time in the biological sense is measured by cycles that range from milliseconds to years. Circadian rhythms, which measure time on a scale of 24 h, are generated by one of the most ubiquitous and well-studied timing systems. At the core of this timing mechanism is an intricate molecular mechanism that ticks away in many different tissues throughout the body.

Steven M. Reppert; David R. Weaver

2002-01-01

400

Circadian rhythms in handwriting kinematics and legibility  

Microsoft Academic Search

The aim of the present study was to analyze the circadian rhythmicity in handwriting kinematics and legibility and to compare the performance between Dutch and German writers. Two subject groups underwent a 40h sleep deprivation protocol under Constant Routine conditions either in Groningen (10 Dutch subjects) or in Berlin (9 German subjects). Both groups wrote every 3h a test sentence

Isabelle Jasper; Marijke Gordijn; Andreas Häußler; Joachim Hermsdörfer

2011-01-01

401

Circadian tempo: a paradigm for genome stability?  

PubMed

Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis. PMID:17092657

Shadan, Farhad F

2007-01-01

402

Resilient circadian oscillator revealed in individual cyanobacteria  

Microsoft Academic Search

Circadian oscillators, which provide internal daily periodicity, are found in a variety of living organisms, including mammals, insects, plants, fungi and cyanobacteria. Remarkably, these biochemical oscillators are resilient to external and internal modifications, such as temperature and cell division cycles. They have to be `fluctuation (noise) resistant' because relative fluctuations in the number of messenger RNA and protein molecules forming

Irina Mihalcescu; Weihong Hsing; Stanislas Leibler

2004-01-01

403

Resonating Circadian Clocks Enhance Fitness in Cyanobacteria  

Microsoft Academic Search

In some organisms longevity, growth, and developmental rate are improved when they are maintained on a light\\/dark cycle, the period of which ``resonates'' optimally with the period of the endogenous circadian clock. However, to our knowledge no studies have demonstrated that reproductive fitness per se is improved by resonance between the endogenous clock and the environmental cycle. We tested the

Yan Ouyang; Carol R. Andersson; Takao Kondo; Susan S. Golden; Carl Hirschie Johnson

1998-01-01

404

Circadian Clocks in Human Red Blood Cells  

PubMed Central

Summary Circadian (~24 hour) clocks are fundamentally important for coordinated physiology in organisms as diverse as cyanobacteria and humans. All current models of the clockwork in eukaryotic cells are based on transcription-translation feedback loops. Non-transcriptional mechanisms in the clockwork have been difficult to study in mammalian systems. We circumvented these problems by developing novel assays using human red blood cells (RBCs), which have no nucleus (or DNA), and therefore cannot perform transcription. Our results show that transcription is, in fact, not required for circadian oscillations in humans, and that non-transcriptional events appear sufficient to sustain cellular circadian rhythms. Using RBCs, we found that peroxiredoxins, highly conserved antioxidant proteins, undergo ~24 hour redox cycles, which persist for many days under constant conditions (i.e. in the absence of external cues). Moreover, these rhythms are entrainable (i.e. tunable by environmental stimuli), and temperature-compensated, both key features of circadian rhythms. We anticipate our findings will facilitate more sophisticated cellular clock models, highlighting the interdependency of transcriptional and non-transcriptional oscillations in potentially all eukaryotic cells. PMID:21270888

O’Neill, John S.; Reddy, Akhilesh B.

2010-01-01

405

Procedures for numerical analysis of circadian rhythms  

PubMed Central

This article reviews various procedures used in the analysis of circadian rhythms at the populational, organismal, cellular and molecular levels. The procedures range from visual inspection of time plots and actograms to several mathematical methods of time series analysis. Computational steps are described in some detail, and additional bibliographic resources and computer programs are listed. PMID:23710111

REFINETTI, ROBERTO; LISSEN, GERMAINE CORNÉ; HALBERG, FRANZ

2010-01-01

406

Circadian Typology and Style of Thinking Differences  

ERIC Educational Resources Information Center

The purpose of the present study aims to investigate the relationship between circadian typology and learning-thinking styles conceptualised as a preference toward information processing typical of the right vs. the left cerebral hemisphere. A sample of 1254 undergraduates (380 boys and 874 girls; mean age=21.86+/-2.37,) was administered the…

Fabbri, Marco; Antonietti, Alessandro; Giorgetti, Marisa; Tonetti, Lorenzo; Natale, Vincenzo

2007-01-01

407

Functional genomics of the avian circadian system  

E-print Network

. Investigation of the pineal and retina transcriptomes determined the mRNA profiles of several thousand genes over the course of one day in LD (daily) and one day in DD (circadian) conditions. Several avian orthologs of mammalian clock genes were identified...

Bailey, Michael J

2006-04-12

408

In vitro investigation of eddy current effect on pacemaker operation generated by low frequency magnetic field.  

PubMed

This paper presents in vitro investigation of the eddy current induction effects to the cardiac pacemaker exposed to low frequency magnetic fields. The method used in this study is based to the interaction by inductive coupling through the loop formed by the pacemaker and its leads and the surrounding medium. This interaction results in an induced electromotive force between the terminals of the pacemaker which can potentially disturb the operation of this last. In this article we present experimental results, analytical calculations and numerical simulations using the finite element method. PMID:18003302

Babouri, A; Hedjeidj, A

2007-01-01

409

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.  

PubMed

Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12?000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement. PMID:25349171

Bunney, B G; Li, J Z; Walsh, D M; Stein, R; Vawter, M P; Cartagena, P; Barchas, J D; Schatzberg, A F; Myers, R M; Watson, S J; Akil, H; Bunney, W E

2015-02-01

410

Circadian expression profiles of chromatin remodeling factor genes in Arabidopsis.  

PubMed

The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock. PMID:25315904

Lee, Hong Gil; Lee, Kyounghee; Jang, Kiyoung; Seo, Pil Joon

2015-01-01

411

Circadian rhythms, sleep, and performance in space  

NASA Technical Reports Server (NTRS)

Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and performance proficiency in both ground-based simulations and space mission studies, as described in the 2003 NASA Task Book, will be reviewed.

Mallis, M. M.; DeRoshia, C. W.

2005-01-01

412

Calcium, cellular aging, and selective neuronal vulnerability in Parkinson's disease  

PubMed Central

Parkinson's disease (PD) is the second most common neurodegenerative disease in developed countries. The core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Why these neurons, and other restricted sets of non-dopamine neuron, succumb in PD is not clear. One potential clue has come from the observation that the engagement of L-type Ca2+ channels during autonomous pacemaking elevates the sensitivity of SNc DA neurons to mitochondrial toxins used to create animal models of PD, suggesting that Ca2+ entry is a factor in their selective vulnerability. Epidemiological data also supports a linkage between L-type Ca2+ channels and the risk of developing PD. This review examines the hypothesis that the primary factor driving neurodegenerative changes in PD is the metabolic stress created by sustained Ca2+ entry, particularly in the face of genetic or environmental factors that compromise oxidative defenses or proteostatic competence. PMID:20053445

Surmeier, D. James; Guzman, Jaime N.; Sanchez-Padilla, Javier

2011-01-01

413

Deactivation of Pacemakers and Implantable Cardioverter-Defibrillators  

PubMed Central

Cardiac implantable electrical devices (CIEDs), including pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs), are the most effective treatment for life-threatening arrhythmias. Patients or their surrogates may request device deactivation to avoid prolongation of the dying process or in other settings, such as after device-related complications or with changes in their health care goals. Despite published guidelines outlining theoretical and practical aspects of this common clinical scenario, significant uncertainty remains for both patients and health care providers regarding the ethical and legal status of CIED deactivation. This review outlines the ethical and legal principles supporting CIED deactivation at patients’ request, centered upon patient autonomy and authority over their own medical treatment. The empirical literature describing stakeholder views and experiences surrounding CIED deactivation is described, along with lessons for future research and practice guidance surrounding the care of patients with CIEDs. PMID:23217433

Kramer, Daniel B.; Mitchell, Susan L.; Brock, Dan W.

2013-01-01

414

Unusual Treatment of Pacemaker Pocket Infection: A Case Report  

PubMed Central

Pocket infection of a cardiac device is usually treated by removing the device and re-implanting it in a new site after complete treatment of the infection. This report illustrates a complicated case of pocket infection in the wake of the implantation of a permanent pacemaker (cardiac resynchronization therapy). The patient was treated conservatively through daily irrigation and dressing, broad-spectrum antibiotics, and debridement without the device being removed; the generator was kept out of the pocket for 5 weeks and then re-implanted in the same location successfully. The method of treatment presented herein can be of value, not least in the elderly population who might experience life-threatening events following the replacement of their cardiac devices. PMID:23074594

Kazemisaeed, Ali; Moezzi, Ali; Shafiee, Akbar; Ghazanchai, Fatemeh

2010-01-01

415

Circadian Output, Input, and Intracellular Oscillators: Insights into the Circadian Systems of Single Cells  

PubMed Central

Circadian output comprises the business end of circadian systems in terms of adaptive significance. Work on Neurospora pioneered the molecular analysis of circadian output mechanisms, and insights from this model system continue to illuminate the pathways through which clocks control metabolism and overt rhythms. In Neurospora, virtually every strain examined in the context of rhythms bears the band allele that helps to clarify the overt rhythm in asexual development. Recent cloning of band showed it to be an allele of ras-1 and to affect a wide variety of signaling pathways yielding enhanced light responses and asexual development. These can be largely phenocopied by treatments that increase levels of intracellular reactive oxygen species. Although output is often unidirectional, analysis of the prd-4 gene provided an alternative paradigm in which output feeds back to affect input. prd-4 is an allele of checkpoint kinase-2 that bypasses the requirement for DNA damage to activate this kinase; FRQ is normally a substrate of activated Chk2, so in Chk2PRD-4, FRQ is precociously phosphorylated and the clock cycles more quickly. Finally, recent adaptation of luciferase to fully function in Neurospora now allows the core FRQ/WCC feedback loop to be followed in real time under conditions where it no longer controls the overt rhythm in development. This ability can be used to describe the hierarchical relationships among FRQ-Less Oscillators (FLOs) and to see which are connected to the circadian system. The nitrate reductase oscillator appears to be connected, but the oscillator controlling the long-period rhythm elicited upon choline starvation appears completely disconnected from the circadian system; it can be seen to run with a very long noncompensated 60–120-hour period length under conditions where the circadian FRQ/WCC oscillator continues to cycle with a fully compensated circadian 22-hour period. PMID:18419278

Loros, J.J.; Dunlap, J.C.; Larrondo, L.F.; Shi, M.; Belden, W.J.; Gooch, V.D.; Chen, C.-H.; Baker, C.L.; Mehra, A.; Colot, H.V.; Schwerdtfeger, C.; Lambreghts, R.; Collopy, P.D.; Gamsby, J.J.; Hong, C.I.

2013-01-01

416

Predictive factors for pacemaker requirement after transcatheter aortic valve implantation  

PubMed Central

Background Transcatheter aortic valve implantation (TAVI) has been established as a treatment option for inoperable patients with symptomatic aortic valve stenosis. However, patients suffer frequently from conduction disturbances after TAVI. Methods Baseline, procedural as well as surface and intracardiac ECG parameters were evaluated for patients treated with TAVI and a comparison between patients requiring pacemaker with those not suffering from relevant conduction disorders were done. Results TAVI was successfully in all patients (n=45). Baseline surface and intracardiac ECG recording revealed longer PQ (197.1±51.2 msec versus 154.1±32.1 msec; p<0.001), longer AH (153.6±43.4 msec versus 116.1±31.2 msec; p<0.001) and HV interval (81.7±17.8 msec versus 56.8±8.5 msec; p<0.001) in patients with need for a pacemaker (n=23) versus control group (n=22); furthermore, 7-day follow-up analysis showed a higher prevalence of new left bundle branch block (LBBB) (87.0% versus 31.9%; p<0.001). Multivariate analysis revealed that only new LBBB, QRS duration >120 msec and a PQ interval >200 msec immediately (within 60 minutes) after implantation of the aortic valve were predictors for high-grade (type II second-degree and third-degree) AV block. Other clinical parameters as well as baseline electrocardiographic parameters had no impact on critical conduction delay. Conclusion Cardiac conduction disturbances are common after TAVI. The need for pacing after TAVI is predictable by surface ECG evaluation immediately (within 60 minutes) after the procedure. PMID:23035864

2012-01-01

417

Timing of Neuropeptide Coupling Determines Synchrony and Entrainment in the Mammalian Circadian Clock  

PubMed Central

Robust synchronization is a critical feature of several systems including the mammalian circadian clock. The master circadian clock in mammals consists of about 20000 ‘sloppy’ neuronal oscillators within the hypothalamus that keep robust time by synchronization driven by inter-neuronal coupling. The complete understanding of this synchronization in the mammalian circadian clock and the mechanisms underlying it remain an open question. Experiments and computational studies have shown that coupling individual oscillators can achieve robust synchrony, despite heterogeneity and different network topologies. But, much less is known regarding the mechanisms and circuits involved in achieving this coupling, due to both system complexity and experimental limitations. Here, we computationally study the coupling mediated by the primary coupling neuropeptide, vasoactive intestinal peptide (VIP) and its canonical receptor, VPAC2R, using the transcriptional elements and generic mode of VIP-VPAC2R signaling. We find that synchrony is only possible if VIP (an inducer of Per expression) is released in-phase with activators of Per expression. Moreover, anti-phasic VIP release suppresses coherent rhythms by moving the network into a desynchronous state. Importantly, experimentally observed rhythms in VPAC2R have little effect on network synchronization, but can improve the amplitude of the SCN network rhythms while narrowing the network entrainment range. We further show that these findings are valid across several computational network models. Thus, we identified a general design principle to achieve robust synchronization: An activating coupling agent, such as VIP, must act in-phase with the activity of core-clock promoters. More generally, the phase of coupling is as critical as the strength of coupling from the viewpoint of synchrony and entrainment. PMID:24743470

Ananthasubramaniam, Bharath; Herzog, Erik D.; Herzel, Hanspeter

2014-01-01

418

Does Rapid Auditory Stimulation Accelerate an Internal Pacemaker? Don't Bet on It.  

E-print Network

challenges (see, e.g., Buhusi & Meck, 2005; Grondin, 2010). In order to better understand the hypothesized, the administration of certain drugs to laboratory rats has led to behavior suggesting systematic changes in pacemaker

419

Patients, Pacemakers, and Implantable Defibrillators: Human Values and Security for Wireless Implantable  

E-print Network

Terms Design, Human Factors, Security. INTRODUCTION Implantable medical devices (IMDs), such as pacemak Implantable Medical Devices Tamara Denning , Alan Borning , Batya Friedman , Brian T. Gill , Tadayoshi Kohno of Washington Department of Mathematics, Seattle Pacific University + Medical Device Safety Institute, Beth

Anderson, Richard