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1

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

PubMed Central

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, while VRI and PDP1 negatively and positively regulate Clk transcription, respectively. Here, we show that the ? isoform of the Drosophila FOS homolog KAY is required for normal circadian behavior. KAY-? downregulation in circadian pacemaker neurons increases period length by 1.5 hours. This behavioral phenotype is correlated with decreased expression of several circadian proteins. The strongest effects are on CLK and the neuropeptide PIGMENT DISPERSING FACTOR (PDF), 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 KAY-?’s double role in the two transcriptional loops controlling Drosophila circadian behavior brings precision and stability to their oscillations.

Ling, Jinli; Dubruille, Raphaelle; Emery, Patrick

2012-01-01

2

A mechanism for circadian control of pacemaker neuron excitability  

PubMed Central

Although the intracellular molecular clocks that regulate circadian (~24 hr) behavioral rhythms are well-understood, it remains unclear how molecular clock information is transduced into rhythmic neuronal activity that in turn drives behavioral rhythms. To identify potential clock outputs, we generated expression profiles from a homogeneous population of purified pacemaker neurons (LNvs) from wild type and clock mutant Drosophila. We identified a group of genes with enriched expression in LNvs and a second group of genes rhythmically expressed in LNvs in a clock-dependent manner. Only 10 genes fell into both groups: four core clock genes including period and timeless, and six genes previously unstudied in circadian rhythms. We focused on one of these six genes, Ir, which encodes an Inward rectifier K+ channel likely to regulate resting membrane potential and whose expression peaks around dusk. Reducing Ir expression in LNvs increased larval light avoidance and lengthened the period of adult locomotor rhythms, consistent with increased LNv excitability. In contrast, increased Ir expression made adult flies largely arrhythmic and strongly dampened Period protein oscillations. We propose that rhythmic Ir expression contributes to daily rhythms in LNv neuronal activity, which in turn feed back to regulate molecular clock oscillations.

Ruben, Marc; Drapeau, Mark D.; Mizrak, Dogukan; Blau, Justin

2014-01-01

3

Lmo Mutants Reveal a Novel Role for Circadian Pacemaker Neurons in Cocaine-Induced Behaviors  

PubMed Central

Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LNvs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LNv function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LNvs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LNvs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LNvs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug.

2004-01-01

4

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

PubMed

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

2013-04-17

5

Adult-specific electrical silencing of pacemaker neurons uncouples the molecular oscillator from circadian outputs  

PubMed Central

Summary Background Circadian rhythms regulate physiology and behavior through transcriptional feedback loops of clock genes running within specific pacemaker cells. In Drosophila, molecular oscillations in the small ventral Lateral Neurons (sLNvs) command rhythmic behavior under free-running conditions releasing the neuropeptide PIGMENT DISPERSING FACTOR (PDF) in a circadian fashion. Electrical activity in the sLNvs is also required for behavioral rhythmicity. Yet, how temporal information is transduced into behavior remains unclear. Results Here we developed a new tool for temporal control of gene expression to obtain adult-restricted electrical silencing of the PDF circuit, which led to reversible behavioral arrhythmicity. Remarkably, PER oscillations during the silenced phase remained unaltered, indicating that arrhythmicity is a direct consequence of the silenced activity. Accordingly, circadian axonal remodeling and PDF accumulation were severely affected during the silenced phase. Conclusions Although electrical activity of the sLNvs is not a clock component it coordinates circuit outputs leading to rhythmic behavior.

Depetris-Chauvin, Ana; Berni, Jimena; Aranovich, Ezequiel J.; Muraro, Nara I.; Beckwith, Esteban J.; Ceriani, Maria Fernanda

2011-01-01

6

A Multiscale Model to Investigate Circadian Rhythmicity of Pacemaker Neurons in the Suprachiasmatic Nucleus  

PubMed Central

The suprachiasmatic nucleus (SCN) of the hypothalamus is a multicellular system that drives daily rhythms in mammalian behavior and physiology. Although the gene regulatory network that produces daily oscillations within individual neurons is well characterized, less is known about the electrophysiology of the SCN cells and how firing rate correlates with circadian gene expression. We developed a firing rate code model to incorporate known electrophysiological properties of SCN pacemaker cells, including circadian dependent changes in membrane voltage and ion conductances. Calcium dynamics were included in the model as the putative link between electrical firing and gene expression. Individual ion currents exhibited oscillatory patterns matching experimental data both in current levels and phase relationships. VIP and GABA neurotransmitters, which encode synaptic signals across the SCN, were found to play critical roles in daily oscillations of membrane excitability and gene expression. Blocking various mechanisms of intracellular calcium accumulation by simulated pharmacological agents (nimodipine, IP3- and ryanodine-blockers) reproduced experimentally observed trends in firing rate dynamics and core-clock gene transcription. The intracellular calcium concentration was shown to regulate diverse circadian processes such as firing frequency, gene expression and system periodicity. The model predicted a direct relationship between firing frequency and gene expression amplitudes, demonstrated the importance of intracellular pathways for single cell behavior and provided a novel multiscale framework which captured characteristics of the SCN at both the electrophysiological and gene regulatory levels.

Vasalou, Christina; Henson, Michael A.

2010-01-01

7

The anesthetic agents pentobarbital and chloralose block phase shifts of a neuronal in vitro circadian pacemaker.  

PubMed

The anesthetic pentobarbital (6 mM) is capable of blocking light or high K(+)-induced phase shifts of the circadian pacemaker in the isolated eye of Bulla. Pentobarbital alone was effective in generating phase shifts consistent with phase response curves obtained to either extracellular low Ca2+ or hyperpolarizing pulses. Patch clamp recordings from the circadian pacemaker cells indicate that pentobarbital reduces the Ca(2+)-dependent K+ current. Together, these data suggest that pentobarbital acts on the pacemaker by reducing an inward Ca2+ current. Chloralose (3 mM) was effective in blocking light, but not high K(+)-induced phase shifts, and did not generate phase shifts when applied alone, suggesting that chloralose may act as a weak Ca2+ channel inhibitor. PMID:7617298

Khalsa, S B; Michel, S; Block, G D

1995-02-24

8

The Period Clock Gene is Expressed in Central Nervous System Neurons which Also Produce a Neuropeptide that Reveals the Projections of Circadian Pacemaker Cells Within the Brain of Drosophila melanogaster  

Microsoft Academic Search

The period protein (PER) is an essential component of the circadian clock in Drosophila melanogaster. Although PER-containing pacemaker cells have been previously identified in the brain, the neuronal network that comprises the circadian clock remained unknown. Here it is shown that some PER neurons are also immunostained with an antiserum against the crustacean pigment-dispersing hormone (PDH). This antiserum reveals the

Charlotte Helfrich-Forster

1995-01-01

9

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

10

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.

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

2008-01-01

11

Pacemaking kisspeptin neurons.  

PubMed

Kisspeptin (Kiss1) neurons are vital for reproduction. Gonatotrophin-releasing hormone (GnRH) neurons express the kisspeptin receptor (GPR54), and kisspeptins potently stimulate the release of GnRH by depolarizing and inducing sustained action potential firing in GnRH neurons. As such, Kiss1 neurons may be the presynaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons; one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participates in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea-pig and mouse, Kiss1 neurons in general are capable of generating burst-firing behaviour. Essentially, all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. In voltage-clamp conditions, these channels produce distinct currents that can generate burst-firing behaviour in current-clamp conditions. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion, hence reproduction. PMID:23884368

Kelly, Martin J; Zhang, Chunguang; Qiu, Jian; Rønnekleiv, Oline K

2013-11-01

12

Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons  

Microsoft Academic Search

The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC2 (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found

Sara J Aton; Christopher S Colwell; Anthony J Harmar; James Waschek; Erik D Herzog

2005-01-01

13

Circadian Pacemaking in Cells and Circuits of the Suprachiasmatic Nucleus  

PubMed Central

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 ([Ca2+]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/[Ca2+]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.

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

2014-01-01

14

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

15

Olfactory bulb neurons express functional, entrainable circadian rhythms  

PubMed Central

Circadian pacemakers drive many daily molecular, physiological, and behavioral rhythms. We investigated whether the main olfactory bulb is a functional circadian pacemaker in rats. Long-term, multielectrode recordings revealed that individual, cultured bulb neurons expressed near 24-h oscillations in firing rate. Real-time recordings of Period1 gene activity showed that a population of cells within the bulb express synchronized rhythmicity starting on embryonic day 19. This rhythmicity was intrinsic to the mitral, and not the granule, cell layer, entrainable to physiological temperature cycles, and temperature compensated in its period. However, removal of the olfactory bulbs had no effect on running wheel behavior. These results indicate that individual mitral/tufted cells are competent circadian pacemakers which normally synchronize to each other. The daily rhythms in gene expression and firing rate intrinsic to the olfactory bulb are not required for circadian patterns of locomotion, indicating that they are involved in rhythms outside the canonical circadian system.

Granados-Fuentes, Daniel; Saxena, Meera T.; Prolo, Laura M.; Aton, Sara J.; Herzog, Erik D.

2012-01-01

16

A functional analysis of circadian pacemakers in nocturnal rodents  

Microsoft Academic Search

Summary 1.The circadian pacemakers controlling activity rhythms in four species of rodents are compared, as freerunning systems in constant darkness. In analyzing their stability the distinction is made between (1) spontaneous day-to-day instability of frequency, and (2) a longer-term lability, some of which is traceable to identified causes.2.Serial correlation analysis indicates that the precision (day-to-day stability) of the pacemaker's period

Colin S. Pittendrigh; Serge Daan

1976-01-01

17

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

18

Synchronization of Coupled Neurons Controlled by a Pacemaker  

NASA Astrophysics Data System (ADS)

We investigate synchronization of Hindmarsh—Rose neurons with gap junctions under the control of a pacemaker. In a ring Hindmarsh—Rose neuronal network, the coupled neurons with the pacemaker can occur in synchronization more easily than those without the pacemaker. Furthermore, the pacemaker can induce phase synchronization or nearly-complete synchronization of nonidentical neurons. This synchronization can occur more easily when time delay is considered. Theses results can be helpful to understand the activities of the real neuronal system.

Li, Mei-Sheng; Zhang, Hong-Hui; Zhao, Yong; Shi, Xia

2011-01-01

19

Circadian locomotor rhythms in the cricket, Gryllodes sigillatus. II. Interactions between bilaterally paired circadian pacemakers.  

PubMed

The optic lobe is essential for circadian locomotor rhythms in the cricket, Gryllodes sigillatus. We examined potential interactions between the bilaterally paired optic lobes in circadian rhythm generation. When one optic lobe was removed, the free-running period of the locomotor rhythm slightly but significantly lengthened. When exposed to light-dark cycles (LD) with 26 hr period, intact and sham operated animals were clearly entrained to the light cycle, but a large number of animals receiving unilateral optic nerve severance showed rhythm dissociation. In the dissociation, two rhythmic components appeared; one was readily entrained to the given LD and the other free-ran with a period shorter than 24 hr, and activity was expressed only when they were inphase. The period of the free-running component was significantly longer than that of the animals with a single blinded pacemaker kept in LD13:13, suggesting that the pacemaker on the intact side had some influence on the blinded pacemaker even in the dissociated state. The ratio of animals with rhythm dissociation was greater with the lower light intensity of the LD. The results suggest that the bilaterally distributed pacemakers are only weakly coupled to one another but strongly suppress the activity driven by the partner pacemaker during their subjective day. The strong suppression of activity would be advantageous to keep a stable nocturnality for this cricket living indoors. PMID:9450386

Ushirogawa, H; Abe, Y; Tomioka, K

1997-10-01

20

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.

Li, Jie; Baccei, Mark L.

2011-01-01

21

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

22

Retrograde Bone Morphogenetic Protein Signaling Shapes a Key Circadian Pacemaker Circuit  

PubMed Central

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 pdf01. Thus, we have uncovered a novel mechanism that provides an early “tagging” of synaptic targets that will guide circuit refinement later in development.

Gorostiza, E. Axel; Ceriani, M. Fernanda

2013-01-01

23

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.

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

2013-01-01

24

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.

Rojas-Castaneda, Julio Cesar; Vigueras-Villasenor, Rosa Maria; Rojas, Patricia; Chavez-Saldana, Margarita; Perez, Oscar Gutierrez; Montes, Sergio; Rios, Camilo

2011-01-01

25

Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period  

NASA Technical Reports Server (NTRS)

The sensitivity of the human circadian system to light has been the subject of considerable debate. Using computer simulations of a recent quantitative model for the effects of light on the human circadian system, we investigated these effects of light during different experimental protocols. The results of the simulations indicate that the nonuniform distribution over the circadian cycle of exposure to ordinary room light seen in classical free-run studies, in which subjects select their exposure to light and darkness, can result in an observed period of approximately 25 h, even when the intrinsic period of the subject's endogenous circadian pacemaker is much closer to 24 h. Other simulation results suggest that accurate assessment of the true intrinsic period of the human circadian pacemaker requires low ambient light intensities (approximately 10-15 lx) during scheduled wake episodes, desynchrony of the imposed light-dark cycle from the endogenous circadian oscillator, and a study length of at least 20 days. Although these simulations await further experimental substantiation, they highlight the sensitivity to light of the human circadian system and the potential confounding influence of light on the assessment of the intrinsic period of the circadian pacemaker.

Klerman, E. B.; Dijk, D. J.; Kronauer, R. E.; Czeisler, C. A.

1996-01-01

26

Dim nocturnal illumination alters coupling of circadian pacemakers in Siberian hamsters, Phodopus sungorus  

Microsoft Academic Search

The circadian pacemaker of mammals comprises multiple oscillators that may adopt different phase relationships to determine properties of the coupled system. The effect of nocturnal illumination comparable to dim moonlight was assessed in male Siberian hamsters exposed to two re-entrainment paradigms believed to require changes in the phase relationship of underlying component oscillators. In experiment 1, hamsters were exposed to

M. R. Gorman; J. A. Elliott

2004-01-01

27

The transcription factor Mef2 links the Drosophila core clock to Fas2, neuronal morphology, and circadian behavior.  

PubMed

The transcription factor Mef2 regulates activity-dependent neuronal plasticity and morphology in mammals, and clock neurons are reported to experience activity-dependent circadian remodeling in Drosophila. We show here that Mef2 is required for this daily fasciculation-defasciculation cycle. Moreover, the master circadian transcription complex CLK/CYC directly regulates Mef2 transcription. ChIP-Chip analysis identified numerous Mef2 target genes implicated in neuronal plasticity, including the cell-adhesion gene Fas2. Genetic epistasis experiments support this transcriptional regulatory hierarchy, CLK/CYC- > Mef2- > Fas2, indicate that it influences the circadian fasciculation cycle within pacemaker neurons, and suggest that this cycle also contributes to circadian behavior. Mef2 therefore transmits clock information to machinery involved in neuronal remodeling, which contributes to locomotor activity rhythms. PMID:23889933

Sivachenko, Anna; Li, Yue; Abruzzi, Katharine C; Rosbash, Michael

2013-07-24

28

Dynamic resetting of the human circadian pacemaker by intermittent bright light  

NASA Technical Reports Server (NTRS)

In humans, experimental studies of circadian resetting typically have been limited to lengthy episodes of exposure to continuous bright light. To evaluate the time course of the human endogenous circadian pacemaker's resetting response to brief episodes of intermittent bright light, we studied 16 subjects assigned to one of two intermittent lighting conditions in which the subjects were presented with intermittent episodes of bright-light exposure at 25- or 90-min intervals. The effective duration of bright-light exposure was 31% or 63% compared with a continuous 5-h bright-light stimulus. Exposure to intermittent bright light elicited almost as great a resetting response compared with 5 h of continuous bright light. We conclude that exposure to intermittent bright light produces robust phase shifts of the endogenous circadian pacemaker. Furthermore, these results demonstrate that humans, like other species, exhibit an enhanced sensitivity to the initial minutes of bright-light exposure.

Rimmer, D. W.; Boivin, D. B.; Shanahan, T. L.; Kronauer, R. E.; Duffy, J. F.; Czeisler, C. A.

2000-01-01

29

Role of Brain-Derived Neurotrophic Factor in the Circadian Regulation of the Suprachiasmatic Pacemaker by Light  

Microsoft Academic Search

The central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates the generation of mam- malian circadian rhythms, including an oscillation in pacemaker sensitivity to photic signals conveyed by the retinohypotha- lamic tract. Because brain-derived neurotrophic factor (BDNF) has been implicated in the functional regulation of neural input to other targets of visual pathways, the present study examined

Fong-Qi Liang; Gregg Allen; David Earnest

2000-01-01

30

Stability, precision, and near-24-hour period of the human circadian pacemaker  

NASA Technical Reports Server (NTRS)

Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.

Czeisler, C. A.; Duffy, J. F.; Shanahan, T. L.; Brown, E. N.; Mitchell, J. F.; Rimmer, D. W.; Ronda, J. M.; Silva, E. J.; Allan, J. S.; Emens, J. S.; Dijk, D. J.; Kronauer, R. E.

1999-01-01

31

Cellular Analysis of Circadian Rhythmicity in Cultured SCN Neurons.  

National Technical Information Service (NTIS)

Circadian rhythms are generated by brain cells located in the suprachiasmatic nuclei (SCN) of the mammalian hypothalamus, but it is not clear how individual cells contribute to the operation of the circadian clock. SCN neurons dissociated from newborn rat...

S. M. Reppert D. K. Welsh

1994-01-01

32

Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock  

Microsoft Academic Search

The central biological clock of the mammalian brain is located in the suprachiasmatic nucleus. This hypothalamic region contains neurons that generate a circadian rhythm on a single-cell basis. Clock cells transmit their circadian timing signals to other brain areas by diurnal modulation of their spontaneous firing rate. The intracellular mechanism underlying rhythm generation is thought to consist of one or

Nico P. A. Bos

2002-01-01

33

Persistently Active, Pacemaker-Like Neurons in Neocortex  

PubMed Central

The neocortex is spontaneously active, however, the origin of this self-generated, patterned activity remains unknown. To detect potential “pacemaker cells,” we use calcium imaging to directly identify neurons that discharge action potentials in the absence of synaptic transmissionin slices from juvenile mouse visual cortex. We characterize 60 of these neurons electrophysiologically and morphologically, finding that they belong to two classes of cells: one class composed of pyramidal neurons with a thin apical dendritic tree and a second class composed of ascending axon interneurons (Martinotti cells) located in layer 5. In both types of neurons, persistent sodium currents are necessary for the generation of the spontaneous activity. Our data demonstrate that subtypes of neocortical neurons have intrinsic mechanisms to generate persistent activity. Like in central pattern generators (CPGs), these neurons may act as “pacemakers” to initiate or pattern spontaneous activity in the neocortex.

Le Bon-Jego, Morgane; Yuste, Rafael

2007-01-01

34

AKT and TOR Signaling Set the Pace of the Circadian Pacemaker  

PubMed Central

Summary The circadian clock coordinates cellular and organismal energy metabolism [1]. The importance of this circadian timing system is underscored by findings that defects in the clock cause deregulation of metabolic physiology and result in metabolic disorders [2]. On the other hand, metabolism also influences the circadian clock, such that circadian gene expression in peripheral tissues is affected in mammalian models of obesity and diabetes [3, 4]. However, to date there is little to no information on the effect of metabolic genes on the central brain pacemaker which drives behavioral rhythms. We have found that the AKT and TOR-S6K pathways, which are major regulators of nutrient metabolism, cell growth, and senescence, impact the brain circadian clock that drives behavioral rhythms in Drosophila. Elevated AKT or TOR activity lengthens circadian period, whereas reduced AKT signaling shortens it. Effects of TOR-S6K appear to be mediated by SGG/GSK3?, a known kinase involved in clock regulation. Like SGG, TOR signaling affects the timing of nuclear accumulation of the circadian clock protein TIMELESS. Given that activities of AKT and TOR pathways are affected by nutrient/energy levels and endocrine signaling, these data suggest that metabolic disorders caused by nutrient and energy imbalance are associated with altered rest:activity behavior.

Zheng, Xiangzhong; Sehgal, Amita

2011-01-01

35

Association of sleep-wake habits in older people with changes in output of circadian pacemaker  

NASA Technical Reports Server (NTRS)

Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemaker's output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.

Czeisler, C. A.; Dumont, M.; Duffy, J. F.; Steinberg, J. D.; Richardson, G. S.; Brown, E. N.; Sanchez, R.; Rios, C. D.; Ronda, J. M.

1992-01-01

36

Entrainment of the fetal hamster circadian pacemaker by prenatal injections of the dopamine agonist SKF 38393.  

PubMed

Prenatal treatment with the D1-dopamine receptor agonist SKF 38393 or cocaine induces expression of the immediate-early gene c-fos in the fetal rat suprachiasmatic nucleus (SCN) (Weaver et al., 1992). Because the induction of c-fos gene expression in the SCN has been implicated in the entrainment of circadian rhythms by light in mature animals, the present study investigated whether prenatal dopaminergic activation entrains the fetal circadian pacemaker. Injections of SKF 38393 (8 mg/kg) were given to pregnant, SCN-lesioned hamsters during the last 5 d of gestation and the phases of the offspring's wheel-running activity rhythms were measured on postnatal day 20. Pregnant hamsters were each given two injections/day 12 hr apart, but only one of the injections each day contained SKF 38393. One group of hamsters received the drug at 0800 hr while another group received the drug at 2000 hr. The offspring from these treatment groups showed average phases that differed by 11.3 hr, demonstrating that prenatal SKF 38393 set the phase of the offspring's circadian rhythms. These results suggest that the fetal circadian pacemaker can be entrained by dopaminergic activation. In situ hybridization using cRNA probes demonstrated that a single injection of SKF 38393 on the last day of gestation induced c-fos gene expression in the fetal hamster SCN and that mRNA for the D1-dopamine receptor was present in the SCN at that time. It is possible that maternal entrainment of the fetal circadian pacemaker, which normally occurs during development, is mediated by dopaminergic activation within the fetal hypothalamus. PMID:7916044

Viswanathan, N; Weaver, D R; Reppert, S M; Davis, F C

1994-09-01

37

A Functional analysis of circadian pacemakers in nocturnal rodents  

Microsoft Academic Search

Summary 1Phase response curves for 15' bright light pulses of four species of nocturnal rodents are described. All show delay phase shifts early in the subjective night, advance shifts in the late subjective night, and relative insensitivity during the subjective day.2The broad scatter in measured phase-shifts is largely due to error of measurement: the response of the pacemakers to light

Serge Daan; Colin S. Pittendrigh

1976-01-01

38

A functional analysis of circadian pacemakers in nocturnal rodents  

Microsoft Academic Search

Summary 1.In a preceding paper (Pittendrigh and Daan, 1976a) differences in the lability of the freerunning circadian period (t) in constant darkness (DD) were described among four species of rodents. This lability (i) is strongly correlated with the responses of t to (ii) D2O-administration and to (iii) constant light (LL) of various intensities. The question is raised whether these are

Serge Daan; Colin S. Pittendrigh

1976-01-01

39

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

40

Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior  

PubMed Central

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 per01 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 per01 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.

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

2014-01-01

41

Photoperiodic plasticity in circadian clock neurons in insects  

PubMed Central

Since Bünning's observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Photoperiod sets peaks of period (per) or timeless (tim) mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.

Shiga, Sakiko

2013-01-01

42

Central control of circadian phase in arousal-promoting neurons.  

PubMed

Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature. PMID:23826226

Mahoney, Carrie E; Brewer, Judy McKinley; Bittman, Eric L

2013-01-01

43

Central Control of Circadian Phase in Arousal-Promoting Neurons  

PubMed Central

Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature.

Mahoney, Carrie E.; McKinley Brewer, Judy; Bittman, Eric L.

2013-01-01

44

Circadian pacemakers in lizards: phase-response curves and effects of pinealectomy.  

PubMed

Phase-response curves (PRCs) for 6-h fluorescent light pulses are described for both intact (sham-pinealectomized) and pinealectomized iguanid lizards (Sceloporus occidentalis). Although strongly diurnal in habit the PRC for intact lizards is more typical of those seen in nocturnal rodents. Other "nocturnal" characteristics of this lizard include the fact that the average free-running period (tau) is less than 24 h and the average tau in continuous light is longer than that observed in continuous darkness. The PRC for pinealectomized lizards is greatly distorted relative to that obtained from intact lizards. This "distortion" is discussed in terms of the role of the pineal as a coupling device or as a pacemaker within a multioscillator circadian system. In some individuals pinealectomy was also associated with 1) increased instability in free-running activity rhythms or arrhythmicity and 2) nocturnal entrainment to LD 12:12. PMID:6859292

Underwood, H

1983-06-01

45

Refinement of a limit cycle oscillator model of the effects of light on the human circadian pacemaker  

NASA Technical Reports Server (NTRS)

In 1990, Kronauer proposed a mathematical model of the effects of light on the human circadian pacemaker. Although this model predicted many general features of the response of the human circadian pacemaker to light exposure, additional data now available enable us to refine the original model. We first refined the original model by incorporating the results of a dose response curve to light into the model's predicted relationship between light intensity and the strength of the drive onto the pacemaker. Data from three bright light phase resetting experiments were then used to refine the amplitude recovery characteristics of the model. Finally, the model was tested and further refined using data from an extensive phase resetting experiment in which a 3-cycle bright light stimulus was presented against a background of dim light. In order to describe the results of the four resetting experiments, the following major refinements to the original model were necessary: (i) the relationship between light intensity (I) and drive onto the pacemaker was reduced from I1/3 to I0.23 for light levels between 150 and 10,000 lux; (ii) the van der Pol oscillator from the original model was replaced with a higher-order limit cycle oscillator so that amplitude recovery is slower near the singularity and faster near the limit cycle; (iii) a direct effect of light on circadian period (tau x) was incorporated into the model such that as I increases, tau x decreases, which is in accordance with "Aschoff's rule". This refined model generates the following testable predictions: it should be difficult to enhance normal circadian amplitude via bright light; near the critical point of a type 0 phase response curve (PRC) the slope should be steeper than it is in a type 1 PRC; and circadian period measured during forced desynchrony should be directly affected by ambient light intensity.

Jewett, M. E.; Kronauer, R. E.; Brown, E. N. (Principal Investigator)

1998-01-01

46

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.

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

47

Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients  

NASA Technical Reports Server (NTRS)

Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (approximately 10,000 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a "dead zone" of photic insensitivity and was compared with another three-cycle PRC that had used a background of approximately 150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1-2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.

Jewett, M. E.; Rimmer, D. W.; Duffy, J. F.; Klerman, E. B.; Kronauer, R. E.; Czeisler, C. A.

1997-01-01

48

Neuropeptide Secreted from a Pacemaker Activates Neurons to Control a Rhythmic Behavior  

PubMed Central

Summary Background Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 seconds, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Results Here we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G protein-coupled receptor on the GABAergic neurons, as the receptor of NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Conclusions Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors.

Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P.; Dasgupta, Krishnakali; Knowles, James A.; Schoofs, Liliane; Sieburth, Derek

2013-01-01

49

Membrane resonance in bursting pacemaker neurons of an oscillatory network is correlated with network frequency  

PubMed Central

Network oscillations typically span a limited range of frequency. In pacemaker-driven networks, including many Central Pattern Generators (CPGs), this frequency range is determined by the properties of bursting pacemaker neurons and their synaptic connections; thus, factors that affect the burst frequency of pacemaker neurons should play a role in determining the network frequency. We examine the role of membrane resonance of pacemaker neurons on the network frequency in the crab pyloric CPG. The pyloric oscillations (freq ~1 Hz) are generated by a group of pacemaker neurons: the Anterior Burster (AB) and the Pyloric Dilator (PD). We examine the impedance profiles of the AB and PD neurons in response to sinusoidal current injections with varying frequency and find that both neuron types exhibit membrane resonance, i.e. demonstrate maximal impedance at a given preferred frequency. The membrane resonance frequencies of the AB and PD neurons fall within the range of the pyloric network oscillation frequency. Experiments with pharmacological blockers and computational modeling show that both calcium currents ICa and the hyperpolarization-activated inward current Ih, are important in producing the membrane resonance in these neurons. We then demonstrate that both the membrane resonance frequency of the PD neuron and its supra-threshold bursting frequency can be shifted in the same direction by either DC current injection or by using the dynamic clamp technique to inject artificial conductances for Ih or ICa. Together, these results suggest that membrane resonance of pacemaker neurons can be strongly correlated with the CPG oscillation frequency.

Tohidi, Vahid; Nadim, Farzan

2009-01-01

50

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

51

Pacemakers  

MedlinePLUS

... com ct150109 Last reviewed: 01/17/2013 7 Airport security devices do not harm pacemakers. The metal shell ... should not set off the security alarm at airport security checkpoints. However, if this should happen, show your ...

52

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.

Lu, Tom Z.; Feng, Zhong-Ping

2011-01-01

53

Norepinephrine differentially modulates different types of respiratory pacemaker and nonpacemaker neurons.  

PubMed

Pacemakers are found throughout the mammalian CNS. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and nonpacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88% of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE also differentially modulated nonpacemakers. Two types of nonpacemakers were identified: "silent nonpacemakers" stop spiking, whereas "active nonpacemakers" spontaneously spike when isolated from the network. NE selectively induced cadmium-sensitive pacemaker properties in active, but not silent, nonpacemakers. Flufenamic acid (FFA), a blocker of ICAN, blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity; the frequency modulation (FM) was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the FM of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of nonpacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm. PMID:16394066

Viemari, Jean-Charles; Ramirez, Jan-Marino

2006-04-01

54

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

55

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.

CASTEL, MONA; MORRIS, JOHN F.

2000-01-01

56

Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons.  

PubMed

The terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons show spontaneous pacemaker activity whose firing frequency is suggested to regulate the release of GnRH peptides and control motivation for reproductive behaviors. Previous studies of the electrophysiological properties of TN-GnRH neurons reported excitatory modulation of pacemaker activity by auto/paracrine and synaptic modulations, but inhibition of pacemaker activity has not been reported to date. Our recent study suggests that neuropeptide FF, a type of Arg-Phe-amide (RFamide) peptide expressed in TN-GnRH neurons themselves, inhibits the pacemaker activity of TN-GnRH neurons in an auto- and paracrine manner. In the present study, we examined whether RFamide-related peptides (RFRPs), which are produced in the hypothalamus, modulate the pacemaker activity of TN-GnRH neurons as candidate inhibitory synaptic modulators. Bath application of RFRP2, among the three teleost RFRPs, decreased the frequency of firing of TN-GnRH neurons. This inhibition was diminished by RF9, a potent antagonist of GPR147/74, which are candidate RFRP receptors. RFRP2 changed the conductances for Na(+) and K(+). The reversal potential for RFRP2-induced current was altered by inhibitors of the transient receptor potential canonical (TRPC) channel (La(3+) and 2-aminoethoxydiphenyl borate) and by a less selective blocker of voltage-independent K(+) channels (Ba(2+)). By comparing the current-voltage relationship in artificial cerebrospinal fluid with that under each drug, the RFRP2-induced current was suggested to consist of TRPC channel-like current and voltage-independent K(+) current. Therefore, synaptic release of RFRP2 from hypothalamic neurons is suggested to inhibit the pacemaker activity of TN-GnRH neurons by closing TRPC channels and opening voltage-independent K(+) channels. This novel pathway may negatively regulate reproductive behaviors. PMID:23390313

Umatani, Chie; Abe, Hideki; Oka, Yoshitaka

2013-05-01

57

Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons  

Microsoft Academic Search

The mammalian SCN contains a biological clock that drives remarkably precise circadian rhythms in vivo and in vitro. This study asks whether the cycle-to-cycle variability of behavioral rhythms in mice can be attributed to precision of individual circadian pacemakers within the SCN or their interactions. The authors measured the standard deviation of the cycle-to-cycle period from 7-day recordings of running

Erik D. Herzog; Sara J. Aton; Rika Numano; Yoshiyuki Sakaki; Hajime Tei

2004-01-01

58

Temperature Effects on Pacemaker Generation, Membrane Potential, and Critical Firing Threshold in Aplysia Neurons  

PubMed Central

Temperature increases cause a regular and reproducible increase in the frequency of generation of pacemaker potentials in most Aplysia neurons specialized for this type of activity which can only be explained as a direct stimulating effect of temperature upon the ionic mechanisms responsible for pacemaker potentials. At the same time all cells in the visceral ganglion undergo a membrane potential hyperpolarization of approximately 1–2 mv/°C warmed. In spite of the marked variation in resting membrane potential the critical firing threshold remains at a constant membrane potential level at all temperatures in the absence of accommodative changes. The temperature-frequency curves of all types of cells are interpreted as a result of the interaction between the effects of temperature on the pacemaker-generating mechanism and resting membrane potential. Previous observations on the effects of temperature on excitability of mammalian neurons suggest that other types of neurons may undergo similar marked shifts in resting membrane potential with temperature variation.

Carpenter, David O.

1967-01-01

59

Circadian rhythms in mouse suprachiasmatic nucleus explants on multimicroelectrode plates  

Microsoft Academic Search

The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus functions as a circadian pacemaker. This study used multimicroelectrode plates to measure extracellular action potential activity simultaneously from multiple sites within the cultured mouse SCN. Neurons within the isolated mouse SCN expressed a circadian rhythm in spontaneous firing rate for weeks in culture.

Erik D Herzog; Michael E Geusz; Sat Bir S Khalsa; Martin Straume; Gene D Block

1997-01-01

60

Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms  

Microsoft Academic Search

Within the mammalian hypothalamus, the suprachiasmatic nucleus (SCN) contains a circadian clock for timing of diverse neuronal, endocrine, and behavioral rhythms. By culturing cells from neonatal rat SCN on fixed microelectrode arrays, we have been able to record spontaneous action potentials from individual SCN neurons for days or weeks, revealing prominent circadian rhythms in firing rate. Despite abundant functional synapses,

David K. Welsh; Diomedes E. Logothetis; Markus Meister; Steven M. Reppert

1995-01-01

61

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

62

The Human Circadian Pacemaker Can See by the Dawn's Early Light  

Microsoft Academic Search

The authors' previous experiments have shown that dawn simulation at low light intensities can phase advance the circadian rhythm of melatonin in humans. The aim of this study was to compare the effect of repeated dawn signals on the phase position of circadian rhythms in healthy participants kept under controlled light conditions. Nine men participated in two 9-day laboratory sessions

Konstantin V. Danilenko; Anna Wirz-Justice; Kurt Kräuchi; Jakob M. Weber; Michael Terman

2000-01-01

63

The Role of the Electrogenic Sodium Pump in Modulation of Pacemaker Discharge of 'Aplysia' Neurons.  

National Technical Information Service (NTIS)

The discharge of Aplysia pacemaker neurons varies with temperature over the range of 10 to 22C. Three types of temperature-frequency plots are found, with maximal discharge at lowest, intermediate or highest temperatures. In the presence of ouabain, howev...

J. A. Willis G. L. Gaubatz D. O. Carpenter

1974-01-01

64

Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus.  

PubMed

The hypothalamic arcuate nucleus (ARC) integrates and responds to satiety and hunger signals and forms the origins of the central neural response to perturbations in energy balance. Here we show that rat ARC neurons containing neuropeptide Y (NPY) and agouti-related protein (AgRP), which are conditional pacemakers, are activated by orexigens and inhibited by the anorexigen leptin. We propose a neuron-specific signaling mechanism through which central and peripheral signals engage the central neural anabolic drive. PMID:15097991

van den Top, Marco; Lee, Kevin; Whyment, Andrew D; Blanks, Andrew M; Spanswick, David

2004-05-01

65

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

PubMed Central

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. DOI: http://dx.doi.org/10.7554/eLife.02780.001

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

2014-01-01

66

Enteric sensory neurons communicate with interstitial cells of Cajal to affect pacemaker activity in the small intestine.  

PubMed

Enteric sensory neurons (the AH neurons) play a role in control of gastrointestinal motor activity; AH neuron activation has been proposed to change propulsion into segmentation. We sought to find a mechanism underlying this phenomenon. We formulated the hypothesis that AH neurons increase local ICC-MP (interstitial cells of Cajal associated with the myenteric plexus) pacemaker frequency to disrupt peristalsis and promote absorption. To that end, we sought structural and physiological evidence for communication between ICC-MP and AH neurons. We designed experiments that allowed us to simultaneously activate AH neurons and observe changes in ICC calcium transients that underlie its pacemaker activity. Neurobiotin injection in AH neurons together with ICC immunohistochemistry proved the presence of multiple contacts between AH neuron varicosities and the cell bodies and processes of ICC-MP. Generating action potential activity in AH neurons led to increase in the frequency and amplitude of calcium transients underlying pacemaker activity in ICC. When no rhythmicity was seen, rhythmic calcium transients were evoked in ICC. As a control, we stimulated nitrergic S neurons, which led to reduction in ICC calcium transients. Hence, we report here the first demonstration of communication between AH neurons and ICC. The following hypothesis can now be formulated: AH neuron activation can disrupt peristalsis directed by ICC-MP slow wave activity, through initiation of a local pacemaker by increasing ICC pacemaker frequency through increasing the frequency of ICC calcium transients. Evoking new pacemakers distal to the proximal lead pacemaker will initiate both retrograde and antegrade propulsion causing back and forth movements that may disrupt peristalsis. PMID:24101295

Zhu, Yong Fang; Wang, Xuan-Yu; Lowie, Bobbi-Jo; Parsons, Sean; White, Liz; Kunze, Wolfgang; Pawelka, Andrew; Huizinga, Jan D

2014-07-01

67

The orphan receptor Rev-erb? gene is a target of the circadian clock pacemaker  

PubMed Central

Rev-erb? is a ubiquitously expressed orphan nuclear receptor which functions as a constitutive transcriptional repressor and is expressed in vertebrates according to a robust circadian rhythm. We report here that two Rev-erb? mRNA isoforms, namely Rev-erb?1 and Rev-erb?2, are generated through alternative promoter usage and that both show a circadian expression pattern in an in vitro system using serum-shocked fibroblasts. Both promoter regions P1 (Rev-erb?1) and P2 (Rev-erb?2) contain several E-box DNA sequences, which function as response elements for the core circadian-clock components: CLOCK and BMAL1. The CLOCK–BMAL1 heterodimer stimulates the activity of both P1 and P2 promoters in transient transfection assay by 3–6-fold. This activation was inhibited by the overexpression of CRY1, a component of the negative limb of the circadian transcriptional loop. Critical E-box elements were mapped within both promoters. This regulation is conserved in vertebrates since we found that the CLOCK–BMAL1 heterodimer also regulates the zebrafish Rev-erb? gene. In line with these data Rev-erb? circadian expression was strongly impaired in the livers of Clock mutant mice and in the pineal glands of zebrafish embryos treated with Clock and Bmal1 antisense oligonucleotides. Together these data demonstrate that CLOCK is a critical regulator of Rev-erb? circadian gene expression in evolutionarily distant vertebrates and suggest a role for Rev-erb? in the circadian clock output.

Triqueneaux, Gerard; Thenot, Sandrine; Kakizawa, Tomoko; Antoch, Marina P; Safi, Rachid; Takahashi, Joseph S; Delaunay, Franck; Laudet, Vincent

2013-01-01

68

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

69

Differences between Pacemaker and Nonpacemaker Neurons of Aplysia on Voltage Clamping  

PubMed Central

The responses of pacemaker and nonpacemaker Aplysia neurons to voltage clamp commands of less than 200 msec duration are essentially identical. For moderate depolarizing commands there is an early inward transient current followed by a late outward current and an outward tail current when the membrane is clamped back to resting potential. On long (1–2 sec) commands in pacemakers there is a marked sag in the late current and an inward tail current. Etail, the potential of the membrane at which there is no net current flow under the conditions prevailing at the end of the clamp, shifts from about -9.0 mv on short commands to +5.0 mv on long commands. In contrast there is no marked sag of the late current or inward tail current on long commands in nonpacemakers, and Etail is near -9.0 mv for both short and long commands. The current sag and shift in Etail can be ascribed to a decreased conductance (presumably to K+) at the end of the long as compared to the short command in half of the pacemaker neurons. In the remaining cells the essential difference from nonpacemakers appears to be either a greater restricted extracellular space or a more active potential-dependent electrogenic Na+ pump in pacemakers.

Alving, Barbara O.

1969-01-01

70

Cell Culture Models for Oscillator and Pacemaker Function: Recipes for Dishes with Circadian Clocks?  

Microsoft Academic Search

Primary cell cultures of avian pinealocytes and the mammalian suprachiasmatic nucleus (SCN), immortalized cell lines derived from the SCN (SCN2.2), and fibroblasts derived from mice and rats have been employed as in vitro models to study the cellular and molecular mechanisms underlying circadian biological clocks. This article compares and contrasts these model systems and describes methods for avian pinealocyte cultures,

David J. Earnest; Vincent M. Cassone

2005-01-01

71

Increased late night response to light controls the circadian pacemaker in a nocturnal primate.  

PubMed

The mammalian endogenous circadian clock, the suprachiasmatic nuclei, receives environmental inputs, namely the light-dark cycle, through photopigments located in the eye and from melanopsin-expressing retinal ganglion cells. The authors investigated the influence of light wavelength and intensity on the synchronization of the rest-activity rhythm of the gray mouse lemur, a nocturnal Malagasy primate. Animals were tested at different irradiance levels (320, 45, 13, and 6 nmol x m(-2) x s(- 1)) under several light wavelengths (from 400 to 610 nm). Several parameters including circadian period, activity, and body temperature waveforms were used to assess synchronization to a 12:12 light-dark cycle in comparison to control treatments (12:12 white light or continuous darkness). Entrainment of the circadian rest-activity cycle increased with light intensity. It was more efficient for mid wavelengths relative to shorter or longer wavelengths but not coincident with melanopsin maximal sensitivity, suggesting other photoreceptors are likely involved in lemurs' photoentrainment. The authors obtained a novel synchronization pattern characterized by a clear synchronization to lights-on only without phasing to lights-off. Changes in photo-responsiveness at dusk and dawn highlight differential responses of evening and morning oscillators in the circadian clock. PMID:20484690

Perret, Martine; Gomez, Doris; Barbosa, Alexandra; Aujard, Fabienne; Théry, Marc

2010-06-01

72

THE SPIKE TRAINS OF INHIBITED PACEMAKER NEURONS SEEN THROUGH THE MAGNIFYING GLASS OF NONLINEAR ANALYSES  

Microsoft Academic Search

This communication describes the new information that may be obtained by applying nonlinear analytical techniques to neurobiological time-series. Specifically, we consider the sequence of interspike intervals Ti (the ''timing'') of trains recorded from synaptically inhibited crayfish pacemaker neurons. As reported earlier, diVerent postsynaptic spike train forms (sets of timings with shared properties) are generated by varying the average rate and\\/or

J. P. SEGUNDO; Q G. SUGIHARA; P. DIXON; M. STIBER; L. F. BERSIER

73

A circadian pacemaker in free-living chipmunks: essential for survival?  

PubMed

The importance of circadian timing was evaluated for 18 months from late-April 1997 through October 1998 in a high-density population of free-living eastern chipmunks, Tamias striatus, at a 4-ha forest site in the Allegheny Mountains. Included in the radiocollared field group were 30 chipmunks with supra-chiasmatic nucleus-targeted lesions, 24 surgical controls, and 20 intact controls. An additional 17 chipmunks were used in a laboratory study as lesion-calibration controls to correlate degree of circadian arrhythmicity with extent of supra-chiasmatic nucleus deletion. Survival was documented in the field by daily radio tracking and by regular trapping censuses except during winter hibernation. A significantly higher proportion of supra-chiasmatic nucleus-lesioned than surgical control chipmunks or intact controls were killed by weasel predation during the first 80 days after repatriation. A 28-h continuous census found no surface activity of any chipmunks during hours of darkness. However, episodes of nocturnal movement were detected within the permanent dens by radio telemetric data logging, especially in supra-chiasmatic nucleus-lesioned animals. Excavation and mapping of six chipmunk burrow systems aided in the interpretation of the telemetric activity data. Nighttime restlessness of supra-chiasmatic nucleus-lesioned animals may have acted as a clue to the predator for locating its prey. PMID:10707315

DeCoursey, P J; Walker, J K; Smith, S A

2000-02-01

74

Possible mechanisms underlying bursting pacemaker discharges in invertebrate neurons.  

PubMed

Certain invertebrate neurons generate endogenous bursts of action potentials due to an underlying slow membrane potential oscillation. An early hypothesis for the oscillations proposed a high resting sodium conductance that led to the depolarizing phase, followed by activation of an electrogenic sodium pump coupled to chloride ions, leading to the hyperpolarizing phase. Recent findings contradict this hypothesis. Current thought implicates two conductances in the generation of the oscillations. The depolarizing phase is due to an increase in a sodium or a calcium conductance; the hyperpolarizing phase is due to a subsequent increase in a potassium conductance, which may be either voltage dependent or triggered by an influx of calcium ions. The observation of a negative slope conductance region in the membrane I-V characteristic supports this hypothesis. Bursting cells also usually exhibit anomalous rectification, i.e., a decrease in slope conductance with depolarization, in the I-V characteristic. This decrease may result from a decrease in an outward current or an increase in an inward current. The more important bursting membrane characteristics have been incorporated into an electronic analog. The analog confirms the appropriateness of the two-conductance hypothesis. It also suggests that potassium ion accumulation outside the cell membrane may enhance bursting activity. PMID:658454

Gulrajani, R M; Roberge, F A

1978-06-01

75

Circadian locomotor rhythms in the cricket, Gryllodes sigillatus. I. Localization of the pacemaker and the photoreceptor.  

PubMed

Circadian locomotor rhythm and its underlying mechanism were investigated in the cricket, Gryllodes sigillatus. Adult male crickets showed a nocturnal locomotor rhythm peaking early in the dark phase of a light to dark cycle. This rhythm persisted under constant darkness (DD) with a free-running period averaging 23.1 +/- 0.3 hr. Although constant bright light made most animals arrhythmic, about 40% of the animals showed free-running rhythms with a period longer than 24 hr under constant dim light condition. On transfer to DD, all arrhythmic animals restored the locomotor rhythm. Bilateral optic nerve severance resulted in free-running of the rhythm even under light-dark cycles. The free-running period of the optic nerve severed animals was significantly longer than sham operated crickets in DD, suggesting that the compound eye plays some role in determining the free-running period. Removal of bilateral lamina-medulla portion of the optic lobe abolished the rhythm under DD. These results demonstrate that the photoreceptor for entrainment is the compound eye and the optic lobe is indispensable for persistence of the rhythm. However, 75% and 54% of the optic lobeless animals showed aberrant rhythms with a period very close to 24 hr under light and temperature cycles, respectively, suggesting that there are neural and/or humoral mechanisms for the aberrant rhythms outside of the optic lobe. Since ocelli removal did not affect the photoperiodically induced rhythm, it is likely that the photoreception for the rhythm is performed through an extraretinal photoreceptor. PMID:9450385

Abe, Y; Ushirogawa, H; Tomioka, K

1997-10-01

76

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.

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

2012-01-01

77

HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents.  

PubMed

General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA(A) receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (Ih) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal Ih and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of Ih involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V(1/2) and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics. PMID:15958747

Chen, Xiangdong; Sirois, Jay E; Lei, Qiubo; Talley, Edmund M; Lynch, Carl; Bayliss, Douglas A

2005-06-15

78

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.

Varga, Viktor; Hangya, Balazs; Kranitz, Kinga; Ludanyi, Aniko; Zemankovics, Rita; Katona, Istvan; Shigemoto, Ryuichi; Freund, Tamas F; Borhegyi, Zsolt

2008-01-01

79

Persistent Sodium Current Drives Conditional Pacemaking in CA1 Pyramidal Neurons under Muscarinic Stimulation  

PubMed Central

Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state current–voltage curve was dominated by inward TTX-sensitive persistent sodium current (INaP) that activated near ?75 mV and increased steeply with depolarization. In control, total membrane current was net outward (hyperpolarizing) near ?70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation current so that total membrane current near ?70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of INaP, which then depolarizes the cell from ?70 mV to spike threshold. We quantified the relative contributions of INaP, hyperpolarization-activated cation current (Ih), and calcium current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive sodium current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium current were minimal. Thus, spontaneous activity is driven primarily by activation of INaP in a positive feedback loop starting near ?70 mV and providing increasing inward current to threshold. These results show that the pacemaking “engine” from INaP is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane current near ?70 mV, as by muscarinic stimulation.

Yamada-Hanff, Jason

2013-01-01

80

Persistent sodium current drives conditional pacemaking in CA1 pyramidal neurons under muscarinic stimulation.  

PubMed

Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state current-voltage curve was dominated by inward TTX-sensitive persistent sodium current (I(NaP)) that activated near -75 mV and increased steeply with depolarization. In control, total membrane current was net outward (hyperpolarizing) near -70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation current so that total membrane current near -70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of I(NaP), which then depolarizes the cell from -70 mV to spike threshold. We quantified the relative contributions of I(NaP), hyperpolarization-activated cation current (I(h)), and calcium current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive sodium current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium current were minimal. Thus, spontaneous activity is driven primarily by activation of I(NaP) in a positive feedback loop starting near -70 mV and providing increasing inward current to threshold. These results show that the pacemaking "engine" from I(NaP) is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane current near -70 mV, as by muscarinic stimulation. PMID:24048831

Yamada-Hanff, Jason; Bean, Bruce P

2013-09-18

81

Circadian Rhythm of Redox State Regulates Excitability in Suprachiasmatic Nucleus Neurons  

PubMed Central

Daily rhythms of mammalian physiology, metabolism, and behavior parallel the day-night cycle. They are orchestrated by a central circadian clock in the brain, the suprachiasmatic nucleus (SCN). Transcription of clock genes is sensitive to metabolic changes in reduction and oxidation (redox); however, circadian cycles in protein oxidation have been reported in anucleate cells, where no transcription occurs. We tested whether the SCN also expresses redox cycles and how such metabolic oscillations might affect neuronal physiology. We detected self-sustained circadian rhythms of SCN redox state that required the molecular clockwork. The redox oscillation could determine the excitability of SCN neurons through non-transcriptional modulation of multiple K+ channels. Thus, dynamic regulation of SCN excitability appears to be closely tied to metabolism that engages the clockwork machinery.

Wang, Tongfei A.; Yu, Yanxun V.; Govindaiah, Gubbi; Ye, Xiaoying; Artinian, Liana; Coleman, Todd P.; Sweedler, Jonathan V.; Cox, Charles L.; Gillette, Martha U.

2012-01-01

82

[Multilayered control of the Mammalian circadian system].  

PubMed

Abstract All mammals show daily rhythms in their physiological activity, for example, sleep-wake cycles. This rhythmicity is endogenously generated by a system called the circadian clock, and is composed of reactions occurring in several neural/cellular layers of multicellular organisms. Inter-cellular and inter-organ communication is important for the synchronous action of circadian rhythmicity across the whole body. The heart of the circadian system lies in the rhythmic neuronal activity of the suprachiasmatic nuclei (SCN) in the brain. The oscillation emerges as cell-autonomous rhythmic gene expression observed in individual SCN neurons. Inter-neuronal communication synchronizes the circadian phase of each neuron within the SCN. The integrated rhythmic SCN activity works as a pacemaker for the circadian clocks of non-SCN cells, each of which also rhythmically express clock genes. The -24-h period length of the circadian rhythm is predominantly determined by reactions at the molecular level. Cell-autonomous circadian oscillation is driven by a negative feedback loop of transcription regulation, where CRY/PER heterodimers act as the transcriptional repressors of their own genes. One of the rate limiting steps of circadian cycling is a phosphorylation of CRY and PER proteins followed by proteasome-mediated degradation of those proteins. Pharmacological and genetic perturbation of the phosphorylation or degradation pathways alters the circadian period length. This review provides a hierarchical view of the circadian system, which is important to uncover the different effects of medical or social perturbations on circadian regulation of inter-cellular synchronization, or cell-autonomous oscillation. PMID:24899350

Ode, Koji L; Ueda, Hiroki R

2014-06-01

83

Fetal Alcohol Exposure Disrupts Metabolic Signaling in Hypothalamic Proopiomelanocortin Neurons via a Circadian Mechanism in Male Mice.  

PubMed

Early-life ethanol feeding (ELAF) alters the metabolic function of proopiomelanocortin (POMC)-producing neurons and the circadian expression of clock regulatory genes in the hypothalamus. We investigated whether the circadian mechanisms control the action of ELAF on metabolic signaling genes in POMC neurons. Gene expression measurements of Pomc and a selected group of metabolic signaling genes, Stat3, Sirt1, Pgc1-?, and Asb4 in laser-captured microdissected POMC neurons in the hypothalamus of POMC-enhanced green fluorescent protein mice showed circadian oscillations under light/dark and constant darkness conditions. Ethanol programmed these neurons such that the adult expression of Pomc, Stat3, Sirt, and Asb4 gene transcripts became arrhythmic. In addition, ELAF dampened the circadian peak of gene expression of Bmal1, Per1, and Per2 in POMC neurons. We crossed Per2 mutant mice with transgenic POMC-enhanced green fluorescent protein mice to determine the role of circadian mechanism in ELAF-altered metabolic signaling in POMC neurons. We found that ELAF failed to alter arrhythmic expression of most circadian genes, with the exception of the Bmal1 gene and metabolic signaling regulating genes in Per2 mutant mice. Comparison of the ELAF effects on the circadian blood glucose in wild-type and Per2 mutant mice revealed that ELAF dampened the circadian peak of glucose, whereas the Per2 mutation shifted the circadian cycle and prevented the ELAF dampening of the glucose peak. These data suggest the possibility that the Per2 gene mutation may regulate the ethanol actions on Pomc and the metabolic signaling genes in POMC neurons in the hypothalamus by blocking circadian mechanisms. PMID:24797626

Agapito, Maria A; Zhang, Changqing; Murugan, Sengottuvelan; Sarkar, Dipak K

2014-07-01

84

Millimeter waves thermally alter the firing rate of the Lymnaea pacemaker neuron  

SciTech Connect

The effects of millimeter waves (mm-waves, 75 GHz) and temperature elevation on the firing rate of the BP-4 pacemaker neuron of the pond snail Lymnaea stagnalis were studied by using microelectrode techniques. The open end of a rectangular waveguide covered with a thin Teflon film served as a radiator. Specific absorption rates (SARs), measured in physiological solution at the radiator outlet, ranged from 600 to 4,200 W/kg, causing temperature rises from 0.3 to 2.2 C, respectively. Irradiation at an SAR of 4,200 W/kg caused a biphasic change in the firing rate, i.e., a transient decrease in the firing rate followed by a gradual increase to a new level that was 68 {+-} 21% above control. The biphasic changes in the firing rate were reproduced by heating under the condition that the magnitude (2 C) and the rate of temperature rise were equal to those produced by the irradiation. The addition of 0.05 mM of ouabain caused the disappearance of transient responses of the neuron to the irradiation. It was shown that the rate of temperature rise played an important role in the development of a transient neuronal response. The threshold stimulus for a transient response of the BP-4 neutron found in warming experiments was a temperature rise of 0.0025 C/s.

Alekseev, S.I.; Kochetkova, N.V. [Russian Academy of Sciences, Puschino (Russian Federation). Inst. of Cell Biophysics] [Russian Academy of Sciences, Puschino (Russian Federation). Inst. of Cell Biophysics; Ziskin, M.C.; Bolshakov, M.A. [Temple Univ. Medical School, Philadelphia, PA (United States). Center for Biomedical Physics] [Temple Univ. Medical School, Philadelphia, PA (United States). Center for Biomedical Physics

1997-05-01

85

Survival of Adult Generated Hippocampal Neurons Is Altered in Circadian Arrhythmic Mice  

PubMed Central

The subgranular zone of the hippocampal formation gives rise to new neurons that populate the dentate gyrus throughout life. Cells in the hippocampus exhibit rhythmic clock gene expression and the circadian clock is known to regulate the cycle of cell division in other areas of the body. These facts suggest that the circadian clock may regulate adult neurogenesis in the hippocampus as well. In the present study, neurogenesis in the hippocampal subgranular zone was examined in arrhythmic Bmal1 knockout (-KO) mice and their rhythmic heterozygous and wildtype littermates. Proliferation and survival of newly generated subgranular zone cells were examined using bromodeoxyuridine labelling, while pyknosis (a measure of cell death) and hippocampal volume were examined in cresyl violet stained sections. There was no significant difference in cellular proliferation between any of the groups, yet survival of proliferating cells, 6 weeks after the bromodeoxyuridine injection, was significantly greater in the BMAL1-KO animals. The number of pyknotic cells was significantly decreased in Bmal1-KO animals, yet hippocampal volume remained the same across genotypes. These findings suggest that while a functional circadian clock is not necessary for normal proliferation of neuronal precursor cells, the normal pruning of newly generated neurons in the hippocampus may require a functional circadian clock.

Rakai, Brooke D.; Chrusch, Michael J.; Spanswick, Simon C.; Dyck, Richard H.; Antle, Michael C.

2014-01-01

86

Interaction of NMDA Receptor and Pacemaking Mechanisms in the Midbrain Dopaminergic Neuron  

PubMed Central

Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether–a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

Ha, Joon; Kuznetsov, Alexey

2013-01-01

87

A role for Drosophila ATX2 in activation of PER translation and circadian behavior  

PubMed Central

A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of Ataxin-2 (ATX2) – an RNA binding protein implicated in human neurodegenerative diseases - was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons, and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. Indeed, ATX2 formed a complex with TYF, and promoted its interaction with Poly-A binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing, and reveals that this protein functions as an activator of PER translation in circadian neurons.

Zhang, Yong; Ling, Jinli; Yuan, Chunyan; Dubruille, Raphaelle; Emery, Patrick

2014-01-01

88

Aging of the Mammalian Circadian Timing System: Changes in the Central Pacemaker and Its Regulation by Photic and Nonphotic Signals  

Microsoft Academic Search

Aging alters many aspects of endogenously regulated, 24-hour (circadian) rhythms, such as their amplitude, relationship to the ambient lighting cycle, and sensitivity to phase resetting signals. In order to elucidate the mechanisms responsible for these age-related changes, many studies have investigated age-related changes in the neural components of the circadian timing system, which include the hypothalamic suprachiasmatic nucleus (SCN), the

Marilyn J. Duncan

2007-01-01

89

Ultrastructure of pigment-dispersing hormone-immunoreactive neurons in a three-dimensional model of the accessory medulla of the cockroach Leucophaea maderae  

Microsoft Academic Search

Locomotor activity rhythms of the cockroach Leucophaea maderae are orchestrated by two bilaterally symmetric, mutually coupled, circadian pacemakers. They lie in the optic lobes of the brain and are confined to the accessory medulla (AMe), ventro-medially to the medulla. The AMe is innervated by approximately 12 pigment-dispersing hormone (PDH)-immunoreactive anterior medulla neurons (PDHMe), which are circadian pacemaker candidates in the

Thomas Reischig; Monika Stengl

2003-01-01

90

The membrane potential waveform of bursting pacemaker neurons is a predictor of their preferred frequency and the network cycle frequency  

PubMed Central

Many oscillatory networks involve neurons that exhibit intrinsic rhythmicity, but possess a large variety of voltage-gated currents which interact in a complex fashion making it difficult to determine which factors control frequency. Yet, these neurons often have preferred (resonance) frequencies that can be close to the network frequency. Because the preferred frequency results from the dynamics of ionic currents, it can be assumed to depend on parameters that determine the neuron’s oscillatory waveform shape. The pyloric network frequency in the crab Cancer borealis is correlated with the preferred frequency of its bursting pacemaker neurons AB and PD. We measure the preferred frequency of the PD neuron in voltage-clamp, which allows control of the oscillation voltage range and waveforms (sine waves and realistic oscillation waveforms), and showthat1) the preferred frequency depends on the voltage range of the oscillating voltage waveform; 2) the slope of the waveform near its peak has a strongly negative correlation with the preferred frequency; and 3) correlations between parameters of the PD neuron oscillation waveform and its preferred frequency can be used to predict shifts in the network frequency. As predicted by these results, dynamic clamp shifts of the upper or lower voltage limits of the PD neuron waveform during ongoing oscillations changed the network frequency, consistent with the predictions from the preferred frequency. These results show that the voltage waveform of oscillatory neurons can be predictive of their preferred frequency and thus the network oscillation frequency.

Tseng, Hua-an; Nadim, Farzan

2010-01-01

91

Role of the axodendritic tree in the functioning of Helix bursting neurons: generation of pacemaker activity and propagation of action potentials along the axon  

Microsoft Academic Search

The purpose of this study was to determine the role of the axodendritic tree in the generation of bursting pacemaker activity in the identified Helix RPa1 neuron, which is homologous to the Aplysia R15 cell, and propagation of action potentials along the axons. In doing so, I used recording of RPa1 neuron electrical activity after cutting off the right or

N. I Kononenko

2000-01-01

92

The Differential Effects of Ionizing Radiation on the Circadian Oscillator and Other Functions in the Eye of Aplysia  

Microsoft Academic Search

Ionizing radiation has been used to selectively separate the circadian oscillator function of the eye of Aplysia from some of its other functions--synchronous compound action potential (CAP) generation, the light response, synaptic transmission between photoreceptors and output neurons, and the bursting pacemaker mechanism. Doses of 4-krad (50 kV peak) x-rays have a minimal effect on the circadian rhythm of CAP

John C. Woolum; Felix Strumwasser

1980-01-01

93

Myoinhibitory peptides in the brain of the cockroach Leucophaea maderae and colocalization with pigment-dispersing factor in circadian pacemaker cells.  

PubMed

Myoinhibitory peptides (MIPs) are a family of insect W(X(6))Wamides with inhibitory effects on visceral muscles and juvenile hormone synthesis. Although MIPs are widely distributed within the nervous system, a detailed analysis of their distribution and function in insect brains is still missing. We analyzed the distribution of MIPs in the brain of the cockroach Leucophaea maderae. We focused on the accessory medulla (AMe), a small neuropil near the medulla that acts as the master circadian clock. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) and Nano-LC electrospray ionization (ESI) mass spectrometry revealed five Lem-MIPs in preparations of the AMe and corpora cardiaca. The complete sequences of two of these peptides were identified. Immunocytochemistry revealed wide distribution of MIP-related peptides in the cockroach brain. The superior median protocerebrum, parts of the central complex, and the tritocerebrum showed particularly dense immunostaining. In contrast, only a few local interneurons were stained in the antennal lobe and a few extrinsic neurons in the mushroom body, including a giant neuron innervating the calyces. The noduli of the AMe showed dense immunostaining, and neurons in all AMe cell groups except the anterior neurons were labeled. Pigment-dispersing factor- (PDF) and MIP immunostaining was colocalized in two neurons of the AMe. No colocalization of MIP- and PDF immunostaining was detected in the anterior optic commissure, but two small PDF-immunoreactive commissural fibers near the posterior optic commissure showed colocalized MIP immunostaining. The results suggest that several MIPs participate in different functional circuits of the circadian system and are involved in multiple brain circuits of the Madeira cockroach. PMID:22095637

Schulze, Julia; Neupert, Susanne; Schmidt, Lilia; Predel, Reinhard; Lamkemeyer, Tobias; Homberg, Uwe; Stengl, Monika

2012-04-01

94

PDF Receptor Expression Reveals Direct Interactions between Circadian Oscillators in Drosophila  

PubMed Central

Daily rhythms of behavior are controlled by a circuit of circadian pacemaking neurons. In Drosophila, 150 pacemakers participate in this network, and recent observations suggest the network is divisible into M and E oscillators which normally interact and synchronize. Sixteen oscillator neurons (the small and large LNvs) express a neuropeptide called pigment dispersing factor (PDF) whose signaling is often equated with M oscillator output. Given the significance of PDF signaling to numerous aspects of behavioral and molecular rhythms, determining precisely where and how signaling via the PDF receptor (PDFR) occurs is now a central question in the field. Here we show that GAL4-mediated rescue of pdfr phenotypes using a UAS-PDFR transgene is insufficient to provide complete behavioral rescue. In contrast, we describe a ~70 kB PDF receptor (pdfr) transgene which does rescue the entire pdfr circadian behavioral phenotype. The transgene is widely but heterogeneously expressed among pacemakers, and also among a limited number of non-pacemakers. Our results support an important hypothesis: the small LNv cells directly target a subset of the other crucial pacemaker neurons cells. Furthermore, expression of the transgene confirms an autocrine feedback signaling by PDF back to PDF-expressing cells. Finally, the results present an unexpected PDF receptor site: the large LNv cells appear to target a population of non-neuronal cells that resides at the base of the eye.

Im, Seol Hee; Taghert, Paul H.

2010-01-01

95

Electrical pacemakers of canine proximal colon are functionally innervated by inhibitory motor neurons.  

PubMed

Pacemaker activity in the canine proximal colon occurs at the submucosal and myenteric borders of the circular layer [Am. J. Physiol. 252 (Cell Physiol. 21): C215-C224 and C290-C299, 1987]. The present study investigated the neural regulation of rhythmic electrical activity. Spontaneous inhibitory junction potentials (IJPs) were observed in intracellular recordings from circular muscle cells near the myenteric border. The amplitudes of these events decayed with distance through the circular layer. Stimulation at the myenteric plexus surface evoked IJPs that mimicked the spontaneous events. Stimulation at the submucosal surface evoked IJPs in adjacent cells that were of shorter duration and of different waveform than myenteric IJPs. Amplitudes of IJPs evoked by stimulation near either surface decayed with distance from the site of stimulation. The decay functions for IJPs were essentially identical to the decay of spontaneous slow waves or myenteric potential oscillations. Spontaneous and evoked IJPs affected the amplitudes, durations, and patterns of ongoing rhythmic electrical activity. The data suggest that myenteric and submucosal pacemaker populations may be innervated by different populations of inhibitory nerve fibers. Innervation appears to be heterogeneous with dense populations of inhibitory nerve fibers predominantly located in the pacemaker regions. Neural regulations of pacemaker activity influences rhythmic electrical activity throughout the muscularis. PMID:2564251

Smith, T K; Reed, J B; Sanders, K M

1989-03-01

96

Circadian misalignment in major depressive disorder.  

PubMed

It has been hypothesized that the circadian pacemaker plays a role in major depressive disorder (MDD). We sought to determine if misalignment between the timing of sleep and the pacemaker correlated with symptom severity in MDD. Depression severity correlated with circadian misalignment: the more delayed, the more severe the symptoms. PMID:19524304

Emens, Jonathan; Lewy, Alfred; Kinzie, John Mark; Arntz, Diana; Rough, Jennifer

2009-08-15

97

A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus  

PubMed Central

Background In mammals, the synchronized activity of cell autonomous clocks in the suprachiasmatic nuclei (SCN) enables this structure to function as the master circadian clock, coordinating daily rhythms in physiology and behavior. However, the dominance of this clock has been challenged by the observations that metabolic duress can over-ride SCN controlled rhythms, and that clock genes are expressed in many brain areas, including those implicated in the regulation of appetite and feeding. The recent development of mice in which clock gene/protein activity is reported by bioluminescent constructs (luciferase or luc) now enables us to track molecular oscillations in numerous tissues ex vivo. Consequently we determined both clock activities and responsiveness to metabolic perturbations of cells and tissues within the mediobasal hypothalamus (MBH), a site pivotal for optimal internal homeostatic regulation. Results Here we demonstrate endogenous circadian rhythms of PER2::LUC expression in discrete subdivisions of the arcuate (Arc) and dorsomedial nuclei (DMH). Rhythms resolved to single cells did not maintain long-term synchrony with one-another, leading to a damping of oscillations at both cell and tissue levels. Complementary electrophysiology recordings revealed rhythms in neuronal activity in the Arc and DMH. Further, PER2::LUC rhythms were detected in the ependymal layer of the third ventricle and in the median eminence/pars tuberalis (ME/PT). A high-fat diet had no effect on the molecular oscillations in the MBH, whereas food deprivation resulted in an altered phase in the ME/PT. Conclusion Our results provide the first single cell resolution of endogenous circadian rhythms in clock gene expression in any intact tissue outside the SCN, reveal the cellular basis for tissue level damping in extra-SCN oscillators and demonstrate that an oscillator in the ME/PT is responsive to changes in metabolism.

Guilding, Clare; Hughes, Alun TL; Brown, Timothy M; Namvar, Sara; Piggins, Hugh D

2009-01-01

98

Activation of glycine receptor phase-shifts the circadian rhythm in neuronal activity in the mouse suprachiasmatic nucleus  

PubMed Central

Abstract In mammals, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is composed of numerous synchronized oscillating cells that drive daily behavioural and physiological processes. Several entrainment pathways, afferent inputs to the SCN with their neurotransmitter and neuromodulator systems, can reset the circadian system regularly and also modulate neuronal activity within the SCN. In the present study, we investigated the function of the inhibitory neurotransmitter glycine on neuronal activity in the mouse SCN and on resetting of the circadian clock. The effects of glycine on the electrical activity of SCN cells from C57Bl/6 mice were studied either by patch-clamp recordings from acute brain slices or by long-term recordings from organotypic brain slices using multi-microelectrode arrays (MEA). Voltage-clamp recordings confirmed the existence of glycine-induced, chloride-selective currents in SCN neurons. These currents were reversibly suppressed by strychnine, phenylbenzene ?-phosphono-?-amino acid (PMBA) or ginkgolide B, selective blockers of glycine receptors (GlyRs). Long-term recordings of the spontaneous activity of SCN neurons revealed that glycine application induces a phase advance during the subjective day and a phase delay during the early subjective night. Both effects were suppressed by strychnine or by PMBA. These results suggest that glycine is able to modulate circadian activity by acting directly on its specific receptors in SCN neurons.

Mordel, Jerome; Karnas, Diana; Inyushkin, Alexey; Challet, Etienne; Pevet, Paul; Meissl, Hilmar

2011-01-01

99

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

Microsoft Academic Search

channelwasshowntoparticipateinthetasynchronizationofthemedialseptum.Here,wetested 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

Viktor Varga; B. Hangya; K. Kranitz; A. Ludanyi; R. Zemankovics; I. Katona; R. Shigemoto; T. F. Freund; Z. Borhegyi

2008-01-01

100

Food-entrained circadian rhythms in rats are insensitive to deuterium oxide  

Microsoft Academic Search

Rats anticipate a scheduled daily meal by entrainment of a circadian pacemaker separate from the light-entrainable circadian pacemaker located in the suprachiasmatic nuclei (SCN). The site and molecular mechanisms of the food-entrainable pacemaker are unknown. The intrinsic period (?) of the SCN pacemaker is significantly lengthened by deuteriation. Sensitivity of food-entrained circadian rhythms to D2O (25% in drinking water) was

Ralph E. Mistlberger; Elliott G. Marchant; Tod E. Kippin

2001-01-01

101

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); Erik D. Herzog (Washington University;Department of Biology REV)

2003-11-18

102

How coupling determines the entrainment of circadian clocks  

NASA Astrophysics Data System (ADS)

Autonomous circadian clocks drive daily rhythms in physiology and behaviour. A network of coupled neurons, the suprachiasmatic nucleus (SCN), serves as a robust self-sustained circadian pacemaker. Synchronization of this timer to the environmental light-dark cycle is crucial for an organism's fitness. In a recent theoretical and experimental study it was shown that coupling governs the entrainment range of circadian clocks. We apply the theory of coupled oscillators to analyse how diffusive and mean-field coupling affects the entrainment range of interacting cells. Mean-field coupling leads to amplitude expansion of weak oscillators and, as a result, reduces the entrainment range. We also show that coupling determines the rigidity of the synchronized SCN network, i.e. the relaxation rates upon perturbation. Our simulations and analytical calculations using generic oscillator models help to elucidate how coupling determines the entrainment of the SCN. Our theoretical framework helps to interpret experimental data.

Bordyugov, G.; Granada, A. E.; Herzel, H.

2011-08-01

103

Pigment-dispersing hormone in Daphnia interneurons, one type homologous to insect clock neurons displaying circadian rhythmicity.  

PubMed

We report identification of a beta-type pigment-dispersing hormone (PDH) identical in two water flea species, Daphnia magna and Daphnia pulex. It has been identified by cloning of precursors, chromatographic isolation from tissue extracts followed by immunoassays and de novo-mass spectrometric sequencing. The peptide is restricted to a complex system of distinct interneurons in the brain and visual ganglia, but does not occur in neurosecretory cells projecting to neurohemal organs as in decapod crustaceans. Thirteen neuron types individually identified and reconstructed by immunohistochemistry were almost identical in terms of positions and projection patterns in both species. Several neurons invade and form plexuses in visual ganglia and major brain neuropils including the central body. Five neuron types show contralateral pathways and form plexuses in the lateral, dorsal, or postlateral brain neuropils. Others are local interneurons, and a tritocerebral neuron connects the protocerebrum with the neuropil of the locomotory second antenna. Two visual ganglia neuron types lateral to the medulla closely resemble insect medulla lateral circadian clock neurons containing pigment-dispersing factor based upon positional and projectional criteria. Experiments under 12:12 h light/dark cycles and constant light or darkness conditions showed significant circadian changes in numbers and activities of one type of medulla lateral PDH neuron with an acrophase in the evening. This simple PDH system shows striking homologies to PDH systems in decapod crustaceans and well-known clock neurons in several insects, which suggests evolutionary conservation of an ancient peptidergic interneuronal system that is part of biological clocks. PMID:21365282

Strauss, Johannes; Zhang, Qian; Verleyen, Peter; Huybrechts, Jurgen; Neupert, Susanne; Predel, Reinhard; Pauwels, Kevin; Dircksen, Heinrich

2011-10-01

104

Pacemaker (image)  

MedlinePLUS

A pacemaker is a small, battery-operated electronic device which is inserted under the skin to help the heart beat regularly and at an appropriate rate. The pacemaker has leads that travel through a large vein ...

105

A defined heteromeric KV1 channel stabilizes the intrinsic pacemaking and regulates the output of deep cerebellar nuclear neurons to thalamic targets.  

PubMed

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with K(V)1 channels produced by mandatory multi-merization of K(V)1.1, 1.2 ? and KV ?2 subunits. Being constitutively active, the K(+) current (IK(V)1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IK(V)1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IK(V)1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back-propagating action potentials into the somato-dendritic compartment. The latter is also demonstrated to secure the dominance of clock-like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modelling and retro-axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established. PMID:23318870

Ovsepian, Saak V; Steuber, Volker; Le Berre, Marie; O'Hara, Liam; O'Leary, Valerie B; Dolly, J Oliver

2013-04-01

106

A defined heteromeric KV1 channel stabilizes the intrinsic pacemaking and regulates the output of deep cerebellar nuclear neurons to thalamic targets  

PubMed Central

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with KV1 channels produced by mandatory multi-merization of KV1.1, 1.2 ? and KV?2 subunits. Being constitutively active, the K+ current (IKV1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IKV1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IKV1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back-propagating action potentials into the somato-dendritic compartment. The latter is also demonstrated to secure the dominance of clock-like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modelling and retro-axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established.

Ovsepian, Saak V; Steuber, Volker; Le Berre, Marie; O'Hara, Liam; O'Leary, Valerie B; Dolly, J Oliver

2013-01-01

107

A simple model for circadian timing by mammals.  

PubMed

Circadian timing is structured in such a way as to receive information from the external and internal environments, and its function is the timing organization of the physiological and behavioral processes in a circadian pattern. In mammals, the circadian timing system consists of a group of structures, which includes the suprachiasmatic nucleus (SCN), the intergeniculate leaflet and the pineal gland. Neuron groups working as a biological pacemaker are found in the SCN, forming a biological master clock. We present here a simple model for the circadian timing system of mammals, which is able to reproduce two fundamental characteristics of biological rhythms: the endogenous generation of pulses and synchronization with the light-dark cycle. In this model, the biological pacemaker of the SCN was modeled as a set of 1000 homogeneously distributed coupled oscillators with long-range coupling forming a spherical lattice. The characteristics of the oscillator set were defined taking into account the Kuramoto's oscillator dynamics, but we used a new method for estimating the equilibrium order parameter. Simultaneous activities of the excitatory and inhibitory synapses on the elements of the circadian timing circuit at each instant were modeled by specific equations for synaptic events. All simulation programs were written in Fortran 77, compiled and run on PC DOS computers. Our model exhibited responses in agreement with physiological patterns. The values of output frequency of the oscillator system (maximal value of 3.9 Hz) were of the order of magnitude of the firing frequencies recorded in suprachiasmatic neurons of rodents in vivo and in vitro (from 1.8 to 5.4 Hz). PMID:19219305

Cardoso, F R G; de O Cruz, F A; Silva, D; Cortez, C M

2009-01-01

108

The Tau Mutation of Casein Kinase 1{epsilon} Sets the Period of the Mammalian Pacemaker via Regulation of Period1 or Period2 Clock Proteins.  

PubMed

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

2014-04-01

109

Programmable Pacemaker  

NASA Technical Reports Server (NTRS)

St. Jude Medical's Cardiac Rhythm Management Division, formerly known as Pacesetter Systems, Inc., incorporated Apollo technology into the development of the programmable pacemaker system. This consists of the implantable pacemaker together with a physician's console containing the programmer and a data printer. Physician can communicate with patient's pacemaker by means of wireless telemetry signals transmitted through the communicating head held over the patient's chest. Where earlier pacemakers deliver a fixed type of stimulus once implanted, Programalith enables surgery free "fine tuning" of device to best suit the patient's changing needs.

1980-01-01

110

Epigenetic control and the circadian clock: linking metabolism to neuronal responses.  

PubMed

Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape. PMID:24486964

Orozco-Solis, R; Sassone-Corsi, P

2014-04-01

111

Molecular Cloning and Circadian Regulation of Cryptochrome Genes in Japanese Quail (Coturnix coturnix japonica)  

Microsoft Academic Search

The circadian system is thought to have three components: input, pacemaker (internal clock), and output. Cryptochromes (Cry) are important clock genes, and recent findings indicate that these genes not only act as circadian photoreceptors but are also essential components in the negative feedback of the circadian system. As a first step toward understanding the avian circadian system, the authors tried

Zhengwei Fu; Misako Inaba; Tadashi Noguchi; Hisanori Kato

2002-01-01

112

Photoperiodic modulation of circadian rhythms in the cricket Gryllus bimaculatus.  

PubMed

The waveform and the free-running period of circadian rhythms in constant conditions are often modulated by preceding lighting conditions. We have examined the modulatory effect of variable length of light phase of a 24h light cycle on the ratio of activity (alpha) and rest phase (rho) as well as on the free-running period of the locomotor rhythm in the cricket Gryllus bimaculatus. When experienced the longer light phases, the alpha/rho-ratio was smaller and the free-running period was shorter. The magnitude of changes in alpha/rho-ratio was dependent on the number of cycles exposed, while the free-running period was changed by a single exposure, suggesting that there are separate regulatory mechanisms for the waveform and the free-running period. The neuronal activity of the optic lobe showed the alpha/rho-ratio changing with the preceding photoperiod. When different photoperiodic conditions were given to each of the two optic lobe pacemakers, the alpha/rho-ratio of a single pacemaker was rather intermediate between those of animals treated with either of the two conditions. These results suggest that the storage of the photoperiodic information occurs at least in part in the optic lobe pacemaker, and that the mutual interaction between the bilateral optic lobe pacemakers is involved in the photoperiodic modulation. PMID:15993131

Koga, Mika; Ushirogawa, Hiroshi; Tomioka, Kenji

2005-06-01

113

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

114

UNC79 and UNC80, Putative Auxiliary Subunits of the NARROW ABDOMEN Ion Channel, Are Indispensable for Robust Circadian Locomotor Rhythms in Drosophila  

PubMed Central

In the fruit fly Drosophila melanogaster, a network of circadian pacemaker neurons drives daily rhythms in rest and activity. The ion channel NARROW ABDOMEN (NA), orthologous to the mammalian sodium leak channel NALCN, functions downstream of the molecular circadian clock in pacemaker neurons to promote behavioral rhythmicity. To better understand the function and regulation of the NA channel, we have characterized two putative auxiliary channel subunits in Drosophila, unc79 (aka dunc79) and unc80 (aka CG18437). We have generated novel unc79 and unc80 mutations that represent strong or complete loss-of-function alleles. These mutants display severe defects in circadian locomotor rhythmicity that are indistinguishable from na mutant phenotypes. Tissue-specific RNA interference and rescue analyses indicate that UNC79 and UNC80 likely function within pacemaker neurons, with similar anatomical requirements to NA. We observe an interdependent, post-transcriptional regulatory relationship among the three gene products, as loss of na, unc79, or unc80 gene function leads to decreased expression of all three proteins, with minimal effect on transcript levels. Yet despite this relationship, we find that the requirement for unc79 and unc80 in circadian rhythmicity cannot be bypassed by increasing NA protein expression, nor can these putative auxiliary subunits substitute for each other. These data indicate functional requirements for UNC79 and UNC80 beyond promoting channel subunit expression. Immunoprecipitation experiments also confirm that UNC79 and UNC80 form a complex with NA in the Drosophila brain. Taken together, these data suggest that Drosophila NA, UNC79, and UNC80 function together in circadian clock neurons to promote rhythmic behavior.

Lear, Bridget C.; Darrah, Eric J.; Aldrich, Benjamin T.; Gebre, Senetibeb; Scott, Robert L.; Allada, Ravi

2013-01-01

115

Programmable Pacemaker.  

National Technical Information Service (NTIS)

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, In...

1996-01-01

116

The circadian clock transcriptional complex: metabolic feedback intersects with epigenetic control  

PubMed Central

Chromatin remodeling is a prerequisite for most nuclear functions, including transcription, silencing, and DNA replication. Accumulating evidence shows that many physiological processes require highly sophisticated events of chromatin remodeling. Recent findings have linked cellular metabolism, epigenetic state, and the circadian clock. The control of a large variety of neuronal, behavioral, and physiological responses follows diurnal rhythms. This is possible through a transcriptional regulatory network that governs a significant portion of the genome. The harmonic oscillation of gene expression is paralleled by critical events of chromatin remodeling that appear to provide specificity and plasticity in circadian regulation. Accumulating evidence shows that the circadian epigenome appears to share intimate links with cellular metabolic processes. These notions indicate that the circadian epigenome might integrate tissue specificity within biological pacemakers, bridging systems physiology to metabolic control. This review highlights several advances related to the circadian epigenome, the contribution of NAD+ as a critical signaling metabolite, and its effects on epigenetic state, followed by more recent reports on circadian metabolomics analyses.

Masri, Selma; Zocchi, Loredana; Katada, Sayako; Mora, Eugenio; Sassone-Corsi, Paolo

2012-01-01

117

Effects of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) on sleep and circadian rhythms.  

PubMed

Abuse of stimulant drugs invariably leads to a disruption in sleep-wake patterns by virtue of the arousing and sleep-preventing effects of these drugs. Certain stimulants, such as 3,4-methylenedioxymethamphetamine (MDMA), may also have the potential to produce persistent alterations in circadian regulation and sleep because they can be neurotoxic toward brain monoaminergic neurons involved in normal sleep regulation. In particular, MDMA has been found to damage brain serotonin (5-HT) neurons in a variety of animal species, including nonhuman primates, with growing evidence that humans are also susceptible to MDMA-induced brain 5-HT neurotoxicity. 5-HT is an important modulator of sleep and circadian rhythms and, therefore, individuals who sustain MDMA-induced 5-HT neurotoxicity may be at risk for developing chronic abnormalities in sleep and circadian patterns. In turn, such abnormalities could play a significant role in other alterations reported in abstinent in MDMA users (e.g., memory disturbance). This paper will review preclinical and clinical studies that have explored the effects of prior MDMA exposure on sleep, circadian activity, and the circadian pacemaker, and will highlight current gaps in knowledge and suggest areas for future research. PMID:17982598

McCann, Una D; Ricaurte, George A

2007-01-01

118

Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase  

NASA Technical Reports Server (NTRS)

The biological basis of preferences for morning or evening activity patterns ("early birds" and "night owls") has been hypothesized but has remained elusive. The authors reported that, compared with evening types, the circadian pacemaker of morning types was entrained to an earlier hour with respect to both clock time and wake time. The present study explores a chronobiological mechanism by which the biological clock of morning types may be set to an earlier hour. Intrinsic period, a fundamental property of the circadian system, was measured in a month-long inpatient study. A subset of participants also had their circadian phase assessed. Participants completed a morningness-eveningness questionnaire before study. Circadian period was correlated with morningness-eveningness, circadian phase, and wake time, demonstrating that a fundamental property of the circadian pacemaker is correlated with the behavioral trait of morningness-eveningness.

Duffy, J. F.; Rimmer, D. W.; Czeisler, C. A.

2001-01-01

119

GABA and $G_{io}$ Differentially Control Circadian Rhythms and Synchrony in Clock Neurons  

Microsoft Academic Search

Neurons in the mammalian suprachiasmatic nuclei (SCN) generate daily rhythms in physiology and behavior, but it is unclear how they maintain and synchronize these rhythms in vivo. We hypothesized that parallel signaling pathways in the SCN are required to synchronize rhythms in these neurons for coherent output. We recorded firing and clock-gene expression patterns while blocking candidate signaling pathways for

Sara J. Aton; James E. Huettner; Martin Straume; Erik D. Herzog

2006-01-01

120

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

121

Identification of a circadian output circuit for rest:activity rhythms in Drosophila.  

PubMed

Though much is known about the cellular and molecular components of the circadian clock, output pathways that couple clock cells to overt behaviors have not been identified. We conducted a screen for circadian-relevant neurons in the Drosophila brain and report here that cells of the pars intercerebralis (PI), a functional homolog of the mammalian hypothalamus, comprise an important component of the circadian output pathway for rest:activity rhythms. GFP reconstitution across synaptic partners (GRASP) analysis demonstrates that PI cells are connected to the clock through a polysynaptic circuit extending from pacemaker cells to PI neurons. Molecular profiling of relevant PI cells identified the corticotropin-releasing factor (CRF) homolog, DH44, as a circadian output molecule that is specifically expressed by PI neurons and is required for normal rest:activity rhythms. Notably, selective activation or ablation of just six DH44+ PI cells causes arrhythmicity. These findings delineate a circuit through which clock cells can modulate locomotor rhythms. PMID:24766812

Cavanaugh, Daniel J; Geratowski, Jill D; Wooltorton, Julian R A; Spaethling, Jennifer M; Hector, Clare E; Zheng, Xiangzhong; Johnson, Erik C; Eberwine, James H; Sehgal, Amita

2014-04-24

122

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

123

Circadian Control of Neuroendocrine Circuits Regulating Female Reproductive Function  

PubMed Central

Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary–gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

Williams, Wilbur P.; Kriegsfeld, Lance J.

2012-01-01

124

Synaptophysin is involved in resetting of the mammalian circadian clock  

PubMed Central

Background Mammals can adapt to changing light/dark conditions by advancing or delaying their circadian clock phase. Light pulses evoke changes in gene expression and neuronal activity in the suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system. Alterations in neuronal activity are partially mediated by changes in synaptic vesicle (SV) fusion at the presynaptic membrane, which modulates release of neurotransmitters. Methods Male synaptophysin (Syp) knock-out and littermate control wild type mice were tested in an Aschoff type I resetting paradigm. Additionally, gene expression of cFos, Per1 and Per2 was assessed in the SCN. Finally, complexes between the synaptic vesicle proteins Syp and synaptobrevin (Syb) were studied in order to correlate behavior with protein complexes at synaptic vesicles. Results Here we show that mice lacking Syp, a modulator of neurotransmitter release, are defective in delaying clock phase. In contrast, clock phase advances as well as clock period are normal in Syp-/- knock-out mice. This correlates with the formation of Syp/Syb complexes. Conclusions Our findings suggest that Syp is involved specifically in the response to a nocturnal light pulse occurring in the early night. It appears that the SV component Syp is critically involved in the delay portion of the resetting mechanism of the circadian clock.

2013-01-01

125

PDP1? functions downstream of the circadian oscillator to mediate behavioral rhythms Abbreviated title: PDP1? function in the circadian clock  

PubMed Central

The Drosophila circadian oscillator is comprised of autoregulatory period/timeless (per/tim) and Clock (Clk) feedback loops that control rhythmic transcription. In the Clk loop, CLOCK-CYCLE (CLK-CYC) heterodimers activate vrille (vri) and PAR domain protein 1? (Pdp1?) transcription, then sequential repression by VRI and activation by PDP1? mediate rhythms in Clk transcription. Since VRI and PDP1? bind the same regulatory element, the VRI/PDP1? ratio is thought to control the level of Clk transcription. Thus, constant high or low PDP1? levels in clock cells should eliminate Clk mRNA cycling and disrupt circadian oscillator function. Here we show that reducing PDP1? levels in clock cells by ~70% via RNA interference or increasing PDP1? levels by ~10-fold in clock cells does not alter Clk mRNA cycling or circadian oscillator function. However, constant low or high PDP1? levels in clock cells disrupt locomotor activity rhythms despite persistent circadian oscillator function in brain pacemaker neurons that extend morphologically normal projections into the dorsal brain. These results demonstrate that the VRI/PDP1? ratio neither controls Clk mRNA cycling nor circadian oscillator function, and argue that PDP1? is not essential for Clk activation. PDP1? is nevertheless required for behavioral rhythmicity, which suggests that it functions to regulate oscillator output.

Benito, Juliana; Zheng, Hao; Hardin, Paul E.

2007-01-01

126

Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons.  

PubMed

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; Beckstead, Michael J

2014-07-01

127

Pacemaker automaticity  

Microsoft Academic Search

The automated measurement of the main electrical parameters of pacemakers, such as battery voltage, current drain, pacing impedance, sensing levels, and pacing thresholds enables a continuous monitoring of the adequate functioning of the implanted device. New technologies in device interrogation, data transfer, and patient alert functions will enhance therapy safety significantly by the immediate detection of all, including transient, device

Joerg Neuzner; Thorsten Schwarz; Johannes Sperzel

2000-01-01

128

Distinct visual pathways mediate Drosophila larval light avoidance and circadian clock entrainment  

PubMed Central

Visual organs perceive environmental stimuli required for rapid initiation of behaviors and can also entrain the circadian clock. The larval eye of Drosophila is capable of both functions. Each eye contains only 12 photoreceptors (PRs), which can be subdivided into two subtypes. Four PRs express blue-sensitive rhodopsin5 (rh5) and eight express green-sensitive rhodopsin6 (rh6). We found that either PR-subtype is sufficient to entrain the molecular clock by light, while only the Rh5-PR subtype is essential for light avoidance. Acetylcholine (ACh) released from PRs confers both functions. Both subtypes of larval PRs innervate the main circadian pacemaker neurons of the larva, the PDF-expressing lateral neurons (LNs), providing sensory input to control circadian rhythms. However, we show that PDF-expressing LNs are dispensable for light avoidance, and a distinct set of three clock neurons is required. Thus we have identified distinct sensory and central circuitry regulating light avoidance behavior and clock entrainment. Our findings provide insights into the coding of sensory information for distinct behavioral functions and the underlying molecular and neuronal circuitry.

Keene, Alex C.; Mazzoni, Esteban O.; Zhen, Jamie; Younger, Meg A.; Yamaguchi, Satoko; Blau, Justin; Desplan, Claude; Sprecher, Simon G.

2011-01-01

129

[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

130

Photopic transduction implicated in human circadian entrainment  

NASA Technical Reports Server (NTRS)

Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.

Zeitzer, J. M.; Kronauer, R. E.; Czeisler, C. A.

1997-01-01

131

Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of Drosophila revealed by real-time cyclic AMP imaging  

PubMed Central

Summary The neuropeptide PDF is released by sixteen clock neurons in Drosophila and helps maintain circadian activity rhythms by coordinating a network of ~150 neuronal clocks. Whether PDF acts directly on elements of this neural network remains unknown. We address this question by adapting Epac1-camps, a genetically encoded cAMP FRET sensor, for use in the living brain. We find that a subset of the PDF-expressing neurons respond to PDF with long-lasting cAMP increases, and confirm that such responses require the PDF receptor. In contrast, an unrelated Drosophila neuropeptide, DH 31, stimulates large cAMP increases in all PDF-expressing clock neurons. Thus the network of ~150 clock neurons displays widespread, though not uniform, PDF receptivity. This work introduces a sensitive means of measuring cAMP changes in a living brain with sub-cellular resolution. Specifically, it experimentally confirms the longstanding hypothesis that PDF is a direct modulator of most neurons in the Drosophila clock network.

Shafer, Orie T.; Kim, Dong Jo; Dunbar-Yaffe, Richard; Nikolaev, Viacheslav O.; Lohse, Martin J.; Taghert, Paul H.

2008-01-01

132

Neurochemical Control of Circadian Rhythms.  

National Technical Information Service (NTIS)

The suprachiasmatic nucleus (SCN), which appears to act as a circadian clock, contains a large subpopulation of local circuit neurons in which vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are co-localized. We are continuing t...

H. E. Albers

1990-01-01

133

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

134

Calcium-activated potassium channels in insect pacemaker neurons as unexpected target site for the novel fumigant dimethyl disulfide.  

PubMed

Dimethyl disulfide (DMDS), a plant-derived insecticide, is a promising fumigant as a substitute for methyl bromide. To further understand the mode of action of DMDS, we examined its effect on cockroach octopaminergic neurosecretory cells, called dorsal unpaired median (DUM) neurons, using whole-cell patch-clamp technique, calcium imaging and antisense oligonucleotide strategy. At low concentration (1 microM), DMDS modified spontaneous regular spike discharge into clear bursting activity associated with a decrease of the amplitude of the afterhyperpolarization. This effect led us to suspect alterations of calcium-activated potassium currents (IKCa) and [Ca(2+)](i) changes. We showed that DMDS reduced amplitudes of both peak transient and sustained components of the total potassium current. IKCa was confirmed as a target of DMDS by using iberiotoxin, cadmium chloride, and pSlo antisense oligonucleotide. In addition, we showed that DMDS induced [Ca(2+)](i) rise in Fura-2-loaded DUM neurons. Using calcium-free solution, and (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxy-phenyl)ethyl]-acetamide (LOE 908) [an inhibitor of transient receptor potential (TRP)gamma], we demonstrated that TRPgamma initiated calcium influx. By contrast, omega-conotoxin GVIA (an inhibitor of N-type high-voltage-activated calcium channels), did not affect the DMDS-induced [Ca(2+)](i) rise. Finally, the participation of the calcium-induced calcium release mechanism was investigated using thapsigargin, caffeine, and ryanodine. Our study revealed that DMDS-induced elevation in [Ca(2+)](i) modulated IKCa in an unexpected bell-shaped manner via intracellular calcium. In conclusion, DMDS affects multiple targets, which could be an effective way to improve pest control efficacy of fumigation. PMID:17942746

Gautier, Hélène; Auger, Jacques; Legros, Christian; Lapied, Bruno

2008-01-01

135

Circadian rhythms and fractal fluctuations in forearm motion  

NASA Astrophysics Data System (ADS)

Recent studies have shown that the circadian pacemaker --- an internal body clock located in the brain which is normally synchronized with the sleep/wake behavioral cycles --- influences key physiologic functions such as the body temperature, hormone secretion and heart rate. Surprisingly, no previous studies have investigated whether the circadian pacemaker impacts human motor activity --- a fundamental physiologic function. We investigate high-frequency actigraph recordings of forearm motion from a group of young and healthy subjects during a forced desynchrony protocol which allows to decouple the sleep/wake cycles from the endogenous circadian cycle while controlling scheduled behaviors. We investigate both static properties (mean value, standard deviation), dynamical characteristics (long-range correlations), and nonlinear features (magnitude and Fourier-phase correlations) in the fluctuations of forearm acceleration across different circadian phases. We demonstrate that while the static properties exhibit significant circadian rhythms with a broad peak in the afternoon, the dynamical and nonlinear characteristics remain invariant with circadian phase. This finding suggests an intrinsic multi-scale dynamic regulation of forearm motion the mechanism of which is not influenced by the circadian pacemaker, thus suggesting that increased cardiac risk in the early morning hours is not related to circadian-mediated influences on motor activity.

Hu, Kun; Hilton, Michael F.

2005-03-01

136

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

137

A G Protein-Coupled Receptor, groom-of-PDF, Is Required for PDF Neuron Action in Circadian Behavior  

Microsoft Academic Search

Summary The neuropeptide Pigment-Dispersing Factor (PDF) plays a critical role in mediating circadian control of behavior in Drosophila. Here we identify mutants (groom-of-PDF; gop) that display phase-advanced evening activity and poor free-running rhythmicity, phenocopying pdf mutants. In gop mutants, a sponta- neous retrotransposon disrupts a coding exon of a G protein-coupled receptor, CG13758. Disruption of the receptor is accompanied by

Bridget C. Lear; C. Elaine Merrill; Jui-Ming Lin; Analyne Schroeder; Luoying Zhang; Ravi Allada

2005-01-01

138

Circadian dimension and severity of depression.  

PubMed

The cyclic nature of depressive illness, disturbance of diurnal mood variations, and disturbed sleep-wake and physiological rhythms all suggest that dysfunction of the circadian time-keeping system may underlie the pathophysiology of depression. Circadian misalignment of the phase-delayed type appears to be the most common shift in unipolar disorder patients and misalignment between the timing of sleep and the pacemaker is correlated with depressive symptom severity. Profiles of diurnal mood variation are associated with risks of depression severity and may predict response to treatments. As circadian disturbances are at the core of depression, normalizing circadian rhythm may be a fruitful avenue for new therapeutic targets in depression. The innovative antidepressant agomelatine possesses resynchronizing properties that may be related to its original profile and offers an opportunity to achieve our goals in treating depressed people. PMID:22959112

Courtet, Philippe; Olié, Emilie

2012-01-01

139

Bioluminescence Imaging of Individual Fibroblasts Reveals Persistent, Independently Phased Circadian Rhythms of Clock Gene Expression  

Microsoft Academic Search

Circadian (ca. 24 hr) oscillations in expression of mammalian “clock genes” are found not only in the suprachiasmatic nucleus (SCN), the central circadian pacemaker, but also in peripheral tissues [1]. Under constant conditions in vitro, however, rhythms of peripheral tissue explants [2] or immortalized cells [3] damp partially or completely. It is unknown whether this reflects an inability of peripheral

David K. Welsh; Seung-Hee Yoo; Andrew C. Liu; Joseph S. Takahashi; Steve A. Kay

2004-01-01

140

Modulation of metabolic and clock gene mRNA rhythms by pineal and retinal circadian oscillators  

Microsoft Academic Search

Avian circadian organization involves interactions between three neural pacemakers: the suprachiasmatic nuclei (SCN), pineal, and retina. Each of these structures is linked within a neuroendocrine loop to influence downstream processes and peripheral oscillations. However, the contribution of each structure to drive or synchronize peripheral oscillators or circadian outputs in avian species is largely unknown. To explore these interactions in the

Stephen P. Karaganis; Paul A. Bartell; Vikram R. Shende; Ashli F. Moore; Vincent M. Cassone

2009-01-01

141

Periodically-modulated inhibition of living pacemaker neurons--III. The heterogeneity of the postsynaptic spike trains, and how control parameters affect it.  

PubMed

Codings involving spike trains at synapses with inhibitory postsynaptic potentials on pacemakers were examined in crayfish stretch receptor organs by modulating presynaptic instantaneous rates periodically (triangles or sines; frequencies, slopes and depths under, respectively, 5.0 Hz, 40.0/s/s and 25.0/s). Timings were described by interspike and cross-intervals ("phases"); patterns (dispersions, sequences) and forms (timing classes) were identified using pooled graphs (instant along the cycle when a spike occurs vs preceding interval) and return maps (plots of successive intervals). A remarkable heterogeneity of postsynaptic intervals and phases characterizes each modulation. All cycles separate into the same portions: each contains a particular form and switches abruptly to the next. Forms differ in irregularity and predictability: they are (see text) "p:q alternations", "intermittent", "phase walk-throughs", "messy erratic" and "messy stammering". Postsynaptic cycles are asymmetric (hysteresis). This contrasts with the presynaptic homogeneity, smoothness and symmetry. All control parameters are, individually and jointly, strongly influential. Presynaptic slopes, say, act through a postsynaptic sensitivity to their magnitude and sign; when increasing, hysteresis augments and forms change or disappear. Appropriate noise attenuates between-train contrasts, providing modulations are under 0.5 Hz. Postsynaptic natural intervals impose critical time bases, separating presynaptic intervals (around, above or below them) with dissimilar consequences. Coding rules are numerous and have restricted domains; generalizations are misleading. Modulation-driven forms are trendy pacemaker-driven forms. However, dissimilarities, slight when patterns are almost pacemaker, increase as inhibition departs from pacemaker and incorporate unpredictable features. Physiological significance-(1) Pacemaker-driven forms, simple and ubiquitous, appear to be elementary building blocks of synaptic codings, present always but in each case distorted typically. (2) Synapses are prototype: similar behaviours should be widespread, and networks simulations benefit by nonlinear units generating all forms. (3) Relevant to periodic functions are that few variables need be involved in form selection, that distortions are susceptible to noise levels and, if periods are heterogeneous, that simple input cycles impose heterogeneous outputs. (4) Slow Na inactivations are necessary for obtaining complex forms and hysteresis. Formal significance--(1) Pacemaker-driven forms and presumably their modulation-driven counterparts, pertain to universal periodic, intermittent, quasiperiodic and chaotic categories whose formal properties carry physiological connotations. (2) Only relatively elaborate, nonlinear geometric models show all forms; simpler ones, show only alternations and walk-throughs. (3) Bifurcations resemble those of simple maps that can provide useful guidelines. (4) Heterogeneity poses the unanswered question of whether or not the entire cycle and all portions have the same behaviours: therefore, whether trajectories are continuous or have discontinuities and/or singular points. PMID:9722139

Segundo, J P; Vibert, J F; Stiber, M

1998-11-01

142

Circadian Disruption  

PubMed Central

Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted circadian rhythmicity, a prominent feature of modern-day society, promotes the development and/or progression of a wide variety of diseases, including inflammatory, metabolic, and alcohol-associated disorders. This article will discuss the influence of interplay between alcohol consumption and circadian rhythmicity and how circadian rhythm disruption affects immune function and metabolism as well as potential epigenetic mechanisms that may be contributing to this phenomenon.

Voigt, Robin M.; Forsyth, Christopher B.; Keshavarzian, Ali

2013-01-01

143

Continued Evaluation of Cardiac Pacemakers.  

National Technical Information Service (NTIS)

The nuclear powered pacemaker evaluation was designed to characterize the operating characteristics of such pacemakers and identify potential failure mechanisms. More than 30 nuclear powered pacemakers were implanted in dogs and 15 were subjected to high ...

E. E. Brueschke E. F. Uretz R. G. Hauser

1976-01-01

144

Circadian Regulation of A-Type Potassium Currents in the Suprachiasmatic Nucleus  

PubMed Central

In mammals, the precise circadian timing of many biological processes depends on the generation of oscillations in neural activity of pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus. Understanding the ionic mechanisms underlying these rhythms is an important goal of research in chronobiology. Previous work has shown that SCN neurons express A-type potassium currents (IAs), but little is known about the properties of this current in the SCN. We sought to characterize some of these properties, including the identities of IA channel subunits found in the SCN and the circadian regulation of IA itself. In this study, we were able to detect significant hybridization for Shal-related family members 1 and 2 (Kv4.1 and 4.2) within the SCN. In addition, we used Western blot to show that the Kv4.1 and 4.2 proteins are expressed in SCN tissue. We further show that the magnitude of the IA current exhibits a diurnal rhythm that peaks during the day in the dorsal region of the mouse SCN. This rhythm seems to be driven by a subset of SCN neurons with a larger peak current and a longer decay constant. Importantly, this rhythm in neurons in the dorsal SCN continues in constant darkness, providing an important demonstration of the circadian regulation of an intrinsic voltage-gated current in mammalian cells. We conclude that the anatomical expression, biophysical properties, and pharmacological profiles measured are all consistent with the SCN IA current being generated by Kv4 channels. Additionally, these data suggest a role for IA in the regulation of spontaneous action potential firing during the transitions between day/night and in the integration of synaptic inputs to SCN neurons throughout the daily cycle.

Itri, Jason N.; Vosko, Andrew M.; Schroeder, Analyne; Dragich, Joanna M.; Michel, Stephan

2010-01-01

145

Plasticity of the Intrinsic Period of the Human Circadian Timing System  

Microsoft Academic Search

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian

Frank A. J. L. Scheer; Kenneth P. Wright; Richard E. Kronauer; Charles A. Czeisler; Miguel Nicolelis

2007-01-01

146

Acute exposure to 2G phase shifts the rat circadian timing system  

NASA Technical Reports Server (NTRS)

The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cures (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination, but exhibit a 'free-running' condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.

Hoban-Higgins, T. M.; Murakami, D. M.; Tandon, T.; Fuller, C. A.

1995-01-01

147

A Test of the Hypothesis that D2O Affects Circadian Oscillations by Diminishing the Apparent Temperature  

Microsoft Academic Search

The period (tau ) of a circadian pacemaker in the cockroach Leucophaea maderae is a nonmonotonic function of temperature. The slope of the curve (tau as a function of temperature) is negative at 20 degrees and positive at 30 degrees. When these insects are deuterated at 20 degrees and 30 degrees the period (tau ) of the pacemaker lengthens in

Patricia C. Caldarola; Colin S. Pittendrigh

1974-01-01

148

Two Novel doubletime Mutants Alter Circadian Properties and Eliminate the Delay between RNA and Protein in Drosophila  

Microsoft Academic Search

Phosphorylation is an important feature of pacemaker organiza- tion in Drosophila. Genetic and biochemical evidence suggests involvement of the casein kinase I homolog doubletime (dbt )i n the Drosophila circadian pacemaker. We have characterized two novel dbt mutants. Both cause a lengthening of behavioral period and profoundly alter period ( per) and timeless (tim) transcript and protein profiles. The PER

Vipin Suri; Jeffery C. Hall; Michael Rosbash

2000-01-01

149

Circadian oscillators in the epithalamus.  

PubMed

The habenula complex is implicated in a range of cognitive, emotional and reproductive behaviors, and recently this epithalamic structure was suggested to be a component of the brain's circadian system. Circadian timekeeping is driven in cells by the cyclical activity of core clock genes and proteins such as per2/PER2. There are currently no reports of rhythmic clock gene/protein expression in the habenula and therefore the question of whether this structure has an intrinsic molecular clock remains unresolved. Here, using videomicroscopy imaging and photon-counting of a PER2::luciferase (LUC) fusion protein together with multiunit electrophysiological recordings, we tested the endogenous circadian properties of the mouse habenula in vitro. We show that a circadian oscillator is localized primarily to the medial portion of the lateral habenula. Rhythms in PER2:: LUC bioluminescence here are visualized in single cells and oscillations continue in the presence of the sodium channel blocker, tetrodotoxin, indicating that individual cells have intrinsic timekeeping properties. Ependymal cells lining the dorsal third ventricle also express circadian oscillations of PER2. These findings establish that neurons and non-neuronal cells in the epithalamus express rhythms in cellular and molecular activities, indicating a role for circadian oscillators in the temporal regulation of habenula controlled processes and behavior. PMID:20547209

Guilding, C; Hughes, A T L; Piggins, H D

2010-09-15

150

AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation  

Microsoft Academic Search

Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or ``entrainment,'' mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine

Katja A. Lamia; Uma M. Sachdeva; Luciano DiTacchio; Elliot C. Williams; Jacqueline G. Alvarez; Daniel F. Egan; Debbie S. Vasquez; Henry Juguilon; Satchidananda Panda; Reuben J. Shaw; Craig B. Thompson; Ronald M. Evans

2009-01-01

151

Intracellular Calcium Spikes in Rat Suprachiasmatic Nucleus Neurons Induced by BAPTA-Based Calcium Dyes  

PubMed Central

Background Circadian rhythms in spontaneous action potential (AP) firing frequencies and in cytosolic free calcium concentrations have been reported for mammalian circadian pacemaker neurons located within the hypothalamic suprachiasmatic nucleus (SCN). Also reported is the existence of “Ca2+ spikes” (i.e., [Ca2+]c transients having a bandwidth of 10?100 seconds) in SCN neurons, but it is unclear if these SCN Ca2+ spikes are related to the slow circadian rhythms. Methodology/Principal Findings We addressed this issue based on a Ca2+ indicator dye (fluo-4) and a protein Ca2+ sensor (yellow cameleon). Using fluo-4 AM dye, we found spontaneous Ca2+ spikes in 18% of rat SCN cells in acute brain slices, but the Ca2+ spiking frequencies showed no day/night variation. We repeated the same experiments with rat (and mouse) SCN slice cultures that expressed yellow cameleon genes for a number of different circadian phases and, surprisingly, spontaneous Ca2+ spike was barely observed (<3%). When fluo-4 AM or BAPTA-AM was loaded in addition to the cameleon-expressing SCN cultures, however, the number of cells exhibiting Ca2+ spikes was increased to 13?14%. Conclusions/Significance Despite our extensive set of experiments, no evidence of a circadian rhythm was found in the spontaneous Ca2+ spiking activity of SCN. Furthermore, our study strongly suggests that the spontaneous Ca2+ spiking activity is caused by the Ca2+ chelating effect of the BAPTA-based fluo-4 dye. Therefore, this induced activity seems irrelevant to the intrinsic circadian rhythm of [Ca2+]c in SCN neurons. The problems with BAPTA based dyes are widely known and our study provides a clear case for concern, in particular, for SCN Ca2+ spikes. On the other hand, our study neither invalidates the use of these dyes as a whole, nor undermines the potential role of SCN Ca2+ spikes in the function of SCN.

Hong, Jin Hee; Min, Cheol Hong; Jeong, Byeongha; Kojiya, Tomoyoshi; Morioka, Eri; Nagai, Takeharu; Ikeda, Masayuki; Lee, Kyoung J.

2010-01-01

152

21 CFR 870.3670 - Pacemaker charger.  

Code of Federal Regulations, 2010 CFR

...Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a rechargeable pacemaker. (b) Classification....

2012-04-01

153

21 CFR 870.3670 - Pacemaker charger.  

Code of Federal Regulations, 2010 CFR

...Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a rechargeable pacemaker. (b) Classification....

2010-04-01

154

21 CFR 870.3670 - Pacemaker charger.  

Code of Federal Regulations, 2010 CFR

...Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a rechargeable pacemaker. (b) Classification....

2011-04-01

155

A role for the circadian genes in drug addiction  

PubMed Central

Summary 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.

Falcon, Edgardo; McClung, Colleen A.

2009-01-01

156

Local photic entrainment of the retinal circadian oscillator in the absence of rods, cones, and melanopsin.  

PubMed

Synchronization of the mammalian master circadian pacemaker to the daily light/dark cycle is mediated exclusively through retinal photoreceptors. The mammalian retina itself is also a self-sustained circadian oscillator. Here we report that the retinal molecular circadian clock can be entrained by lighting cycles in vitro, but that rods, cones, and melanopsin (Opn4) are not required for this entrainment. In vivo, retinas of Opn4(-/-);rd1/rd1 mice synchronize to light/dark cycles regardless of the phase of the master circadian pacemakers of the suprachiasmatic nuclei or the behavior of the animal. These data demonstrate that the retina uses a separate mechanism for local entrainment of its circadian clock than for entrainment of organism-level rhythmicity. PMID:24843129

Buhr, Ethan D; Van Gelder, Russell N

2014-06-10

157

Electromagnetic Interference on Pacemakers  

PubMed Central

External sources, either within or outside the hospital environment, may interfere with the appropriate function of pacemakers which are being implanted all around the world in current medical practice. The patient and the physician who is responsible for follow-up of the pacing systems may be confronted with some specific problems regarding the various types of electromagnetic interference (EMI). To avoid these unwanted EMI effects one must be aware of this potential problem and need to take some precautions. The effects of EMI on pacemaker function and precautions to overcome some specific problems were discussed in this review article. There are many sources of EMI interacting with pacemakers. Magnetic resonance imaging creates real problem and should be avoided in pacemaker patients. Cellular phones might be responsible for EMI when they were held on the same side with the pacemaker. Otherwise they don't cause any specific type of interaction with pacemakers. Sale security systems are not a problem if one walks through it without lingering in or near it. Patients having unipolar pacemaker systems are prone to develop EMI because of pectoral muscle artifacts during vigorous active physical exercise.

Erdogan, Okan

2002-01-01

158

Circadian rhythms influence hematopoietic stem cells  

PubMed Central

Purpose of review Hematopoiesis is tightly regulated in the bone marrow (BM) through the microenvironment, soluble factors from the circulation and neural inputs from the autonomic nervous system. Most physiological processes are not uniform but rather vary according to the time of day. There is increasing evidence showing the impact of biological rhythms in the traffic of hematopoietic stem cells (HSC) and their proliferation and differentiation capacities. Recent findings Recent evidence supports the role of the sympathetic nervous system (SNS) in the regulation of HSC behavior, both directly and through supporting stromal cells. In addition, the SNS transduces circadian information from the central pacemaker in the brain, the suprachiasmatic nucleus (SCN), to the BM microenvironment, directing circadian oscillations in hematopoiesis and HSC migration. Summary HSC traffic and hematopoiesis do not escape the circadian regulation that control most physiological processes. Clinically, the timing of stem cell harvest or infusion may impact the yield or engraftment, respectively, and may result in better therapeutic outcomes.

Mendez-Ferrer, Simon; Chow, Andrew; Merad, Miriam; Frenette, Paul S.

2014-01-01

159

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.

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

2010-01-01

160

Light-induced suppression of endogenous circadian amplitude in humans  

NASA Technical Reports Server (NTRS)

A recent demonstration that the phase of the human circadian pacemaker could be inverted using an unconventional three-cycle stimulus has led to an investigation of whether critically timed exposure to a more moderate stimulus could drive that oscillator toward its singularity, a phaseless position at which the amplitude of circadian oscillation is zero. It is reported here that exposure of humans to fewer cycles of bright light, centered around the time at which the human circadian pacemaker is most sensitive to light-induced phase shifts, can markedly attenuate endogenous cicadian amplitude. In some cases this results in an apparent loss of rhythmicity, as expected to occur in the region of singularity.

Jewett, Megan; Czeisler, Charles A.; Kronauer, Richard E.

1991-01-01

161

Circadian rhythms and addiction: mechanistic insights and future directions.  

PubMed

Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. PMID:24731209

Logan, Ryan W; Williams, Wilbur P; McClung, Colleen A

2014-06-01

162

Effect of Network Architecture on Synchronization and Entrainment Properties of the Circadian Oscillations in the Suprachiasmatic Nucleus  

PubMed Central

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker. The SCN receives light signals from the retina and controls peripheral circadian clocks (located in the cortex, the pineal gland, the liver, the kidney, the heart, etc.). This hierarchical organization of the circadian system ensures the proper timing of physiological processes. In each SCN neuron, interconnected transcriptional and translational feedback loops enable the circadian expression of the clock genes. Although all the neurons have the same genotype, the oscillations of individual cells are highly heterogeneous in dispersed cell culture: many cells present damped oscillations and the period of the oscillations varies from cell to cell. In addition, the neurotransmitters that ensure the intercellular coupling, and thereby the synchronization of the cellular rhythms, differ between the two main regions of the SCN. In this work, a mathematical model that accounts for this heterogeneous organization of the SCN is presented and used to study the implication of the SCN network topology on synchronization and entrainment properties. The results show that oscillations with larger amplitude can be obtained with scale-free networks, in contrast to random and local connections. Networks with the small-world property such as the scale-free networks used in this work can adapt faster to a delay or advance in the light/dark cycle (jet lag). Interestingly a certain level of cellular heterogeneity is not detrimental to synchronization performances, but on the contrary helps resynchronization after jet lag. When coupling two networks with different topologies that mimic the two regions of the SCN, efficient filtering of pulse-like perturbations in the entrainment pattern is observed. These results suggest that the complex and heterogeneous architecture of the SCN decreases the sensitivity of the network to short entrainment perturbations while, at the same time, improving its adaptation abilities to long term changes.

Hafner, Marc; Koeppl, Heinz; Gonze, Didier

2012-01-01

163

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.

164

Pacemaker lead endocarditis  

PubMed Central

We present a patient with a pacemaker lead endocarditis who showed no signs of pocket infection but with high fever and signs of infection in the routine laboratory tests. A diagnosis of pacemaker lead endocarditis must be considered in all patients with fever and infection parameters who have a pacemaker inserted, not only in the first weeks after implantation but also late after implantation, as long as no other cause of infection has been found. Transthoracal echocardiography alone is not sensitive enough to establish the correct diagnosis. Transoesophageal echocardiography (TEE) is mandatory to demonstrate the presence or absence of a vegetation on a pacemaker lead. ImagesFigure 1Figure 2Figure 3Figure 4

Scheffer, M.; van der Linden, E.; van Mechelen, R.

2003-01-01

165

The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin-3 receptors?  

PubMed

Obesity, insulin resistance and increased propensity for type 2 diabetes and cardiovascular disease result from an imbalance between energy intake and expenditure. The cloning of genes involved in energy homeostasis produced a simple feedback model for the homeostatic regulation of adipose mass. Serum leptin secreted from adipocytes signals nutrient sufficiency, curbing appetite and supporting energy expenditure. A rapid decline in leptin during nutrient scarcity instigates adaptive mechanisms, including increased appetite and reduced energy expenditure. Hypothalamic melanocortin neurons are important mediators of this response, integrating inputs of energy status from leptin with other peripheral signals. While this feedback response prolongs survival during fasting, other mechanisms allowing the prediction of nutrient availability also confer a selective advantage. This adaptation has been commonly studied in rodents using restricted feeding paradigms constraining food intake to limited periods at 24-h intervals. Restricted feeding rapidly elicits rhythmic bouts of activity and wakefulness anticipating food presentation. While the response exhibits features suggesting a clock-like mechanism, the neuromolecular mechanisms governing expression of food anticipatory behaviours are poorly understood. Here we discuss a model whereby melanocortin neurons regulating the homeostatic adaptation to variable caloric availability also regulate inputs into neural networks governing anticipatory rhythms in wakefulness, activity and metabolism. PMID:19849798

Begriche, K; Sutton, G M; Fang, J; Butler, A A

2009-11-01

166

Fibroblast PER2 Circadian Rhythmicity Depends on Cell Density  

PubMed Central

Like neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in the brain, single fibroblasts can function as independent oscillators. In the SCN, synaptic and paracrine signaling among cells creates a robust, synchronized circadian oscillation, whereas there is no evidence for such integration in fibroblast cultures. However, interactions among single-cell fibroblast oscillators cannot be completely excluded, because fibroblasts were not isolated in previous work. In this study, we tested the autonomy of fibroblasts as single-cell circadian oscillators in high and low density culture, by single-cell imaging of cells from PER2::LUC circadian reporter mice. We found greatly reduced PER2::LUC rhythmicity in low density cultures, which could result from lack of either constitutive or rhythmic paracrine signals from neighboring fibroblasts. To discriminate between these two possibilities, we mixed PER2::LUC wild type (WT) cells with non-luminescent, non-rhythmic Bmal1?/? cells, so that density of rhythmic cells was low but overall cell density remained high. In this condition, WT cells showed clear rhythmicity similar to high density cultures. We also mixed PER2::LUC WT cells with non-luminescent, long period Cry2?/? cells. In this condition, WT cells showed a period no different from cells cultured with rhythmic WT cells or non-rhythmic Bmal1?/? cells. In previous work, we found that low K+ suppresses fibroblast rhythmicity, and we and others have found that either low K+ or low Ca2+ suppresses SCN rhythmicity. Therefore, we attempted to rescue rhythmicity of low density fibroblasts with high K+ (21 mM), high Ca2+ (3.6 mM), or conditioned medium. Conditioned medium from high density fibroblast cultures rescued rhythmicity of low density cultures, whereas high K+ or Ca2+ medium did not consistently rescue rhythmicity. These data suggest that fibroblasts require paracrine signals from adjacent cells for normal expression of rhythmicity, but that these signals do not have to be rhythmic, and that rhythmic signals from other cells do not affect the intrinsic periods of fibroblasts.

Noguchi, Takako; Wang, Lexie L.; Welsh, David K.

2013-01-01

167

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

168

Plasticity of the intrinsic period of the human circadian timing system.  

PubMed

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2)) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration. PMID:17684566

Scheer, Frank A J L; Wright, Kenneth P; Kronauer, Richard E; Czeisler, Charles A

2007-01-01

169

Plasticity of the Intrinsic Period of the Human Circadian Timing System  

PubMed Central

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light (?450 lux; ?1.2 W/m2) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.

Scheer, Frank A.J.L.; Wright, Kenneth P.; Kronauer, Richard E.; Czeisler, Charles A.

2007-01-01

170

Effects of neurotensin on discharge rates of rat suprachiasmatic nucleus neurons in vitro.  

PubMed

The neuropeptide neurotensin and two classes of its receptors, the neurotensin receptor-1 and 2, are present in the suprachiasmatic nucleus of the mammalian hypothalamus. The suprachiasmatic nucleus houses the mammalian central circadian pacemaker, but the effects of neurotensin on cellular activity in this circadian pacemaker are unknown. In this study, we examined the effects of neurotensin on the spontaneous discharge rate of rat SCN cells in an in vitro slice preparation. Neurotensin (1-10 microM) increased cell firing rate in approximately 50% of cells tested, while approximately 10% of suprachiasmatic cells tested showed a decrease in firing rate in response to neurotensin. These effects of neurotensin were not altered by the GABA receptor antagonist bicuculline (20 microM) or the glutamate receptor antagonists, D-aminophosphopentanoic acid (50 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). The neurotensin receptor selective antagonists SR48692 and SR142948a (10 microM) failed to antagonise neurotensin responses in the majority of cells examined. Compounds that function as agonists selective for the neurotensin-receptor subtypes 1 and 2, JMV-510 and JMV-431 respectively, elicited neurotensin-like responses in approximately 90% of cells tested. Six out of seven cells tested responded to both JMV-510 and JMV-431. Neuropeptide Y (100nM) treatment of suprachiasmatic nucleus slices was found to elicit profound suppression of neuronal firing rate. Co-application of neurotensin with neuropeptide Y significantly (P<0.05) reduced the duration of the response, as compared to that elicited with neuropeptide Y alone. Together, these results demonstrate for the first time the actions of neurotensin in the suprachiasmatic nucleus and raise the possibility that this neuropeptide may play a role in modulating circadian pacemaker function. PMID:11274786

Coogan, A N; Rawlings, N; Luckman, S M; Piggins, H D

2001-01-01

171

Clinical testing of implanted pacemakers  

Microsoft Academic Search

The function of implanted pacemakers was assessed at a special pacemaker clinic at intervals of three to six months. Measurements of the basic discharge rate of the pacemaker were made and the waveform was recovered from skin electrodes and displayed on an oscilloscope screen. The impulse was photographed from the screen and subsequent waveform analysis was carried out. Reproducible results

Edgar Sowton; Kenneth Gray

1971-01-01

172

Triboelectric simulation of pacemaker malfunction.  

PubMed

We report the occurrence of a triboelectric phenomenon (static electricity) that mimicked malfunction of a contemporary pacemaker by creating an electrocardiograpic artifact virtually identical to the pacemaker stimuli. The diagnosis was established by observing a subtle overshoot of the questionable deflection that was absent from pacemaker stimuli. PMID:12134980

Kahan, S; Miller, C W; Hayes, D L; Barold, S S

2002-07-01

173

Triboelectric simulation of pacemaker malfunction  

Microsoft Academic Search

We report the occurrence of a triboelectric phenomenon (static electricity) that mimicked malfunction of a contemporary pacemaker by creating an electrocardiograpic artifact virtually identical to the pacemaker stimuli. The diagnosis was established by observing a subtle overshoot of the questionable deflection that was absent from pacemaker stimuli.

S. Kahan; C. W. Miller; D. L. Hayes; S. S. Barold

2002-01-01

174

Regulation of circadian rhythms in mammals by behavioral arousal.  

PubMed

Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light-entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID:24773430

Webb, Ian C; Antle, Michael C; Mistlberger, Ralph E

2014-06-01

175

Differential Expression of the Small-Conductance, Calcium Activated Potassium Channel SK3 Is Critical for Pacemaker Control in Dopaminergic Midbrain Neurons  

Microsoft Academic Search

The physiological activity of dopaminergic midbrain (DA) neu- rons is important for movement, cognition, and reward. Altered activity of DA neurons is a key finding in schizophrenia, but the cellular mechanisms have not been identified. Recently, KCNN3, a gene that encodes a member (SK3) of the small- conductance, calcium-activated potassium (SK) channels, has been proposed as a candidate gene for

Jakob Wolfart; Henrike Neuhoff; Oliver Franz; Jochen Roeper

2001-01-01

176

Metabolic compensation and circadian resilience in prokaryotic cyanobacteria.  

PubMed

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

2014-06-01

177

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

178

Reuse of permanent cardiac pacemakers.  

PubMed Central

Cardiac pacemakers are part of a growing group of expensive implantable electronic devices; hospitals in which 100 pacemakers are implanted per year must budget over $300 000 for these devices. This cost represents a considerable burden to health care resources. Since the "life-span" of modern pacemakers often exceeds that of the patients who receive them, the recovery and reuse of these devices seems logical. Pacemakers can be resterilized and tested with current hospital procedures. Reuse should be acceptable under Canadian law, but the manner in which the pacemakers are recovered and the patients selected should follow careful guidelines. Every patient should provide written informed consent before receiving a recovered pacemaker. Properly executed, reuse of pacemakers should provide a high level of health care while maintaining or reducing the cost of these devices.

Rosengarten, M D; Portnoy, D; Chiu, R C; Paterson, A K

1985-01-01

179

Plasticity of Circadian Behavior and the Suprachiasmatic Nucleus Following Exposure to Non24Hour Light Cycles  

Microsoft Academic Search

Period aftereffects are a form of behavioral plasticity in which the free-running period of circadian behavior undergoes experience-dependent changes. It is unclear whether this plasticity is age dependent and whether the changes in behavioral period relate to changes in the SCN or the retina, 2 known circadian pacemakers in mammals. To determine whether these changes vary with age, Per1-luc transgenic

Sara J. Aton; Gene D. Block; Hajime Tei; Shin Yamazaki; Erik D. Herzog

2004-01-01

180

Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis.  

PubMed

Inspiratory and expiratory rhythms in mammals are thought to be generated by pacemaker-like neurons in 2 discrete brainstem regions: pre-Bötzinger complex (preBötC) and parafacial respiratory group (pFRG). How these putative pacemakers or pacemaker networks may interact to set the overall respiratory rhythm in synchrony remains unclear. Here, we show that a pacemakers 2-way "handshake" process comprising pFRG excitation of the preBötC, followed by reverse inhibition and postinhibitory rebound (PIR) excitation of the pFRG and postinspiratory feedback inhibition of the preBötC, can provide a phase-locked mechanism that sequentially resets and, hence, synchronizes the inspiratory and expiratory rhythms in neonates. The order of this handshake sequence and its progression vary depending on the relative excitabilities of the preBötC vs. the pFRG and resultant modulations of the PIR in various excited and depressed states, leading to complex inspiratory and expiratory phase-resetting behaviors in neonates and adults. This parsimonious model of pacemakers synchronization and mutual entrainment replicates key experimental data in vitro and in vivo that delineate the developmental changes in respiratory rhythm from neonates to maturity, elucidating their underlying mechanisms and suggesting hypotheses for further experimental testing. Such a pacemakers handshake process with conjugate excitation-inhibition and PIR provides a reinforcing and evolutionarily advantageous fail-safe mechanism for respiratory rhythmogenesis in mammals. PMID:19008356

Wittmeier, Steffen; Song, Gang; Duffin, James; Poon, Chi-Sang

2008-11-18

181

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

182

Cardiac pacemaker power sources  

Microsoft Academic Search

A review of chemical and radioisotope batteries used in cardiac ; pacemakers is presented. The battery systems are examined in terms of longevity, ; reliability, cost, size and shape, energy density, weight, internal resistance ; versus time, end-of-life voltage, chemical compatibility, and potential failure ; mechanisms. (TFD)

K. A. Gasper; K. E. Fester

1975-01-01

183

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

184

The relationship between nutrition and circadian rhythms in mammals  

Microsoft Academic Search

The master clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus regulates circadian rhythms in mammals. The clock is an intracellular, transcriptional mechanism sharing the same molecular components in SCN neurons and in peripheral cells, such as the liver, intestine, and retina. The circadian clock controls food processing and energy homeostasis by regulating the expression and\\/or activity of

Oren Froy

2007-01-01

185

Candidates for the light entrainment pathway to the circadian clock of the Madeira cockroach Rhyparobia maderae.  

PubMed

The circadian pacemaker controlling locomotor activity rhythms in the Madeira cockroach is located at the accessory medulla (AMe). The ipsi- and contralateral compound eyes provide light input to the AMe, possibly via the ?-aminobutyric acid (GABA)-immunoreactive (-ir) distal tract, which connects the glomeruli of the AMe to the ipsilateral medulla and lamina. To identify possible light-entrainment pathways, double-label immunocytochemistry was performed employing antibodies against GABA, myoinhibitory peptide (MIP), allatotropin (AT) and orcokinin (ORC). While all antisera tested, except the anti-ORC, prominently stained the glomeruli of the AMe, colocalization with anti-GABA was detected neither in the glomeruli nor in the distal tract. However, one median neuron that colocalized GABA-, AT- and MIP-immunoreactivity appeared to connect all glomeruli of the AMe to the medulla and lamina. Furthermore, one distal-frontoventral local neuron with arborizations in all glomeruli of the AMe colocalized anti-AT- and anti-MIP immunoreactivity. As candidates for contralateral light entrainment pathways, one ventromedian and one ventral neuron colocalized MIP- and ORC immunoreactivity, projecting via posterior and anterior commissures. Both branched in the interglomerular region of the AMe, where arborizations co-labeled with anti-ORC- and anti-MIP antisera. A possible role for MIP in light entrainment is supported also by injections of Rhyparobia maderae-specific MIP-2, which generated an all-advance phase-response curve late at night. Future experiments will challenge our hypothesis that GABA-, MIP- and AT-ir neurons provide ipsilateral light entrainment to all glomeruli, while MIP- and ORC-ir neurons carry contralateral light entrainment to the AMe's interglomerular region, either delaying or advancing AMe neurons light-dependently. PMID:24322392

Schendzielorz, Julia; Stengl, Monika

2014-02-01

186

Circadian regulation of cortisol release in behaviorally split golden hamsters.  

PubMed

The master circadian clock located within the hypothalamic suprachiasmatic nucleus (SCN) is necessary for the circadian rhythm of glucocorticoid (GC) release. The pathways by which the SCN sustains rhythmic GC release remain unclear. We studied the circadian regulation of cortisol release in the behaviorally split golden hamster, in which the single bout of circadian locomotor activity splits into two bouts approximately 12 h apart after exposing the animals to constant light conditions. We show that unsplit control hamsters present a single peak of cortisol release that is concomitant with a single peak of ACTH release. In contrast, split hamsters show two peaks of cortisol release that are approximately 12 h appart and are appropriately phased to each locomotor activity bout but surprisingly do not rely on rhythmic release of ACTH. Our results are consistent with a model in which the circadian pacemaker within the SCN regulates the circadian release of GC via input to the hypothalamo-pituitary-adrenal axis and via a second regulatory pathway, which likely involves sympathetic innervation of the adrenal and can operate even in the absence of ACTH circadian rhythmic release. Furthermore, we show that although the overall 24-h cortisol output in split hamsters is lower than in unsplit controls, split hamsters release constant low levels of ACTH. This result suggests that the timing, rather than the absolute amount, of cortisol release is more critical for the induction of negative feedback effects that regulate the hypothalamo-pituitary-adrenal axis. PMID:22128030

Lilley, Travis R; Wotus, Cheryl; Taylor, Daniel; Lee, Jennifer M; de la Iglesia, Horacio O

2012-02-01

187

Circadian Regulation of Lipid Mobilization in White Adipose Tissues  

PubMed Central

In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity-associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, Clock?19, and Bmal1?/? circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis.

Shostak, Anton; Meyer-Kovac, Judit; Oster, Henrik

2013-01-01

188

Effects of circadian disruption on the cardiometabolic system  

Microsoft Academic Search

The presence of day–night variations in cardiovascular and metabolic functioning is well known. However, only recently it\\u000a has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep\\/wake cycle but are\\u000a partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac\\u000a autonomic activity, glucose metabolism and leptin—involved

Melanie Rüger; Frank A. J. L. Scheer

2009-01-01

189

Circadian rhythm disruption in cancer biology.  

PubMed

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

190

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.

Savvidis, Christos; Koutsilieris, Michael

2012-01-01

191

Experimental evidence of a chaotic region in a neural pacemaker  

NASA Astrophysics Data System (ADS)

In this Letter, we report the finding of period-adding scenarios with chaos in firing patterns, observed in biological experiments on a neural pacemaker, with fixed extra-cellular potassium concentration at different levels and taken extra-cellular calcium concentration as the bifurcation parameter. The experimental bifurcations in the two-dimensional parameter space demonstrate the existence of a chaotic region interwoven with the periodic region thereby forming a period-adding sequence with chaos. The behavior of the pacemaker in this region is qualitatively similar to that of the Hindmarsh-Rose neuron model in a well-known comb-shaped chaotic region in two-dimensional parameter spaces.

Gu, Hua-Guang; Jia, Bing; Chen, Guan-Rong

2013-03-01

192

Plasticity and Specificity of the Circadian Epigenome  

PubMed Central

Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of a significant portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate how epigenetic processes are involved in creating transcriptional environments that are permissive to tissue-specific gene expression programs, which work in concert with the circadian machinery. Accumulating data shows that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events. A detailed understanding of the communication cues between the central and peripheral clocks is crucial for a more complete understanding of the circadian system and the multiple levels of control that are implicated in maintaining biological timekeeping.

Masri, Selma; Sassone-Corsi, Paolo

2014-01-01

193

Time’s arrow flies like a bird: Two paradoxes for avian circadian biology  

Microsoft Academic Search

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

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

2009-01-01

194

Circadian System, Sleep and Endocrinology  

PubMed Central

Levels of numerous hormones vary across the day and night. Such fluctuations are not only attributable to changes in sleep/wakefulness and other behaviors but also to a biological timing system governed by the suprachiasmatic nucleus of the hypothalamus. Sleep has a strong effect on levels of some hormones such as growth hormone but little effect on others which are more strongly regulated by the biological timing system (e.g., melatonin). Whereas the exact mechanisms through which sleep affects circulating hormonal levels are poorly understood, more is known about how the biological timing system influences the secretion of hormones. The suprachiasmatic nucleus exerts its influence on hormones via neuronal and humoral signals but it is also now apparent that peripheral cells can rhythmically secrete hormones independent of signals from the suprachiasmatic nucleus. Under normal circumstances, behaviors and the biological timing system are synchronized and consequently hormonal systems are exquisitely regulated. However, many individuals (e.g., shift-workers) frequently undergo circadian misalignment by desynchronizing their sleep/wake cycle from the biological timing system. Recent experiments indicate that circadian misalignment has an adverse effect on metabolic and hormonal factors such as glucose and insulin. Further research is needed to determine the underlying mechanisms that cause the negative effects induced by circadian misalignment. Such research could aid the development of countermeasures for circadian misalignment.

Morris, Christopher J.; Aeschbach, Daniel; Scheer, Frank A.J.L.

2011-01-01

195

In Vivo Monitoring of Multi-Unit Neural Activity in the Suprachiasmatic Nucleus Reveals Robust Circadian Rhythms in Period1?/? Mice  

PubMed Central

The master pacemaker in the suprachiasmatic nucleus (SCN) controls daily rhythms of behavior in mammals. C57BL/6J mice lacking Period1 (Per1?/?) are an anomaly because their SCN molecular rhythm is weak or absent in vitro even though their locomotor activity rhythm is robust. To resolve the contradiction between the in vitro and in vivo circadian phenotypes of Per1?/? mice, we measured the multi-unit activity (MUA) rhythm of the SCN neuronal population in freely-behaving mice. We found that in vivo Per1?/? SCN have high-amplitude MUA rhythms, demonstrating that the ensemble of neurons is driving robust locomotor activity in Per1?/? mice. Since the Per1?/? SCN electrical activity rhythm is indistinguishable from wild-types, in vivo physiological factors or coupling of the SCN to a known or unidentified circadian clock(s) may compensate for weak endogenous molecular rhythms in Per1?/? SCN. Consistent with the behavioral light responsiveness of Per1?/? mice, in vivo MUA rhythms in Per1?/? SCN exhibited large phase shifts in response to light. Since the acute response of the MUA rhythm to light in Per1?/? SCN is equivalent to wild-types, an unknown mechanism mediates enhanced light responsiveness of Per1?/? mice. Thus, Per1?/? mice are a unique model for investigating the component(s) of the in vivo environment that confers robust rhythmicity to the SCN as well as a novel mechanism of enhanced light responsiveness.

Takasu, Nana N.; Pendergast, Julie S.; Olivas, Cathya S.; Yamazaki, Shin; Nakamura, Wataru

2013-01-01

196

A Microcalorimeter for Nondestructive Analysis of Pacemakers and Pacemaker Batteries  

Microsoft Academic Search

A microcalorimeter has been built by the authors and used to measure internal losses in primary pacemaker batteries. Power dissipation of 10-50 ¿W has been measured in new pacemaker batteries, much of which is traceable to innocuous exotherm from continuing curing of plastic materials in the battery. True internal shorts have produced 1000-2000 ¿W of heat. Present noise level is

Wilson Greatbatch; Robert McLean; William Holmes; Curtis Holmes

1979-01-01

197

Effect of photoperiod on clock gene expression and subcellular distribution of PERIOD in the circadian clock neurons of the blow fly Protophormia terraenovae  

Microsoft Academic Search

We examined the effect of photoperiod on the expression of circadian clock genes period (per) and timeless (tim), using quantitative real-time polymerase chain reaction (PCR), and the effect of photoperiod on subcellular distribution\\u000a of PERIOD (PER), using immunocytochemistry, in the blow fly, Protophormia terraenovae. Under both short-day and long-day conditions, the mRNA levels of per and tim in the brain

Fumiaki Muguruma; Shin G. Goto; Hideharu Numata; Sakiko Shiga

2010-01-01

198

Inward-rectifying potassium (Kir) channels regulate pacemaker activity in spinal nociceptive circuits during early life  

PubMed Central

Pacemaker neurons in neonatal spinal nociceptive circuits generate intrinsic burst-firing and are distinguished by a lower “leak” membrane conductance compared to adjacent, non-bursting neurons. However, little is known about which subtypes of leak channels regulate the level of pacemaker activity within the developing rat superficial dorsal horn (SDH). Here we demonstrate that a hallmark feature of lamina I pacemaker neurons is a reduced conductance through inward-rectifying potassium (Kir) channels at physiological membrane potentials. Differences in the strength of inward rectification between pacemakers and non-pacemakers indicate the presence of functionally distinct Kir currents in these two populations at room temperature. However, Kir currents in both groups showed high sensitivity to block by extracellular Ba2+ (IC50 ~ 10 µM), which suggests the presence of ‘classical’ Kir (Kir2.x) channels in the neonatal SDH. The reduced Kir conductance within pacemakers is unlikely to be explained by an absence of particular Kir2.x isoforms, as immunohistochemical analysis revealed the expression of Kir2.1, Kir2.2 and Kir2.3 within spontaneously bursting neurons. Importantly, Ba2+ application unmasked rhythmic burst-firing in ~42% of non-bursting lamina I neurons, suggesting that pacemaker activity is a latent property of a sizeable population of SDH cells during early life. In addition, the prevalence of spontaneous burst-firing within lamina I was enhanced in the presence of high internal concentrations of free Mg2+, consistent with its documented ability to block Kir channels from the intracellular side. Collectively, the results indicate that Kir channels are key modulators of pacemaker activity in newborn central pain networks.

Li, Jie; Blankenship, Meredith L.; Baccei, Mark L.

2013-01-01

199

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.

Zhu, Lirong; Zee, Phyllis C.

2012-01-01

200

Quantification of Circadian Rhythms in Single Cells  

PubMed Central

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber).

Westermark, Pal O.; Welsh, David K.; Okamura, Hitoshi; Herzel, Hanspeter

2009-01-01

201

Circadian Role in Daily Pattern of Cardiovascular Risk  

NASA Astrophysics Data System (ADS)

Numerous epidemiological studies demonstrate that sudden cardiac death, pulmonary embolism, myocardial infarction, and stroke have a 24-hour daily pattern with a broad peak between 9-11am. Such a daily pattern in cardiovascular risk could be attributable to external factors, such as the daily behavior patterns, including sleep-wake cycles and activity levels, or internal factors, such as the endogenous circadian pacemaker. Findings of significant alternations in the temporal organization and nonlinear properties of heartbeat fluctuations with disease and with sleep-wake transitions raise the intriguing possibility that changes in the mechanism of control associated with behavioral sleep-wake transition may be responsible for the increased cardiac instability observed in particular circadian phases. Alternatively, we hypothesize that there is a circadian clock, independent of the sleep-wake cycle, which affects the cardiac dynamics leading to increased cardiovascular risk. We analyzed continuous recordings from healthy subjects during 7 cycles of forced desynchrony routine wherein subjects' sleep-wake cycles are adjusted to 28 hours so that their behaviors occur across all circadian phases. Heartbeat data were divided into one-hour segments. For each segment, we estimated the correlations and the nonlinear properties of the heartbeat fluctuations at the corresponding circadian phase. Since the sleep and wake contributions are equally weighted in our experiment, a change of the properties of the heartbeat dynamics with circadian phase suggest a circadian rhythm. We show significant circadian-mediated alterations in the correlation and nonlinear properties of the heartbeat resembling those observed in patients with heart failure. Remarkably, these dynamical alterations are centered at 60 degrees circadian phase, coinciding with the 9-11am window of cardiac risk.

Ivanov, Plamen Ch.; Hu, Kun; Chen, Zhi; Hilton, Michael F.; Stanley, H. Eugene; Shea, Steven A.

2004-03-01

202

Dose-response relationships for resetting of human circadian clock by light  

NASA Technical Reports Server (NTRS)

Since the first report in unicells, studies across diverse species have demonstrated that light is a powerful synchronizer which resets, in an intensity-dependent manner, endogenous circadian pacemakers. Although it is recognized that bright light (approximately 7,000 to 13,000 lux) is an effective circadian synchronizer in humans, it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (approximately 50-300 lux). It has been proposed that the relationship between the resetting effect of light and its intensity follows a compressive nonlinear function, such that exposure to lower illuminances still exerts a robust effect. We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity (approximately 180 lux) significantly phase-shifts the human circadian pacemaker. Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment.

Boivin, D. B.; Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.

1996-01-01

203

Impaired leukocyte trafficking and skin inflammatory responses in hamsters lacking a functional circadian system.  

PubMed

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

2013-08-01

204

Trends in Cardiac Pacemaker Batteries  

PubMed Central

Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads/electrodes have reduced energy requirements by two orders of magnitude. Micro-electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality, reliability, and longevity. It is reported that about 600,000 pacemakers are implanted each year worldwide and the total number of people with various types of implanted pacemaker has already crossed 3 million. A cardiac pacemaker uses half of its battery power for cardiac stimulation and the other half for housekeeping tasks such as monitoring and data logging. The first implanted cardiac pacemaker used nickel-cadmium rechargeable battery, later on zinc-mercury battery was developed and used which lasted for over 2 years. Lithium iodine battery invented and used by Wilson Greatbatch and his team in 1972 made the real impact to implantable cardiac pacemakers. This battery lasts for about 10 years and even today is the power source for many manufacturers of cardiac pacemakers. This paper briefly reviews various developments of battery technologies since the inception of cardiac pacemaker and presents the alternative to lithium iodine battery for the near future.

Mallela, Venkateswara Sarma; Ilankumaran, V; Rao, N.Srinivasa

2004-01-01

205

Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus).  

PubMed Central

1. Light-induced phase shifts of the circadian rhythm of wheel-running activity were used to measure the photic sensitivity of a circadian pacemaker and the visual pathway that conveys light information to it in the golden hamster (Mesocricetus auratus). The sensitivity to stimulus irradiance and duration was assessed by measuring the magnitude of phase-shift responses to photic stimuli of different irradiance and duration. The visual sensitivity was also measured at three different phases of the circadian rhythm. 2. The stimulus-response curves measured at different circadian phases suggest that the maximum phase-shift is the only aspect of visual responsivity to change as a function of the circadian day. The half-saturation constants (sigma) for the stimulus-response curves are not significantly different over the three circadian phases tested. The photic sensitivity to irradiance (1/sigma) appears to remain constant over the circadian day. 3. The hamster circadian pacemaker and the photoreceptive system that subserves it are more sensitive to the irradiance of longer-duration stimuli than to irradiance of briefer stimuli. The system is maximally sensitive to the irradiance of stimuli of 300 s and longer in duration. A quantitative model is presented to explain the changes that occur in the stimulus-response curves as a function of photic stimulus duration. 4. The threshold for photic stimulation of the hamster circadian pacemaker is also quite high. The threshold irradiance (the minimum irradiance necessary to induce statistically significant responses) is approximately 10(11) photons cm-2 s-1 for optimal stimulus durations. This threshold is equivalent to a luminance at the cornea of 0.1 cd m-2. 5. We also measured the sensitivity of this visual pathway to the total number of photons in a stimulus. This system is maximally sensitive to photons in stimuli between 30 and 3600 s in duration. The maximum quantum efficiency of photic integration occurs in 300 s stimuli. 6. These results suggest that the visual pathways that convey light information to the mammalian circadian pacemaker possess several unique characteristics. These pathways are relatively insensitive to light irradiance and also integrate light inputs over relatively long durations. This visual system, therefore, possesses an optimal sensitivity of 'tuning' to total photons delivered in stimuli of several minutes in duration. Together these characteristics may make this visual system unresponsive to environmental 'noise' that would interfere with the entrainment of circadian rhythms to light-dark cycles.

Nelson, D E; Takahashi, J S

1991-01-01

206

Interactions of the Circadian CLOCK System and the HPA Axis  

PubMed Central

Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with each other at different signaling levels, and dysregulation of either system may lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

Nader, Nancy; Chrousos, George P.; Kino, Tomoshige

2010-01-01

207

Effects of bilateral suprachiasmatic nucleus lesions on the circadian rhythms in a diurnal rodent, the Siberian chipmunk ( Eutamias sibiricus )  

Microsoft Academic Search

Effects of bilateral SCN lesions on the circadian rhythms of wheel-running activity and sleep-waking were examined in a diurnal rodent, the Siberian chipmunk,Eutamias sibiricus. The following results suggest that the SCN is a circadian pacemaker in the Siberian chipmunk:1.Retinohypothalamic projection was established in the chipmunk using HRP as an anterograde tracer (Fig. 1). The projection was bilateral and greater to

Tetsu Sato; Hiroshi Kawamura

1984-01-01

208

Electromagnetic and radiation environment effects on pacemakers  

Microsoft Academic Search

The increase, on one hand, of patients bearing pacemakers for cardiac deficiencies and on the other hand, of the number of cancer patients, increases the probability of several simultaneous therapy needs. Cancer radiation therapy involves specific damages to sensitive electronic devices such as pacemakers. Oncologists demand risk evaluation and rules for applying radiation therapy to cancer patients bearing pacemakers. Pacemaker

J. Mouton; R. Trochet; J. Vicrey; M. Sauvage; B. Chauvenet; A. Ostrovski; E. Leroy; R. Haug; B. Dodinot; F. Joffre

1999-01-01

209

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

210

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.

Beckwith, Esteban J.; Gorostiza, E. Axel; Berni, Jimena; Rezaval, Carolina; Perez-Santangelo, Agustin; Nadra, Alejandro D.; Ceriani, Maria Fernanda

2013-01-01

211

Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.  

PubMed

We compared the period of the rhythm of plasma melatonin, driven by the hypothalamic circadian pacemaker, to in vitro periodicity in cultured peripheral fibroblasts to assess the effects on these rhythms of a polymorphism of PER3 (rs57875989), which is associated with sleep timing. In vitro circadian period was determined using luminometry of cultured fibroblasts, in which the expression of firefly luciferase was driven by the promoter of the circadian gene Arntl (Bmal1). The period of the melatonin rhythm was assessed in a 9-d forced desynchrony protocol, minimizing confounding effects of sleep-wake and light-dark cycles on circadian rhythmicity. In vitro periods (32 participants, 24.61±0.33 h, mean±SD) were longer than in vivo periods (31 participants, 24.16±0.17 h; P<0.0001) but did not differ between PER3 genotypes (P>0.4). Analyses of replicate in vitro assessments demonstrated that circadian period was reproducible within individuals (intraclass correlation=0.62), but in vivo and in vitro period assessments did not correlate (P>0.9). In accordance with circadian entrainment theory, in vivo period correlated with the timing of melatonin (P<0.05) at baseline and with diurnal preference (P<0.05). Individual circadian rhythms can be reliably assessed in fibroblasts but may not correlate with physiological rhythms driven by the central circadian pacemaker. PMID:22371527

Hasan, Sibah; Santhi, Nayantara; Lazar, Alpar S; Slak, Ana; Lo, June; von Schantz, Malcolm; Archer, Simon N; Johnston, Jonathan D; Dijk, Derk-Jan

2012-06-01

212

A circadian neuropeptide PDF in the honeybee, Apis mellifera: cDNA cloning and expression of mRNA.  

PubMed

Pigment-dispersing factor (PDF) is a pacemaker hormone regulating the locomotor rhythm in insects. In the present study, we cloned the cDNAs encoding the Apis PDF precursor protein, and found that there are at least seven different pdf mRNAs yielded by an alternative splicing site and five alternative polyadenylation sites in the 5'UTR and 3'UTR regions. The amino acid sequence of Apis PDF peptide has a characteristic novel amino acid residue, aspargine (Asn), at position 17. Quantitative real-time PCR of total and 5'UTR insertion-type pdf mRNAs revealed, for the first time, that the expression levels change in a circadian manner with a distinct trough at the beginning of night in LD conditions, and at the subjective night under DD conditions. In contrast, the expression level of 5'UTR deletion-type pdf mRNAs was about half of that of the insertion type, and the expression profile failed to show a circadian rhythm. As the expression profile of the total pdf mRNA exhibited a circadian rhythm, transcription regulated at the promoter region was supposed to be controlled by some of the clock components. Whole mount in situ hybridization revealed that 14 lateral neurons at the frontal margin of the optic lobe express these mRNA isoforms. PDF expressing cells examined with a newly produced antibody raised against Apis PDF were also found to have a dense supply of axon terminals in the optic lobes and the central brain. PMID:22132787

Sumiyoshi, Miho; Sato, Seiji; Takeda, Yukimasa; Sumida, Kazunori; Koga, Keita; Itoh, Tsunao; Nakagawa, Hiroyuki; Shimohigashi, Yasuyuki; Shimohigashi, Miki

2011-12-01

213

Dual-chamber cardiac pacemaker tester.  

PubMed

To investigate the operation of dual-chamber cardiac pacemakers, a pacemaker tester is developed that is able to examine pacemaker parameters, demand modes and rate-adaptive modes. The tester generates simplified electrograms and responds to pacemaker pulses in a closed-loop simulation. The authors describe the hardware and the software algorithm of the tester. To demonstrate the capabilities of the tester, four tests are presented, together with their results on a rate-adaptive dual-chamber pacemaker. PMID:9684467

Galuschky, C W; Webster, J G

1998-03-01

214

1978 Pacemaker Newspaper Awards: What Makes a Pacemaker?  

ERIC Educational Resources Information Center

Lists the nine high school and college newspapers, and the one newsmagazine, that won Pacemaker Awards in 1978; discusses characteristics that make each of them outstanding, and provides reproductions of a front page from each publication. (GT)

Brasler, Wayne

1979-01-01

215

Development of a Pacemaker Monitor with Cardiac Simulator.  

National Technical Information Service (NTIS)

A cardiac pacemaker monitoring system was developed for use in testing cardiac pacemakers in RF fields. The system provided for both continuous monitoring of the pacemaker output and simulating normal cardiac activity at the pacemaker leads. Fiber optics ...

T. O. Steiner

1975-01-01

216

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

217

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

Microsoft Academic Search

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

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

2010-01-01

218

Two circadian rhythms in the human electroencephalogram during wakefulness.  

PubMed

The influence of the circadian pacemaker and of the duration of time awake on the electroencephalogram (EEG) was investigated in 19 humans during approximately 40 h of sustained wakefulness. Two circadian rhythms in spectral power density were educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and exhibited a minimum approximately 1 h after the onset of melatonin secretion. The second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and exhibited a minimum close to the body temperature minimum. The latter rhythm showed a close temporal association with the rhythms in subjective alertness, plasma melatonin, and body temperature. In addition, increasing time awake was associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to 20. 0-Hz ranges. It is concluded that the waking EEG undergoes changes that can be attributed to circadian and homeostatic (i.e., sleep-wake dependent) processes. The distinct circadian variations of EEG activity in the theta band and in the high-frequency alpha band may represent electrophysiological correlates of different aspects of the circadian rhythm in arousal. PMID:10600925

Aeschbach, D; Matthews, J R; Postolache, T T; Jackson, M A; Giesen, H A; Wehr, T A

1999-12-01

219

Dissociation of Circadian and Circatidal Timekeeping in the Marine Crustacean Eurydice pulchra  

PubMed Central

Summary Background Tidal (12.4 hr) cycles of behavior and physiology adapt intertidal organisms to temporally complex coastal environments, yet their underlying mechanism is unknown. However, the very existence of an independent “circatidal” clock has been disputed, and it has been argued that tidal rhythms arise as a submultiple of a circadian clock, operating in dual oscillators whose outputs are held in antiphase i.e., ?12.4 hr apart. Results We demonstrate that the intertidal crustacean Eurydice pulchra (Leach) exhibits robust tidal cycles of swimming in parallel to circadian (24 hr) rhythms in behavioral, physiological and molecular phenotypes. Importantly, ?12.4 hr cycles of swimming are sustained in constant conditions, they can be entrained by suitable stimuli, and they are temperature compensated, thereby meeting the three criteria that define a biological clock. Unexpectedly, tidal rhythms (like circadian rhythms) are sensitive to pharmacological inhibition of Casein kinase 1, suggesting the possibility of shared clock substrates. However, cloning the canonical circadian genes of E. pulchra to provide molecular markers of circadian timing and also reagents to disrupt it by RNAi revealed that environmental and molecular manipulations that confound circadian timing do not affect tidal timing. Thus, competent circadian timing is neither an inevitable nor necessary element of tidal timekeeping. Conclusions We demonstrate that tidal rhythms are driven by a dedicated circatidal pacemaker that is distinct from the circadian system of E. pulchra, thereby resolving a long-standing debate regarding the nature of the circatidal mechanism.

Zhang, Lin; Hastings, Michael H.; Green, Edward W.; Tauber, Eran; Sladek, Martin; Webster, Simon G.; Kyriacou, Charalambos P.; Wilcockson, David C.

2013-01-01

220

Dual KaiC-based oscillations constitute the circadian system of cyanobacteria  

PubMed Central

In the cyanobacterium Synechococcus elongatus PCC 7942, the KaiA, KaiB, and KaiC proteins are essential for the generation of circadian rhythms. Both in vivo and in vitro, phosphorylation of KaiC is regulated positively by KaiA and negatively by KaiB and shows circadian rhythmicity. The autonomous circadian cycling of KaiC phosphorylation is thought to be the basic pacemaker of the circadian clock and to control genome-wide gene expression in cyanobacteria. In this study, we found that temperature-compensated circadian oscillations of gene expression persisted even when KaiC was arrested in the phosphorylated state due to kaiA overexpression. Moreover, two phosphorylation mutants showed transcriptional oscillation with a long period. In kaiA-overexpressing and phosphorylation-deficient strains, KaiC oscillated and transient overexpression of phosphorylation-deficient kaiC reset the phase of the rhythm. These results suggest that transcription- and translation-based oscillations in KaiC abundance are also important for circadian rhythm generation in cyanobacteria. Furthermore, at low temperature, cyanobacteria can show circadian rhythms only when both the KaiC phosphorylation cycle and the transcription and translation cycle are intact. Our findings indicate that multiple coupled oscillatory systems based on the biochemical properties of KaiC are important to maintain robust and precise circadian rhythms in cyanobacteria.

Kitayama, Yohko; Nishiwaki, Taeko; Terauchi, Kazuki; Kondo, Takao

2008-01-01

221

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

222

Weakly Circadian Cells Improve Resynchrony  

PubMed Central

The mammalian suprachiasmatic nuclei (SCN) contain thousands of neurons capable of generating near 24-h rhythms. When isolated from their network, SCN neurons exhibit a range of oscillatory phenotypes: sustained or damping oscillations, or arrhythmic patterns. The implications of this variability are unknown. Experimentally, we found that cells within SCN explants recover from pharmacologically-induced desynchrony by re-establishing rhythmicity and synchrony in waves, independent of their intrinsic circadian period We therefore hypothesized that a cell's location within the network may also critically determine its resynchronization. To test this, we employed a deterministic, mechanistic model of circadian oscillators where we could independently control cell-intrinsic and network-connectivity parameters. We found that small changes in key parameters produced the full range of oscillatory phenotypes seen in biological cells, including similar distributions of period, amplitude and ability to cycle. The model also predicted that weaker oscillators could adjust their phase more readily than stronger oscillators. Using these model cells we explored potential biological consequences of their number and placement within the network. We found that the population synchronized to a higher degree when weak oscillators were at highly connected nodes within the network. A mathematically independent phase-amplitude model reproduced these findings. Thus, small differences in cell-intrinsic parameters contribute to large changes in the oscillatory ability of a cell, but the location of weak oscillators within the network also critically shapes the degree of synchronization for the population.

Thoroughman, Kurt A.; Doyle, Francis J.; Herzog, Erik D.

2012-01-01

223

Circadian Clocks and Metabolism  

PubMed Central

Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health.

Marcheva, Biliana; Ramsey, Kathryn M.; Peek, Clara B.; Affinati, Alison; Maury, Eleonore; Bass, Joseph

2014-01-01

224

Inference on periodicity of circadian time series.  

PubMed

Estimation of the period length of time-course data from cyclical biological processes, such as those driven by the circadian pacemaker, is crucial for inferring the properties of the biological clock found in many living organisms. We propose a methodology for period estimation based on spectrum resampling (SR) techniques. Simulation studies show that SR is superior and more robust to non-sinusoidal and noisy cycles than a currently used routine based on Fourier approximations. In addition, a simple fit to the oscillations using linear least squares is available, together with a non-parametric test for detecting changes in period length which allows for period estimates with different variances, as frequently encountered in practice. The proposed methods are motivated by and applied to various data examples from chronobiology. PMID:23743206

Costa, Maria J; Finkenstädt, Bärbel; Roche, Véronique; Lévi, Francis; Gould, Peter D; Foreman, Julia; Halliday, Karen; Hall, Anthony; Rand, David A

2013-09-01

225

Comparison of the effects of aging on 5HT 7 and 5HT 1A receptors in discrete regions of the circadian timing system in hamsters  

Microsoft Academic Search

The circadian timekeeping system exhibits many functional changes with aging, including a loss of sensitivity to time cues such as systemic injections of the serotonergic agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In order to elucidate the neurochemical mechanisms responsible for this age-related loss of sensitivity of the circadian pacemaker to serotonin agonists, the present study used quantitative autoradiography to determine whether aging decreases

Marilyn J Duncan; Joshua Short; Deborah L Wheeler

1999-01-01

226

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

227

Brain circadian oscillators and redox regulation in mammals.  

PubMed

Abstract Significance: Functional states of organisms vary rhythmically with a period of about a day (i.e., circadian). This endogenous dynamic is shaped by day-night alternations in light and energy. Mammalian circadian rhythms are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN), a brain region specialized for timekeeping. These autonomous ?24-h oscillations are cell-based, requiring transcription-translation-based regulation. SCN circadian oscillations include the maintenance of intrinsic rhythms, sensitivities to input signals, and generation of output signals. These change predictably as time proceeds from dawn to day, dusk, and through the night. SCN neuronal excitability, a highly energy-demanding process, also oscillates over ?24?h. The nature of the relationship of cellular metabolism and excitability had been unknown. Recent Advances: Global SCN redox state was found to undergo an autonomous circadian rhythm. Redox state is relatively reduced in daytime, when neuronal activity is high, and oxidized during nighttime, when neurons are relatively inactive. Redox modulates neuronal excitability via tight coupling: imposed reducing or oxidizing shifts immediately alter membrane excitability. Whereas an intact transcription-translation oscillator is necessary for the redox oscillation, metabolic modulation of excitability is too rapid to be under clockwork control. Critical Issues: Our observations lead to the hypothesis that redox state and neuronal activity are coupled nontranscriptional circadian oscillators in SCN neurons. Critical issues include discovering molecular and cellular substrates and functional consequences of this redox oscillator. Future Directions: Understanding interdependencies between cellular energy metabolism, neuronal activity, and circadian rhythms is critical to developing therapeutic strategies for treating neurodegenerative diseases and brain metabolic syndromes. Antioxid. Redox Signal. 20, 2955-2965. PMID:24111727

Gillette, Martha U; Wang, Tongfei A

2014-06-20

228

[Pacemaker-Twiddler's Syndrome (author's transl)].  

PubMed

A case of Pacemaker-Twiddler's Syndrome is presented. Rotation of a permanent pacemaker can result in a capstan effect, and the lead is drawn out of the right ventricle. Fixing thouroughly the pacemaker and the lead should be an useful prophylactic measure. PMID:723748

Kolb, P; Kauffmann, P

1978-11-24

229

Reversible Prolonged Pacemaker Failure Due to Electrocautery  

Microsoft Academic Search

Despite improved technology, permanent pacemakers remain susceptible to electromagnetic interference, including electrocautery. We describe sudden, apparently irreversible output loss in a pacemaker associated with the use of electrocautery, despite standard precautionary measures. When tested by the manufacturer several weeks later, pulse generator function was normal and it was functioning in the “reset” mode. We postulate that pacemaker failure was related

Robert W. Peters; Michael R. Gold

1998-01-01

230

The Neurospora Circadian System  

Microsoft Academic Search

The eukaryotic filamentous fungus Neurospora crassa has proven to be a durable and dependable model system for the analysis of the cellular and molecular bases of circadian rhythms. Pioneering genetic analyses identified clock genes, and beginning with the cloning of frequency (frq), work over the past 2 decades has revealed the molecular basis of a core circadian clock feedback loop

Jay C. Dunlap; Jennifer J. Loros

2004-01-01

231

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

232

Circadian clock system in the pineal gland  

Microsoft Academic Search

The pineal gland is a neuroendocrine organ that functions as a central circadian oscillator in a variety of nonmammalian vertebrates.\\u000a In many cases, the pineal gland retains photic input and endocrinal-output pathways both linked tightly to the oscillator.\\u000a This contrasts well with the mammalian pineal gland equipped only with the output of melatonin production that is subject\\u000a to neuronal regulation

Yoshitaka Fukada; Toshiyuki Okano

2002-01-01

233

Circadian rhythms and fertility.  

PubMed

Circadian rhythms impact on a wide range of physiological systems and this impact extends to fertility, such that disruptions to timing systems can impact upon reproductive capacity. This is highlighted most obviously in mutant mouse models whereby deletion or mutation of single genes results not only in disrupted circadian rhythmicity, but also compromised male and female reproductive function. In this review, we discuss the presence of circadian clocks in female and male reproductive tissues and the role these clocks play in the generation of oestrus cycles, ovulation, sperm generation, implantation and the maintenance of pregnancy. Given the increased incidence of shiftwork and international travel which disrupt circadian rhythmicity, and the increasing prevalence of reproductive technologies whereby early embryo development occurs without external time cues, it is important for us to consider the role of circadian rhythms in fertility. PMID:21872642

Kennaway, David J; Boden, Michael J; Varcoe, Tamara J

2012-02-01

234

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.

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

2002-01-01

235

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.

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

2013-01-01

236

[Wide QRS tachycardia preceded by pacemaker spikes].  

PubMed

The differential diagnosis and therapeutic management of wide QRS tachycardia preceded by pacemaker spike is presented. The pacemaker-mediated tachycardia, tachycardia fibrillo-flutter in patients with pacemakers, and runaway pacemakers, have a similar surface electrocardiogram, but respond to different therapeutic measures. The tachycardia response to the application of a magnet over the pacemaker could help in the differential diagnosis, and in some cases will be therapeutic, as in the case of a tachycardia-mediated pacemaker. Although these conditions are diagnosed and treated in hospitals with catheterization laboratories using the application programmer over the pacemaker, patients presenting in primary care clinic and emergency forced us to make a diagnosis and treat the haemodynamically unstable patient prior to referral. PMID:23768570

Romero, M; Aranda, A; Gómez, F J; Jurado, A

2014-04-01

237

Electrical interference in non-competitive pacemakers  

PubMed Central

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. Images

Sowton, E.; Gray, K.; Preston, T.

1970-01-01

238

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.

1976-01-01

239

The role of the circadian system in fractal neurophysiological control.  

PubMed

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

2013-11-01

240

Lithium pacemaker batteries - an overview  

Microsoft Academic Search

Batteries used as power sources in cardiac pacemakers are expected to have high energy density, long storage and operating life and high reliability. They must be nonhazardous under normal operating as well as abusive conditions. Intensive research activities on the past 10-15 years have resulted in the development of a variety of high energy density batteries using Li as the

C. C. Liang; C. F. Holmes

1980-01-01

241

Development of a two-dimension manifold to represent high dimension mathematical models of the intracellular Mammalian circadian clock.  

PubMed

A new focus for mathematical models of the circadian pacemaker involves the encapsulation within the models of detailed biological processes responsible for generating those circadian rhythms. Representing greater biological detail requires more mathematical equations, which pose a greater challenge for the analysis of such systems. Development of a method that retains the predominant dynamics while still providing biologically detailed information is advantageous. Two high-dimension mathematical models of intracellular mammalian circadian pacemakers, Leloup-Goldbeter and Forger-Peskin, with 19 and 73 differential equations, respectively, have been published. The authors projected each of these high-dimension models onto their respective manifold using proper orthogonal functions (POFs) obtained from the empirical decomposition of the model's phase space to obtain a 2-dimension model. The resulting 2-dimension model, represented by 2 differential equations, predicts most of the salient characteristics of a biological clock including approximately 24-h oscillations, entrainment to an LD cycle, phase response curves, and the amplitude recovery dynamics that emerge following amplitude suppression. The manifold representation simplifies the mathematical analysis, since only 2 variables need to be observed and analyzed to understand the behavior of the biological clock. This reduced model derived from a model based on biological variables can be used for the development and analysis of mathematical models of the coupled mammalian oscillators to understand the dynamics of the integrated circadian pacemaker. PMID:16731662

Indic, Premananda; Gurdziel, Katherine; Kronauer, Richard E; Klerman, Elizabeth B

2006-06-01

242

Serotonin-2C receptor involved serotonin-induced Ca2+ mobilisations in neuronal progenitors and neurons in rat suprachiasmatic nucleus  

PubMed Central

The hypothalamic suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, undergoes serotonergic regulation, but the underlying mechanisms remain obscure. Here, we generated a subclone of an SCN progenitor cell line expressing Ca2+ sensors (SCN2.2YC) and compared its 5-HT receptor signalling with that of rat SCN neurons in brain slices. SCN2.2YC cells expressed 5-HT1A/2A/2B/2C, but not 5A/7, while all six subtypes were expressed in SCN tissues. High K+ or 5-HT increased cytosolic Ca2+ in SCN2.2YC cells. The 5-HT responses were inhibited by ritanserin and SB-221284, but resistant to WAY-100635 and RS-127445, suggesting predominant involvement of 5-HT2C for Ca2+ mobilisations. Consistently, Ca2+ imaging and voltage-clamp electrophysiology using rat SCN slices demonstrated post-synaptic 5-HT2C expression. Because 5-HT2C expression was postnatally increased in the SCN and 5-HT-induced Ca2+ mobilisations were amplified in differentiated SCN2.2YC cells and developed SCN neurons, we suggest that this signalling development occurs in accordance with central clock maturations.

Takeuchi, Kouhei; Mohammad, Shahid; Ozaki, Tomoya; Morioka, Eri; Kawaguchi, Kaori; Kim, Juhyon; Jeong, Byeongha; Hong, Jin Hee; Lee, Kyoung J.; Ikeda, Masayuki

2014-01-01

243

Pacemaker Standard: Labeling Requirements, Performance Requirements, and Terminology for Implantable Artificial Cardiac Pacemakers.  

National Technical Information Service (NTIS)

A pacemaker standard was developed by an AAMI Pacemaker Standards Subcommittee consisting of approximately 40 physicians, clinical engineers, and consulting manufacturers. The Subcommittee was broken down into six working groups: labeling; marking and ide...

1975-01-01

244

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870.3650...Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to...

2009-04-01

245

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...Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to...

2010-04-01

246

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

...function analyzer is an electrically powered device that is used to determine pacemaker function or pacemaker battery function by periodically monitoring an implanted pacemaker's pulse rate and pulse width. The device is noninvasive, and it...

2012-04-01

247

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

...function analyzer is an electrically powered device that is used to determine pacemaker function or pacemaker battery function by periodically monitoring an implanted pacemaker's pulse rate and pulse width. The device is noninvasive, and it...

2010-04-01

248

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

...function analyzer is an electrically powered device that is used to determine pacemaker function or pacemaker battery function by periodically monitoring an implanted pacemaker's pulse rate and pulse width. The device is noninvasive, and it...

2011-04-01

249

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 2009-04-01 false Pacemaker repair or replacement material. ...Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material...

2009-04-01

250

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Pacemaker repair or replacement material. ...Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material...

2010-04-01

251

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 2009-04-01 false Pacemaker lead adaptor. 870.3620 Section 870...Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to...

2009-04-01

252

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 2009-04-01 false Pacemaker service tools. 870.3730 Section...Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as...

2009-04-01

253

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Pacemaker lead adaptor. 870.3620 Section 870...Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to...

2010-04-01

254

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Pacemaker service tools. 870.3730 Section...Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as...

2010-04-01

255

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 false Indirect pacemaker generator function analyzer. 870...Devices § 870.3640 Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker generator function analyzer is...

2009-04-01

256

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2010 CFR

... 2009-04-01 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...

2009-04-01

257

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2010 CFR

... 2010-04-01 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...

2010-04-01

258

Pacemakers—A journey through the years  

Microsoft Academic Search

This is an article on the history of artificial cardiac pacemakers. Before the advent of pacemakers, not much could be done\\u000a for patients who suffered from cardiac asystole and other cardiac rhythm disturbances. Although the concept that an artificial\\u000a pacemaker could be used to stimulate the heart in standstill evolved much earlier, it was not until 1952 that the first

Tarun Mittal

2005-01-01

259

Clinical assessment of pacemaker power sources  

Microsoft Academic Search

The development of power sources for cardiac pacemakers has progressed from a 15-year usage of mercury-zinc batteries to widely used and accepted lithium cells. At present, there are about 6 different types of lithium cells incorporated into commercially distributed pacemakers. The authors reviewed experience over a 5-year period with 1711 mercury-zinc, 130 nuclear (P238) and 1912 lithium powered pacemakers. The

M. Bilitch; V. Parsonnet; S. Furman

1980-01-01

260

A short history on pacemakers.  

PubMed

Artificial pacemakers have taken part or possibly driven many developments in cardiac science and medicine and are therefore a very important story to remember. This 300-year journey of discovery has been contributed to by experts from across the Globe. The essential foundation of knowledge such as basic electrophysiology and applied electrotherapy was built in the 18th century and is now academically and socially accepted. This line of inventions and research has seen: early use of meta-analyses, the initial coming together of medical or bioengineering and the concept of cardiac monitoring--now a mainstay in the hospital care of a patient. In the 21st century pacemaker developments are no longer solely about reducing mortality but improving morbidity. Design developments reduce: discomfort, additional surgeries and invasive procedures. New energy sources have become lighter, smaller and with a longer life span. PMID:24083883

Ward, Catherine; Henderson, Susannah; Metcalfe, Neil H

2013-11-15

261

Altered Rest-Activity Patterns Evolve via Circadian Independent Mechanisms in Cave Adapted Balitorid Loaches  

PubMed Central

Circadian rhythms and rest homeostasis are independent processes, each regulating important components of rest-activity patterns. Evolutionarily, the two are distinct from one another; total rest time is maintained unaffected even when circadian pacemaker cells are ablated. Throughout the animal kingdom, there exists a huge variation in rest-activity patterns, yet it is unclear how these behaviors have evolved. Here we show that four species of balitorid cavefish have greatly reduced rest times in comparison to rest times of their surface relatives. All four cave species retained biological rhythmicity, and in three of the four there is a pronounced 24-hour rhythm; in the fourth there is an altered rhythmicity of 38–40 hours. Thus, consistent changes in total rest have evolved in these species independent of circadian rhythmicity. Taken together, our data suggest that consistent reduction in total rest times were accomplished evolutionarily through alterations in rest homeostasis.

Duboue, Erik R.; Borowsky, Richard L.

2012-01-01

262

TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock.  

PubMed Central

The timeless protein (TIM) is a central component of the circadian pacemaker machinery of the fruitfly Drosophila melanogaster. Both TIM and its partner protein, the period protein PER, show robust circadian oscillations in mRNA and protein levels. Yet the role of TIM in the rhythm generation mechanism is largely unknown. To analyze TIM function, we constructed transgenic flies that carry a heat shock-inducible copy of the timeless gene (tim) in an arrhythmic tim loss-of-function genetic background. When heat shocked, TIM levels in these flies rapidly increased and initiated a molecular cycle of PER accumulation and processing with dynamics very similar to the PER cycle observed in wild-type flies. Analysis of period (per) mRNA levels and transcription uncovered a novel role for TIM in clock regulation: TIM increases per mRNA levels through a post-transcriptional mechanism. Our results suggest positive as well as negative autoregulation in the Drosophila circadian clock.

Suri, V; Lanjuin, A; Rosbash, M

1999-01-01

263

Circadian rhythm in olfactory response in the antennae controlled by the optic lobe in the cockroach.  

PubMed

The olfactory response in antennae of the cockroach, Leucophaea maderae, was investigated by measuring electroantennograms (EAGs) in restrained animals. The amplitude of the EAG response to pulses of ethyl acetate, octanol, or fenchone, exhibited a robust, light entrained, circadian rhythm that persisted at least 14 days in constant darkness. Dilution-response curves measured at the peak and trough of the rhythm indicated there was a 10-fold change in sensitivity. The EAG rhythm was abolished by severing the optic tracts, while entrainment was abolished by ablation of the compound eyes. The results indicate that the circadian system modulates olfactory sensitivity in the antennae and that the rhythm is driven by a circadian pacemaker in the optic lobes that is entrained by photoreceptors in the compound eyes. PMID:12837322

Page, Terry L; Koelling, Erin

2003-07-01

264

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

265

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

266

Cell-autonomous circadian clock of hepatocytes drives rhythms in transcription and polyamine synthesis  

PubMed Central

The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in Met murine hepatocytes (MMH)-D3, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that the cell-autonomous clock can drive many rhythms, and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both cophasic and antiphasic organization within a protein–protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase and spermidine synthase. Metabolic profiling revealed that the enzymatic product of spermidine synthase, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis.

Atwood, Ann; DeConde, Robert; Wang, Susanna S.; Mockler, Todd C.; Sabir, Jamal S. M.; Ideker, Trey; Kay, Steve A.

2011-01-01

267

Lithium-iodine pacemaker cell  

SciTech Connect

The lithium-iodine pacemaker cell is described as supplied by several manufacturers. The features of each design are discussed along with their effect on energy density, self-discharge and shape of the discharge curve. Differences in performance characteristics are related to morphology of the lithium iodine electrolyte and to the form of the cathode. A new, high-drain cell is mentioned which can supply 60 /mu/a/cm/sup 2/. 10 refs.

Schneider, A.A.; Snyder, S.E.; DeVan, T.; Harney, M.J.; Harney, D.E.

1980-01-01

268

Neurochemical Control of Circadian Rhythms.  

National Technical Information Service (NTIS)

We have continued our investigation of the neurochemical systems contained in the circadian clock localized within the suprachiasmatic nucleus (SCN). Our primary focus has been to determine the circadian functions of a subpopulation of SCN interneurons in...

A. H. Elliott

1989-01-01

269

Analysis Method and Experimental Conditions Affect Computed Circadian Phase from Melatonin Data  

PubMed Central

Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P?=?0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used.

Klerman, Hadassa; St. Hilaire, Melissa A.; Kronauer, Richard E.; Gooley, Joshua J.; Gronfier, Claude; Hull, Joseph T.; Lockley, Steven W.; Santhi, Nayantara; Wang, Wei; Klerman, Elizabeth B.

2012-01-01

270

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

271

Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture  

NASA Astrophysics Data System (ADS)

Pacemaker interactions can lead to complex wave dynamics seen in certain types of cardiac arrhythmias. We use experimental and mathematical models of pacemakers in heterogeneous excitable media to investigate how pacemaker interactions can be a mechanism for wave break and reentrant wave dynamics. Embryonic chick ventricular cells are cultured invitro so as to create a dominant central pacemaker site that entrains other pacemakers in the medium. Exposure of those cultures to a potassium channel blocker, E-4031, leads to emergence of peripheral pacemakers that compete with each other and with the central pacemaker. Waves emitted by faster pacemakers break up over the slower pacemaker to form reentrant waves. Similar dynamics are observed in a modified FitzHugh-Nagumo model of heterogeneous excitable media with two distinct sites of pacemaking. These findings elucidate a mechanism of pacemaker-induced reentry in excitable media.

Borek, Bart?omiej; Shajahan, T. K.; Gabriels, James; Hodge, Alex; Glass, Leon; Shrier, Alvin

2012-09-01

272

Circadian dysfunction in a rotenone-induced parkinsonian rodent model.  

PubMed

Parkinson's disease (PD) is a neurodegenerative disorder that also involves circadian rhythm alterations. Modifications of circadian rhythm parameters have been shown to occur in both PD patients and toxin-induced PD animal models. In the latter case, rotenone, a potent inhibitor of mitochondrial complex I (nicotinamide adenine dinucleotide [NADH]-quinone reductase), has been used to elicit degeneration of dopaminergic neurons and development of parkinsonian syndrome. The present work addresses alterations induced by rotenone on both locomotor and body temperature circadian rhythms in rats. Rotenone-treated rats exhibited abnormalities in equilibrium, postural instability, and involuntary movements. Long-term subcutaneous administration of rotenone significantly reduced mean daily locomotor activity in most animals. During rotenone administration, mean body temperatures (BTs) and BT rhythm amplitudes were significantly lower than those observed in the control group. After long-term rotenone administration, the circadian rhythms of both locomotor activity (LA) and BT displayed decreased amplitudes, lower interdaily phase stability, and higher rhythm fragmentation, as compared to the control rats. The magnitude of the LA and BT circadian rhythm alterations induced by rotenone positively correlated with degree of motor impairment. These results indicate that rotenone induces circadian dysfunction in rats through some of the same mechanisms as those responsible for the development of motor disturbances. PMID:22324553

Lax, Pedro; Esquiva, Gema; Esteve-Rudd, Julian; Otalora, Beatriz Baño; Madrid, Juan Antonio; Cuenca, Nicolás

2012-03-01

273

Circadian clocks and inflammation: reciprocal regulation and shared mediators.  

PubMed

The immune system is deeply interconnected with the endogenous 24-h oscillators of the circadian system. Indeed, the connection between these two physiological systems occurs at multiple levels and in both directions. On one hand, various aspects of the immune system show daily rhythms, which appear to be essential for healthy immune maintenance and proper immune response. On the other hand, immune responses cause changes in circadian rhythms, disrupting their delicate balance and manifesting in disease. Indeed, immune challenges cause various time-, gene-, and tissue-specific effects on circadian-regulated factors. This article reviews the possible mediators of the cross talk between the circadian clock and the immune system, in particular the inflammatory pathways. The rhythmic expression of cytokines and their receptors, as well as other rhythmically regulated humoral factors such as glucocorticoids, melatonin, leptin, or prostaglandins, could gate the effects of the immune response on the circadian system. In addition, systemic cues such as body temperature and neuronal connections between the brain and peripheral tissues may underlie the immune-circadian communication. PMID:24687370

Cermakian, Nicolas; Westfall, Susan; Kiessling, Silke

2014-08-01

274

Circadian rhythms in drosophila can be driven by period expression in a restricted group of central brain cells  

Microsoft Academic Search

Neural tissues controlling circadian rhythmicity have been identified in a variety of organisms and are often closely associated with the visual system. In Drosophila, the clock gene period (per), which is required for circadian rhythms, is expressed in many neurons and glia throughout the eye and brain. We asked whether biological rhythms could be generated if per expression were restricted

Leslie B. Vosshall; Michael W. Young

1995-01-01

275

Mangalith: a new lithium pacemaker battery  

Microsoft Academic Search

An original lithium battery system is being developed for pacemaker application. The material used, lithium-manganese dioxide, industrially available at the present time for a variety of electronic applications, has been modified and adapted for pacemaker power requirements. The utilization of a different modification of manganese dioxide offers performance advantages. The cell technology is described and performance comparisons between this new

G. Gerbier; G. Lehmann

1980-01-01

276

Design Overview Of Processor Based Implantable Pacemaker  

Microsoft Academic Search

Implantable pacemaker is a battery operated real time embedded system, which includes software\\/hardware codesign strategy. As it is placed within the heart by surgery, battery life is an important constraint to extend device lifetime. In this paper, pacemaker's functionalities like basic pacing, pulse width, refractory period in VOO mode has been realized using ultralow power processor MSP 430F1611 and IAR

Santosh D. Chede; Kishore D. Kulat

2008-01-01

277

Prediction of battery depletion in implanted pacemakers  

Microsoft Academic Search

By the use of a measuring oscilloscope and the standard electrocardiogram limb leads the degree of battery depletion in an implanted pacemaker can be estimated. A formula based on readings obtained by this means has been used to determine when Devices fixed rate pacemakers should be removed. Laboratory tests show that 90% of their useful life is obtained by this

Geoffrey Davies; Harold Siddons

1973-01-01

278

[An exceptional cause of pacemaker dysfunction].  

PubMed

Twiddler syndrome is a very rare and surprising complication of pacemaker treatment. We report the case of a woman with psychiatric disease who presented two cardiac arrests due to loss of ventricular capture. Finally, pacemaker retropectoral implantation resolves the problem. PMID:21890106

Griffet, V; Lopez, M; Guérard, S

2014-02-01

279

The functional testing of external cardiac pacemakers  

Microsoft Academic Search

In common with all other biomedical equipment, cardiac pacemakers should be routinely tested and serviced. Experience has shown that although they are generally very reliable some faults have occurred that might have been detected by regular testing. A testing protocol is suggested that has two levels, routine tests that check the essential functions of the pacemakers and supplementary tests that

M. P. Watts; A. L. Evans

1988-01-01

280

Pacemaker safety and long-distance running  

PubMed Central

Objective To prove that long-distance running is safe for athletes with pacemaker devices, pacemaker function was evaluated in nine long-distance runners. Method Nine runners participated in a nine-month training programme that involved running for 1000 or 2000 km in preparation for either a full or a half marathon. A professional coach, three cardiologists and a technician — all with running experience — conducted the training and medical checkups. Commercial heart rate monitors were used during training to assess heart rates at rest, and during exercise and long-distance running. Sensing and pacing functions of the pacemaker system were tested during training sessions as well as during the race. In addition, the ChampionChip (a time registration device used in competition) and the Polar heart rate monitor (a widely used self-monitoring device) were tested for possible interference with the pacemaker. Results All nine athletes completed the Amsterdam 2001 half or full marathon without any pacemaker dysfunction. A short survey after two years showed no pacemaker dysfunction. Conclusion Long-distance running is safe for athletes with pacemaker implants. Overall fitness and sufficient endurance training remain the prerequisites for maintaining the condition necessary for successful completion of a marathon regardless of medical status. In our study, it became clear that for patients who had received a pacemaker because of complete heart block, the upper rate of the pacemaker programme needed to be adjusted to 170 to 180 ppm to insure 1:1 atrio-ventricular synchrony during high atrial rates. It is concluded that there is no a priori reason for cardiologists to advise against long-distance running in athletes with pacemakers. Patients with known or suspected structural heart disease should be screened according the recommendations.

Bennekers, J.H.; van Mechelen, R.; Meijer, A.

2004-01-01

281

EMF interference detection utilizing the recording feature of cardiac pacemakers  

Microsoft Academic Search

Electromagnetic (EMF) interference with cardiac pacemakers may occur in various work environments. In the case of interfering external signals, the pacemaker may misinterpret the signal as a heart-related problem and initiate treatment procedures unnecessarily. We evaluated the applicability of the interference recording feature of cardiac pacemakers to identify the interfering sources. The pacemakers were exposed to a wide variety of

Tommi Alanko; Maria Tiikkaja; Harri Lindholm; Maila Hietanen

2011-01-01

282

Dim light melatonin onset (DLMO): A tool for the analysis of circadian phase in human sleep and chronobiological disorders  

Microsoft Academic Search

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that, within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is

Seithikurippu R. Pandi-Perumal; Marcel Smits; Warren Spence; Venkataramanujan Srinivasan; Daniel P. Cardinali; Alan D. Lowe; Leonid Kayumov

2007-01-01

283

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

284

Phase control of ultradian feeding rhythms in the common vole (Microtus arvalis): the roles of light and the circadian system.  

PubMed

In their ultradian (2- to 3-hr) feeding rhythm, common voles show intraindividual synchrony from day to day, as well as interindividual synchrony between members of the population, even at remote distances. This study addresses the question of how resetting of the ultradian rhythm, a prerequisite for such synchronization, is achieved. Common voles were subjected to short light-dark cycles (1 hr darkness with light varying between 0.7 and 2.5 hr); to T cycles (long light-dark cycles in the circadian range--16 hr darkness and 3-13 hr light); to light pulses (15 min) during different circadian and ultradian phases; and to addition of D2O to the drinking water (25%). Short light-dark cycles and D2O were also applied to voles without circadian rhythmicity, after lesions of the suprachiasmatic nuclei. In these experiments, four hypotheses on synchronization of ultradian rhythmicity were tested: (I) synchronization by a direct response to light; (II) synchronization via the circadian system with multiple triggers, here called "cogs," each controlling a single ultradian feeding bout; and (III and IV) synchronization via the circadian system with a single "cog," which resets an ultradian oscillator and either (III) originates directly from the circadian pacemaker, or (IV) is mediated via the overt circadian activity rhythm. Short light-dark cycles failed to entrain ultradian rhythms, either in circadian-rhythmic or in non-circadian-rhythmic voles; light pulses did not cause phase shifts; and in extreme T cycles no stable phase relationship with light could be demonstrated. Thus, Hypothesis I was rejected. Changes in the circadian period (tau) were generated as aftereffects of light pulses, by entrainment in various T cycles, and by the addition of D2O to the drinking water. These changes in tau did not lead to parallel, let alone proportional, changes in the ultradian period. This excluded Hypothesis II. Both in T-cycle experiments and in the D2O experiments with circadian-rhythmic voles, the phase of ultradian feeding bouts was locked to the end of circadian activity rather than to the most prominent marker of the pacemaker, the onset of circadian activity. This was not expected under Hypothesis III, but was consistent with entrainment via activity (Hypothesis IV). On the basis of these experiments, we conclude that the most likely mechanism of ultradian entrainment is that of a light-insensitive ultradian oscillator, reset every dawn by the termination of the activity phase controlled by the circadian pacemaker, which is itself entrained by the light-dark cycle. Neither in circadian-rhythmic nor in non-circadian-rhythmic voles was the period of the feeding rhythm lengthened by administration of D2O. This insensitivity to deuterium is exceptional among biological rhythms. PMID:8369551

Gerkema, M P; Daan, S; Wilbrink, M; Hop, M W; van der Leest, F

1993-01-01

285

Circadian rhythm dysfunction in glaucoma: A hypothesis  

Microsoft Academic Search

The absence of circadian zeitgebers in the social environment causes circadian misalignment, which is often associated with sleep disturbances. Circadian misalignment, defined as a mismatch between the sleep-wake cycle and the timing of the circadian system, can occur either because of inadequate exposure to the light-dark cycle, the most important synchronizer of the circadian system, or reduction in light transmission

Girardin Jean-Louis; Ferdinand Zizi; Douglas R Lazzaro; Arthur H Wolintz

2008-01-01

286

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.

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

2014-01-01

287

Impact of circadian nuclear receptor REV-ERB? on midbrain dopamine production and mood regulation.  

PubMed

The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERB?, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erb? gene or pharmacological inhibition of REV-ERB? activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERB? repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERB? could be targeting in the treatment of circadian rhythm-related affective disorders. PMID:24813609

Chung, Sooyoung; Lee, Eun Jeong; Yun, Seongsik; Choe, Han Kyoung; Park, Seong-Beom; Son, Hyo Jin; Kim, Kwang-Soo; Dluzen, Dean E; Lee, Inah; Hwang, Onyou; Son, Gi Hoon; Kim, Kyungjin

2014-05-01

288

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

289

Universal Pacemaker of Genome Evolution  

PubMed Central

A fundamental observation of comparative genomics is that the distribution of evolution rates across the complete sets of orthologous genes in pairs of related genomes remains virtually unchanged throughout the evolution of life, from bacteria to mammals. The most straightforward explanation for the conservation of this distribution appears to be that the relative evolution rates of all genes remain nearly constant, or in other words, that evolutionary rates of different genes are strongly correlated within each evolving genome. This correlation could be explained by a model that we denoted Universal PaceMaker (UPM) of genome evolution. The UPM model posits that the rate of evolution changes synchronously across genome-wide sets of genes in all evolving lineages. Alternatively, however, the correlation between the evolutionary rates of genes could be a simple consequence of molecular clock (MC). We sought to differentiate between the MC and UPM models by fitting thousands of phylogenetic trees for bacterial and archaeal genes to supertrees that reflect the dominant trend of vertical descent in the evolution of archaea and bacteria and that were constrained according to the two models. The goodness of fit for the UPM model was better than the fit for the MC model, with overwhelming statistical significance, although similarly to the MC, the UPM is strongly overdispersed. Thus, the results of this analysis reveal a universal, genome-wide pacemaker of evolution that could have been in operation throughout the history of life.

Snir, Sagi; Wolf, Yuri I.; Koonin, Eugene V.

2012-01-01

290

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.

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

2010-01-01

291

Pacemakers charging using body energy.  

PubMed

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

292

Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical Implications  

NSDL National Science Digital Library

Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations—including obesity, metabolic syndrome, and cardiovascular disease—by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

Tomoshige Kino (NIH;Eunice Kennedy Shriver National Institute of Child Health and Human Development REV)

2012-10-02

293

Pineal Photoreceptor Cells Are Required for Maintaining the Circadian Rhythms of Behavioral Visual Sensitivity in Zebrafish  

PubMed Central

In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry)] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity.

Li, Xinle; Montgomery, Jake; Cheng, Wesley; Noh, Jung Hyun; Hyde, David R.; Li, Lei

2012-01-01

294

Circadian Clock Regulation of the Cell Cycle in the Zebrafish Intestine  

PubMed Central

The circadian clock controls cell proliferation in a number of healthy tissues where cell renewal and regeneration are critical for normal physiological function. The intestine is an organ that typically undergoes regular cycles of cell division, differentiation and apoptosis as part of its role in digestion and nutrient absorption. The aim of this study was to explore circadian clock regulation of cell proliferation and cell cycle gene expression in the zebrafish intestine. Here we show that the zebrafish gut contains a directly light-entrainable circadian pacemaker, which regulates the daily timing of mitosis. Furthermore, this intestinal clock controls the expression of key cell cycle regulators, such as cdc2, wee1, p21, PCNA and cdk2, but only weakly influences cyclin B1, cyclin B2 and cyclin E1 expression. Interestingly, food deprivation has little impact on circadian clock function in the gut, but dramatically reduces cell proliferation, as well as cell cycle gene expression in this tissue. Timed feeding under constant dark conditions is able to drive rhythmic expression not only of circadian clock genes, but also of several cell cycle genes, suggesting that food can entrain the clock, as well as the cell cycle in the intestine. Rather surprisingly, we found that timed feeding is critical for high amplitude rhythms in cell cycle gene expression, even when zebrafish are maintained on a light-dark cycle. Together these results suggest that the intestinal clock integrates multiple rhythmic cues, including light and food, to function optimally.

Peyric, Elodie; Moore, Helen A.; Whitmore, David

2013-01-01

295

Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical Implications  

PubMed Central

Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations—including obesity, metabolic syndrome, and cardiovascular disease—by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

Kino, Tomoshige

2013-01-01

296

Pacemaker stimulus amplitude alteration without loss of capture: an unusual ECG finding in cardiac tamponade from pacemaker lead perforation.  

PubMed

A variation in pacemaker stimulus amplitude can represent pacemaker system dysfunction from generator malfunction, lead insulation defect, lead fracture, or artefact of digital signal processing of the electrocardiography recorder. Pacemaker lead perforation into the pericardial space typically results in loss of capture which was not demonstrated in our patient. In summary, we report an unusual ECG finding of pacemaker stimulus amplitude alteration without loss of capture in the setting of cardiac tamponade from pacemaker lead perforation. PMID:23830112

Suksaranjit, P; Prasidthrathsint, K

2014-01-01

297

Melatonin, The Pineal Gland and Circadian Rhythms.  

National Technical Information Service (NTIS)

Amniote circadian organization derives from the interaction circadian oscillator and photoreceptors located in the hypothalamic suprachiasmatic nuclei (SCN), the pineal gland and the eyes. In mammals, circadian organization is dominated by the SCN which s...

V. M. Cassone

1992-01-01

298

Melatonin, the Pineal Gland, and Circadian Rhythms.  

National Technical Information Service (NTIS)

Amniote circadian organization derives from the interactions of circadian oscillator and photoreceptors located in the hypothalamic suprachiasmatic nuclei (SCN), the pineal gland, and the eyes. In mammals, circadian organization is dominated by the SCN, w...

V. M. Cassone W. S. Warren D. S. Brooks J. Lu

1993-01-01

299

Criteria for pacemaker explant in patients without a precise indication for pacemaker implantation.  

PubMed

Unnecessary pacemaker implantation may cause significant social and psychological consequences, the inconvenience of periodic office visits, and the expense of pulse generator replacement. Establishing adequate criteria for explantingpacemakers is crucial and has notyet been described. This study presents the results of a study protocol for explanting the pacemaker in patients without a clear indication for pacemaker implantation. Seventy pacemaker users without a clear reason for the implantation were included in the study conducted from August 1986 to November 1998 and were prospectively followed. The investigation consisted of clinical and neurological evaluations, echocardiogram, exercise testing, and tilt table testing. When these tests were negative, the pulse generator energy and stimulation rates were reprogrammed to the lowest values. Periodic Holter monitoring was conducted during follow-up. When asymptomatic for 1 year, patients underwent an electrophysiological evaluation of sinus and atrioventricular junction function and ventricular vulnerability. When the electrophysiological study was negative, pacemaker explantation was performed. Of the 70 patients, 35 had their pacemaker explanted; 3 were excluded due to a positive tilt table test and electrophysiological study, and 3 are waitingfor pacemaker explantation. Mean follow-up after pacemaker explantation was 30.3 months, and all patients remained asymptomatic, exceptfor one patient who died of a noncardiac cause. Critical analysis of pacemaker users without a well-established indication is justified because it may allowpacemaker explant in a significant proportion of these patients, and it may bring considerable social, economic, and psychological benefits. PMID:11990655

Martinelli, Martino; Costa, Roberto; Nishioka, Silvana; Pedrosa, Anísio; Siqueira, Sérgio; Crevelari, Elizabeth; Scanavacca, Maurício; d'Avila, André; Sosa, Eduardo

2002-03-01

300

Circadian Regulation of Glutathione Levels and Biosynthesis in Drosophila melanogaster  

PubMed Central

Circadian clocks generate daily rhythms in neuronal, physiological, and metabolic functions. Previous studies in mammals reported daily fluctuations in levels of the major endogenous antioxidant, glutathione (GSH), but the molecular mechanisms that govern such fluctuations remained unknown. To address this question, we used the model species Drosophila, which has a rich arsenal of genetic tools. Previously, we showed that loss of the circadian clock increased oxidative damage and caused neurodegenerative changes in the brain, while enhanced GSH production in neuronal tissue conferred beneficial effects on fly survivorship under normal and stress conditions. In the current study we report that the GSH concentrations in fly heads fluctuate in a circadian clock-dependent manner. We further demonstrate a rhythm in activity of glutamate cysteine ligase (GCL), the rate-limiting enzyme in glutathione biosynthesis. Significant rhythms were also observed for mRNA levels of genes encoding the catalytic (Gclc) and modulatory (Gclm) subunits comprising the GCL holoenzyme. Furthermore, we found that the expression of a glutathione S-transferase, GstD1, which utilizes GSH in cellular detoxification, significantly fluctuated during the circadian day. To directly address the role of the clock in regulating GSH-related rhythms, the expression levels of the GCL subunits and GstD1, as well as GCL activity and GSH production were evaluated in flies with a null mutation in the clock genes cycle and period. The rhythms observed in control flies were not evident in the clock mutants, thus linking glutathione production and utilization to the circadian system. Together, these data suggest that the circadian system modulates pathways involved in production and utilization of glutathione.

Beaver, Laura M.; Klichko, Vladimir I.; Chow, Eileen S.; Kotwica-Rolinska, Joanna; Williamson, Marisa; Orr, William C.; Radyuk, Svetlana N.; Giebultowicz, Jadwiga M.

2012-01-01

301

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression  

Microsoft Academic Search

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent

Marina M. Bellet; Marquis P. Vawter; Blynn G. Bunney; William E. Bunney; Paolo Sassone-Corsi

2011-01-01

302

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

303

How pervasive are circadian oscillations?  

PubMed

Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems. Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations. Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes. PMID:24794425

Patel, V R; Eckel-Mahan, K; Sassone-Corsi, P; Baldi, P

2014-06-01

304

Biventricular Pacemaker Implantation via the Femoral Vein  

PubMed Central

We report the case of biventricular pacemaker implantation via the femoral vein, in a patient with impossibility of using standard superior vein approach and a contraindication to epicardial lead placement.

Agosti, Sergio; Brunelli, Claudio; Bertero, Giovanni

2012-01-01

305

21 CFR 870.3670 - Pacemaker charger.  

Code of Federal Regulations, 2013 CFR

21 Food and Drugs 8 2013-04-01 2013-04-01... 870.3670 Section 870.3670 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT...used transcutaneously to recharge the batteries of a rechargeable pacemaker....

2013-04-01

306

Electrocautery-induced pacemaker malfunction during surgery  

Microsoft Academic Search

We report a case of electrocautery-induced pacemaker failure that resulted in asystole in a 15-year-old girl scheduled for\\u000a cardiac surgery. Her pacemaker was converted to the asynchronous mode the night before surgery. Electromagnetic interference\\u000a from the unipolar electrocautery caused a reducion in the battery voltage, which allowed the digital circuitry, but not the\\u000a voltage control oscillator (VCO), to work properly.

Devanand Mangar; Glen M. Atlas; Peter B. Kane

1991-01-01

307

Service Life of Domestic Implanted Pacemakers  

Microsoft Academic Search

The results obtained for a group of patients from the database of the Moscow Municipal Center for electrocar-dioctimulation\\u000a were processed. The dates of primary implantation and reimplantation of pacemakers were taken into account. A total of 330\\u000a pacemakers were replaced because of battery discharge. Mean, estimated, warranty, and gamma-percentage service life of two\\u000a domestic models and one foreign model of

I. A. Dubrovskii; E. V. Pervova

2009-01-01

308

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.

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

2008-01-01

309

Effects of systemically applied nAChR?7 agonists and antagonists on light-induced phase shifts of hamster circadian activity rhythms.  

PubMed

Many physiological systems in mammals are linked to the body's master circadian rhythm in the sleep/wake cycle and dysfunctions in this rhythm has been associated with neurological diseases such as major depression, Alzheimer's Disease and schizophrenia. There is some evidence that nicotinic cholinergic input to the master circadian pacemaker, the suprachiasmatic nucleus, may modulate circadian activity rhythms, but data employing in vivo preparations is sparse. Therefore we examined the ability of intraperitoneally applied nicotinic agonists and antagonists relatively selective for the ?7 nicotinic receptor to modulate light-induced phase shifts of hamster circadian wheel running rhythms. Hamsters were maintained in constant darkness and exposed to light pulses early and late in their active period, mimicking dusk and dawn respectively, which elicited phase delays and advances of their circadian wheel running rhythms. The ?7 receptor antagonists bPiDDB (0.03-3mg/kg) and methyllacaconitine (0.1-1mg/kg) inhibited both light- induced phase advances and delays of circadian wheel running rhythms by as much as 75% versus vehicle injections. In contrast, systemic injections of the ?7 agonists PHA 543613 and ABT107, both at 0.156-2.5mg/kg, had no effect on light induced phase advances or delays. Further, ?7 nicotinic receptors were identified in the hamster suprachiasmatic nucleus using an antibody that recognizes ?7 nicotinic receptors. These results clearly identify the ability of ?7 nicotinic receptor antagonists to inhibit light-entrainment of the hamster circadian pacemaker. Therefore, nicotinic compounds may be useful for the treatment of circadian dysfunction associated with neurological diseases. PMID:24388152

Gannon, Robert L; Garcia, David A; Millan, Mark J

2014-06-01

310

Sleep and circadian rhythms  

NASA Technical Reports Server (NTRS)

Three interacting processes are involved in the preservation of circadian rhythms: (1) endogenous rhythm generation mechanisms, (2) entrainment mechanisms to keep these rhythms 'on track', and (3) exogenous masking processes stemming from changes in environment and bahavior. These processes, particularly the latter two, can be dramatically affected in individuals of advanced age and in space travelers, with a consequent disruption in sleep and daytime functioning. This paper presents results of a phase-shift experiment investigating the age-related effects of the exogeneous component of circadian rhythms in various physiological and psychological functions by comparing these functions in middle aged and old subjects. Dramatic differences were found between the two age groups in measures of sleep, mood, activation, and performance efficiency.

Monk, Timothy H.

1991-01-01

311

Membrane properties and synaptic inputs of suprachiasmatic nucleus neurons in rat brain slices.  

PubMed Central

1. Whole-cell recordings were made from 390 neurons of the suprachiasmatic nucleus (SCN) in horizontal brain slices during different portions of the circadian day. The locomotor activity of the rats was measured prior to the preparation of brain slices to insure that each rat was entrained to a 12 h-12 h light-dark cycle. 2. The mean input conductance was 42% higher (1.58 nS) in neurons recorded near the subjective dawn than those (1.11 nS) recorded near the subjective dusk. The current required to hold the neurons at -60 mV also showed a circadian variation with a peak in the middle of the subjective day and a nadir in the middle of the subjective night. Analysis of the variations in the input conductance and the holding current at -60 mV suggested that at least two ion conductances are involved in the pacemaking of the circadian rhythms. 3. Voltage-clamped SCN neurons often had both outward and inward spontaneous postsynaptic currents. The outward currents were blocked by bicuculline but not by strychnine, and were identified as IPSCs mediated by GABAA receptors. The inward currents were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and were identified as EPSCs mediated by glutamate. Most spontaneous synaptic currents were miniature currents but action potential-dependent large events were seen more often in IPSCs than in EPSCs. 4. Stimulation of the optic nerve or chiasm usually evoked a monosynaptic EPSC which was mediated by both NMDA and non-NMDA receptors. In 13% of cells, optic nerve stimulation evoked an outward current or an inward current followed by an outward current; all the evoked currents were blocked by 4-aminophosphonovaleric acid (APV) and CNQX whereas the outward current only was blocked by bicuculline, suggesting involvement of an inhibitory interneuron. 5. SCN neurons sum the excitatory inputs from both optic nerves; on average each SCN cell receives innervation from at least 4.8 retinohypothalamic tract (RHT) axons. 6. Focal stimulation in the vicinity of the recorded neuron revealed that nearly all SCN neurons receive local or extranuclear GABAergic inputs operating via GABAA receptors. The EPSCs activated by such stimulation were not significantly different in amplitude and pharmacological properties from those induced by RHT stimulation. 7. One hundred and one neurons were labelled with neurobiotin during whole-cell recording. Based on the dendritic structures, four types of SCN neurons (monopolar, radial, simple bipolar and curly bipolar) were identified. The curly bipolar cells had a higher membrane conductance, holding current and hyperpolarization-activated current (Ih) amplitude than the other neuronal types. Radial neurons did not respond to optic nerve stimulation, which activated EPSCs in the other cell types. Images Figure 4 Figure 10 Figure 11

Jiang, Z G; Yang, Y; Liu, Z P; Allen, C N

1997-01-01

312

Entrainment of Circadian Programs  

Microsoft Academic Search

Of the three defining properties of circadian rhythmicity—persisting free-running rhythm, temperature compensation, and entrainment—the last is often poorly under- stood by many chronobiologists. This paper gives an overview of entrainment. Where have we been? Where are we now? Whence should we be going? Particular emphasis is given to a discussion of the Discrete vs. Continuous models for entrainment. We provide

Carl Hirschie Johnson; Jeffrey A. Elliott; Russell Foster

2003-01-01

313

Sudden pain on pacemaker pocket followed by explosion in a patient with a permanent pacemaker.  

PubMed

An 81-year-old woman with a mercury-zinc powered permanent pacemaker experienced the sudden pain on her pacemaker pocket followed by an explosion. We are aware of no other report of the spontaneous and symptomatic bursting of a generator battery with fracture of the pulse generator capsule. PMID:3816328

Ruiz-Santana, S; Aguado-Bourrey, J M; Martin-Rodriguez, A; Perez-Arriaga, M

1987-03-01

314

The Circadian System Is a Target and Modulator of Prenatal Cocaine Effects  

PubMed Central

Background Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. Methodology and Principle Findings Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH) and neurotransmission (dopamine transporter, zDAT). Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR), demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1) and genes encoding melatonin receptors (zMelR) that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors. Conclusions/Significance These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily variation in these effects of cocaine and their attenuation by melatonin suggest a potential prophylactic or therapeutic role for circadian factors in prenatal cocaine exposure.

Shang, Eva H.; Zhdanova, Irina V.

2007-01-01

315

Circadian disorganization alters intestinal microbiota.  

PubMed

Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases. PMID:24848969

Voigt, Robin M; Forsyth, Christopher B; Green, Stefan J; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H; Turek, Fred W; Keshavarzian, Ali

2014-01-01

316

Circadian timing in cancer treatments.  

PubMed

The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments. PMID:20055686

Lévi, Francis; Okyar, Alper; Dulong, Sandrine; Innominato, Pasquale F; Clairambault, Jean

2010-01-01

317

Circadian Disorganization Alters Intestinal Microbiota  

PubMed Central

Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases.

Voigt, Robin M.; Forsyth, Christopher B.; Green, Stefan J.; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H.; Turek, Fred W.; Keshavarzian, Ali

2014-01-01

318

Improving melatonin circadian phase estimates  

Microsoft Academic Search

The quality and quantity of sleep is to a large extent determined by whether the sleep period is in alignment with the most favor- able circadian time window for sleep. Misalignment results in compromised sleep. In order to determine this circadian time window, the 24-h profile of melatonin secretion is generally considered to provide the most optimal estimate. Melatonin secretion

Eus J. W. Van Someren; Elsbeth Nagtegaal

2007-01-01

319

Improving melatonin circadian phase estimates  

Microsoft Academic Search

The quality and quantity of sleep is to a large extent determined by whether the sleep period is in alignment with the most favorable circadian time window for sleep. Misalignment results in compromised sleep. In order to determine this circadian time window, the 24-h profile of melatonin secretion is generally considered to provide the most optimal estimate. Melatonin secretion occurs

Eus J. W. Van Someren; Elsbeth Nagtegaal

2007-01-01

320

Disrupted circadian rhythms in VIP and PHI-deficient mice  

Microsoft Academic Search

rhythms in VIP- and PHI-deficient mice. Am J Physiol Regul Integr Comp Physiol 285: R939-R949, 2003. First published July 10, 2003; 10.1152\\/ajpregu.00200.2003.—The related neuropeptides vasoactive intestinal peptide (VIP) and pep- tide histidine isoleucine (PHI) are expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN), but their function in the regulation of circadian rhythms is unknown. To study

Christopher S. Colwell; Stephan Michel; Jason Itri; Williams Rodriguez; J. Tam; Vincent Lelievre; Zhou Hu; X. Liu; James A. Waschek

321

Functional Identification of the Mouse Circadian Clock Gene by Transgenic BAC Rescue  

PubMed Central

Summary As a complementary approach to positional cloning, we used in vivo complementation with bacterial artificial chromosome (BAC) clones expressed in transgenic mice to identify the circadian Clock gene. A 140 kb BAC transgene completely rescued both the long period and the loss-of-rhythm phenotypes in Clock mutant mice. Analysis with overlapping BAC transgenes demonstrates that a large transcription unit spanning “100,000 base pairs is the Clock gene and encodes a novel basic–helix-loop-helix–PAS domain protein. Overexpression of the Clock transgene can shorten period length beyond the wild-type range, which provides additional evidence that Clock is an integral component of the circadian pacemaking system. Taken together, these results provide a proof of principle that “cloning by rescue” is an efficient and definitive method in mice.

Antoch, Marina P.; Song, Eun-Joo; Chang, Anne-Marie; Vitaterna, Martha Hotz; Zhao, Yaliang; Wilsbacher, Lisa D.; Sangoram, Ashvin M.; King, David P.; Pinto, Lawrence H.; Takahashi, Joseph S.

2013-01-01

322

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

323

Circadian rhythms, sleep, and the menstrual cycle  

Microsoft Academic Search

Women with ovulatory menstrual cycles have a circadian rhythm superimposed on the menstrual-associated rhythm; in turn, menstrual events affect the circadian rhythm. In this paper, we review circadian rhythms in temperature, selected hormone profiles, and sleep–wake behavior in healthy women at different phases of the menstrual cycle. The effects on menstrual cycle rhythmicity of disrupted circadian rhythms, for example, with

Fiona C. Baker; Helen S. Driver

2007-01-01

324

Real-time monitoring of circadian clock oscillations in primary cultures of mammalian cells using Tol2 transposon-mediated gene transfer strategy  

PubMed Central

Background The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between circadian oscillator and physiological functions in peripheral tissues. However, it is still difficult to investigate the molecular oscillator in primary culture cells. Results In this study, we used a novel Tol2 transposon based Dbp promoter or Bmal1 promoter driven luciferase reporter vector system to detect and analyze the intrinsic molecular oscillator in primary culture cells (mouse embryonic fibroblasts, fetal bovine heart endothelial cells and rat astrocytes). The results showed circadian molecular oscillations in all examined primary culture cells. Moreover, the phase relationship between Dbp promoter driven and Bmal1 promoter driven molecular rhythms were almost anti-phase, which suggested that these reporters appropriately read-out the intrinsic cellular circadian clock. Conclusions Our results indicate that gene transfer strategy using the Tol2 transposon system of a useful and safe non-viral vector is a powerful tool for investigating circadian rhythms in peripheral tissues.

2010-01-01

325

Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders  

PubMed Central

Recent evidence shows that the temporal alignment between the sleep-wake cycle and the circadian pacemaker affects self-assessment of mood in healthy subjects. Despite the differences in affective state between healthy subjects and patients with psychiatric disorders, these results have implications for analyzing diurnal variation of mood in unipolar and bipolar affective disorders and sleep disturbances in other major psychiatric conditions such as chronic schizophrenia. In a good proportion of patients with depression, mood often improves over the course of the day; an extension of waking often has an antidepressant effect. Sleep deprivation has been described as a treatment for depression for more than 30 years, and approximately 50% to 60% of patients with depression respond to this approach, especially those patients who report that their mood improves over the course of the day. The mechanisms by which sleep deprivation exerts its antidepressant effects are still controversial, but a reduction in rapid eye movement sleep (REM sleep), sleep pressure and slow-wave sleep (SWS), or a circadian phase disturbance, have been proposed. Although several studies support each of these hypotheses, none is sufficient to explain all observations reported to date. Unfortunately, the disturbed sleep-wake cycle or behavioural activities of depressed patients often explain several of the abnormalities reported in the diurnal rhythms of these patients. Thus, protocols that specifically manipulate the sleep-wake cycle to unmask the expression of the endogenous circadian pacemaker are greatly needed. In chronic schizophrenia, significant disturbances in sleep continuity, REM sleep, and SWS have been consistently reported. These disturbances are different from those observed in depression, especially with regard to REM sleep. Circadian phase abnormalities in schizophrenic patients have also been reported. Future research is expected to clarify the nature of these abnormalities. Images Fig. 1

Boivin, DB

2000-01-01

326

Diurnal rhythm and stress regulate dendritic architecture and spine density of pyramidal neurons in the rat infralimbic cortex  

Microsoft Academic Search

The medial prefrontal cortex (mPFC) participates in several higher order cognitive functions and is involved in the regulation of the stress response. The infralimbic cortex (ILC), the most ventral part of the mPFC, receives a strong afferent input from the master circadian pacemaker, the suprachiasmatic nucleus. This fact raises the possibility that, similarly to stress, the diurnal rhythm may affect

Claudia Perez-Cruz; Mária Simon; Gabriele Flügge; Eberhard Fuchs; Boldizsár Czéh

2009-01-01

327

Calcium Homeostatasis and Mitochondrial Dysfunction in Dopaminergic Neurons of the Substantia Nigra.  

National Technical Information Service (NTIS)

Key Research Accomplishments: the discovery that calcium entry through L-type channels during normal pacemaking elevates the sensitivity of SNc dopaminergic neurons to toxins; the discovery that L-type calcium channels participate in but are not necessary...

D. J. Surmeier

2010-01-01

328

Pacemaker leads: performance and progress.  

PubMed

Pacing leads remain the "weaker link" of the permanent pacing system. Lead failure has been an issue since the beginning of implantable pacemaker therapy. Modern electronics have brought about considerable progress in pacing technology, but lead design has been slower to evolve and problems persist. IS-1 standardization must be considered a significant advance, but some issues regarding IS-1 standardization persist and have been the cause of some compatibility problems. With respect to lead insulation, silicone has proved to offer total reliability for > 30 years. In the search for better handling characteristics, polyurethane 80A was employed for bipolar leads, but it failed to demonstrate satisfactory insulating properties. New insulation materials, such as ethylene-fluoro-ethylene (ETFE), and coated wire technology look promising, having shown 99.32% survival at 5-year follow-up. Reliability is the main objective in lead design, but leads should provide low battery consumption as well. Low coil resistance, with high electrode impedance in steroid-eluting leads, is the standard at present. Low polarization is a desirable property for 2 main reasons: (1) in conjunction with low-threshold leads, it decreases battery consumption; and (2) it allows capture detection and, therefore, safer pacing at low battery consumption. Lead tip design as well as pacing pulse configuration can influence polarization. PMID:10089864

de Voogt, W G

1999-03-11

329

Pacemaker phase shift in the absence of neural activity in guinea-pig stomach: a microelectrode array study  

PubMed Central

Gastrointestinal (GI) motility is well organized. GI muscles act as a functional syncytium to achieve physiological functions under the control of neurones and pacemaker cells, which generate basal spontaneous pacemaker electrical activity. To date, it is unclear how spontaneous electrical activities are coupled, especially within a micrometre range. Here, using a microelectrode array, we show a spatio-temporal analysis of GI spontaneous electrical activity. The muscle preparations were isolated from guinea-pig stomach, and fixed in a chamber with an array of 8 × 8 planar multielectrodes (with 300 ?m in interpolar distance). The electrical activities (field potentials) were simultaneously recorded through a multichannel amplifier system after high-pass filtering at 0.1 Hz. Dihydropyridine Ca2+ channel antagonists are known to differentiate the electrical pacemaker activity of interstitial cells of Cajal (ICCs) by suppressing smooth muscle activity. In the presence of nifedipine, we observed spontaneous electrical activities that were well synchronized over the array area, but had a clear phase shift depending on the distance. The additional application of tetrodotoxin (TTX) had little effect on the properties of the electrical activity. Furthermore, by constructing field potential images, we visualized the synchronization of pacemaker electrical activities resolving phase shifts that were measurable over several hundred micrometres. The results imply a phase modulation mechanism other than neural activity, and we postulate that this mechanism enables smooth GI motility. In addition, some preparations clearly showed plasticity of the pacemaker phase shift.

Nakayama, Shinsuke; Shimono, Ken; Liu, Hong-Nian; Jiko, Hideyasu; Katayama, Noburu; Tomita, Tadao; Goto, Kazunori

2006-01-01

330

Ischemic stroke after cardiac pacemaker implantation in sick sinus syndrome  

Microsoft Academic Search

The risk of embolic stroke during sick sinus syndrome before cardiac pacemaker insertion is substantial, but stroke after pacemaker insertion has not been well studied. We observed 10 sick sinus syndrome patients who developed an ischemic stroke 4 days to 112 months after pacemaker insertion. Nine patients represented 6% of the 156 ischemic stroke patients observed during a 30-month period.

Marc Fisher; Carlos S. Kase; Barbara Stelle; Mills Roger M. Jr

1988-01-01

331

Antibiotic prophylaxis in permanent pacemaker implantation: a prospective randomised trial  

Microsoft Academic Search

BACKGROUND--Pacemaker pocket infection is a potentially serious problem after permanent pacemaker implantation. Antibiotic prophylaxis is commonly prescribed to reduce the incidence of this complication, but current trial evidence of its efficacy is conflicting. A large prospective randomised trial was therefore performed of antibiotic prophylaxis in permanent pacemaker implantation. The intention was firstly to determine whether antibiotic prophylaxis is efficacious in

J P Mounsey; M J Griffith; M Tynan; F K Gould; A F MacDermott; R G Gold; R S Bexton

1994-01-01

332

Dopaminergic Regulation of Circadian Food Anticipatory Activity Rhythms in the Rat  

PubMed Central

Circadian activity rhythms are jointly controlled by a master pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) and by food-entrainable circadian oscillators (FEOs) located elsewhere. The SCN mediates synchrony to daily light-dark cycles, whereas FEOs generate activity rhythms synchronized with regular daily mealtimes. The location of FEOs generating food anticipation rhythms, and the pathways that entrain these FEOs, remain to be clarified. To gain insight into entrainment pathways, we developed a protocol for measuring phase shifts of anticipatory activity rhythms in response to pharmacological probes. We used this protocol to examine a role for dopamine signaling in the timing of circadian food anticipation. To generate a stable food anticipation rhythm, rats were fed 3h/day beginning 6-h after lights-on or in constant light for at least 3 weeks. Rats then received the D2 agonist quinpirole (1 mg/kg IP) alone or after pretreatment with the dopamine synthesis inhibitor ?-methylparatyrosine (AMPT). By comparison with vehicle injections, quinpirole administered 1-h before lights-off (19h before mealtime) induced a phase delay of activity onset prior to the next meal. Delay shifts were larger in rats pretreated with AMPT, and smaller following quinpirole administered 4-h after lights-on. A significant shift was not observed in response to the D1 agonist SKF81297. These results provide evidence that signaling at D2 receptors is involved in phase control of FEOs responsible for circadian food anticipatory rhythms in rats.

Smit, Andrea N.; Patton, Danica F.; Michalik, Mateusz; Opiol, Hanna; Mistlberger, Ralph E.

2013-01-01

333

Distribution of circadian photoreceptors in the compound eye of the cricket Gryllus bimaculatus.  

PubMed

Adult male crickets (Gryllus bimaculatus) show a nocturnal circadian locomotor rhythm, which is driven by the pacemaker in the optic lamina-medulla complex and synchronizes to the light-dark (LD) cycle received by the compound eye. To see whether there was any specially differentiated circadian photoreceptor area in the eye, we examined the effect of a partial reduction of various areas of the compound eye, in addition to a removal of the contralateral optic lamina-medulla-compound eye complex, on entrainability of the locomotor rhythm. All operated animals showed a response to the LD cycle in their locomotor rhythm, no matter which area of the eye was left intact: They either stably entrained to an LD cycle or showed a sign of weak entrainment. The capacity for stable entrainment was still retained when only 262 ommatidia were left. Transient cycles needed for re-entrainment, following a 6-hr phase advance of the LD cycle, were measured in 20 reduced-eye animals showing clear stable entrainment. They were in inverse proportion to the number of ommatidia in the reduced eye: The fewer ommatidia there were, the more transient cycles were observed (r = -0.76, p less than 0.001). These results suggest that almost the whole area of the compound eye may contain circadian photoreceptors, and that the photic information from each ommatidium may additively affect the circadian clock to entrain via neural integration mechanisms. PMID:2133138

Tomioka, K; Okada, Y; Chiba, Y

1990-01-01

334

Human skin keratinocytes, melanocytes, and fibroblasts contain distinct circadian clock machineries.  

PubMed

Skin acts as a barrier between the environment and internal organs and performs functions that are critical for the preservation of body homeostasis. In mammals, a complex network of circadian clocks and oscillators adapts physiology and behavior to environmental changes by generating circadian rhythms. These rhythms are induced in the central pacemaker and peripheral tissues by similar transcriptional-translational feedback loops involving clock genes. In this work, we investigated the presence of functional oscillators in the human skin by studying kinetics of clock gene expression in epidermal and dermal cells originating from the same donor and compared their characteristics. Primary cultures of fibroblasts, keratinocytes, and melanocytes were established from an abdominal biopsy and expression of clock genes following dexamethasone synchronization was assessed by qPCR. An original mathematical method was developed to analyze simultaneously up to nine clock genes. By fitting the oscillations to a common period, the phase relationships of the genes could be determined accurately. We thereby show the presence of functional circadian machinery in each cell type. These clockworks display specific periods and phase relationships between clock genes, suggesting regulatory mechanisms that are particular to each cell type. Taken together, our data demonstrate that skin has a complex circadian organization. Oscillators are present not only in fibroblasts but also in epidermal keratinocytes and melanocytes and are likely to act in coordination to drive rhythmic functions within the skin. PMID:22627494

Sandu, Cristina; Dumas, Marc; Malan, André; Sambakhe, Diariétou; Marteau, Clarisse; Nizard, Carine; Schnebert, Sylvianne; Perrier, Eric; Challet, Etienne; Pévet, Paul; Felder-Schmittbuhl, Marie-Paule

2012-10-01

335

Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork.  

PubMed

Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers. PMID:22629359

Barclay, Johanna L; Husse, Jana; Bode, Brid; Naujokat, Nadine; Meyer-Kovac, Judit; Schmid, Sebastian M; Lehnert, Hendrik; Oster, Henrik

2012-01-01

336

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

337

Circadian gene variants in cancer.  

PubMed

Abstract 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

338

An intelligent system for pacemaker reprogramming.  

PubMed

The process of reprogramming a cardiac pacemaker can be described in terms similar to those used for describing diagnostic problem solving. In this paper, the process of reprogramming a pacemaker is formalized as a special form of abductive diagnostic reasoning, where observable findings are interpreted with respect to results obtained from diagnostic tests. The dynamics of this process is cast as a diagnostic strategy, where information is gathered in a structured fashion. This abductive theory of pacemaker reprogramming has been used as the basis for an actual system that in its present form is capable of assisting cardiologists in dealing with problems in atrial sensing and pacing. The performance of the system has been evaluated using data from actual patients. PMID:10564843

Lucas, P J; Tholen, A; van Oort, G

1999-11-01

339

Motor Pattern Production in Reciprocally Inhibitory Neurons Exhibiting Postinhibitory Rebound  

Microsoft Academic Search

Pairs of neurons which inhibit each other can produce regular alternating bursts of impulses if they also exhibit postinhibitory rebound (PIR). Computer studies show that stable patterns occur spontaneously in systems of pacemaker neurons with PIR, and can be triggered in systems of nonpacemakers without requiring tonic excitation. The repetition rates of these patterns are determined largely by the PIR

Donald H. Perkel; Brian Mulloney

1974-01-01

340

A test of the hypothesis that D2O affects circadian oscillations by diminishing the apparent temperature.  

PubMed

The period (tau) of a circadian pacemaker in the cockroach Leucophaea maderae is a nonmonotonic function of temperature. The slope of the curve (tau as a function of temperature) is negative at 20 degrees and positive at 30 degrees . When these insects are deuterated at 20 degrees and 30 degrees the period (tau) of the pacemaker lengthens in both cases, although there is a marked temperature dependence of D(2)O action. The increase in tau is nearly three times greater at 20 degrees than 30 degrees . This observation is a flat contradiction of a prediction made earlier that when D(2)O affects circadian pacemakers it does so by diminishing the apparent temperature of the cell. That prediction, however, involves an assumption that may well be unfounded. Unless D(2)O acts nonselectively on all the components in the system regulating tau, the prediction we sought to test is unfounded; and if D(2)O does not act nonselectively, the observed temperature dependence of D(2)O action is understandable in terms of simulating a lower temperature for those components it does affect. PMID:4530988

Caldarola, P C; Pittendrigh, C S

1974-11-01

341

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.

Robertson, Laura; Jones, M. G.

2009-02-01

342

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

343

Translational Profiling of Clock Cells Reveals Circadianly Synchronized Protein Synthesis  

PubMed Central

Abstract 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.

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

2013-01-01

344

Delay-aided stochastic multiresonances on scale-free FitzHugh-Nagumo neuronal networks  

NASA Astrophysics Data System (ADS)

The stochastic resonance in paced time-delayed scale-free FitzHugh-Nagumo (FHN) neuronal networks is investigated. We show that an intermediate intensity of additive noise is able to optimally assist the pacemaker in imposing its rhythm on the whole ensemble. Furthermore, we reveal that appropriately tuned delays can induce stochastic multiresonances, appearing at every integer multiple of the pacemaker's oscillation period. We conclude that fine-tuned delay lengths and locally acting pacemakers are vital for ensuring optimal conditions for stochastic resonance on complex neuronal networks.

Gan, Chun-Biao; Perc, Matjaz; Wang, Qing-Yun

2010-04-01

345

Aberrant Development of the Suprachiasmatic Nucleus and Circadian Rhythms in Mice Lacking the Homeodomain Protein Six6  

PubMed Central

The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and ?-galactosidase, we demonstrated the lack of these SCN markers in all Six6- null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN.

Clark, Daniel D.; Gorman, Michael R.; Hatori, Megumi; Meadows, Jason D.; Panda, Satchidananda; Mellon, Pamela L.

2013-01-01

346

Animal Behaviour and Circadian Rhythms.  

National Technical Information Service (NTIS)

The behavior of various animals is analyzed with them transferred from a natural rhythmic environment to a constant environment. It is suggested that the parameters of the circadian rhythm depend on the experimental conditions. (Author)

V. B. Chernyshev

1975-01-01

347

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.

2013-01-01

348

Aircrew fatigue and circadian rhythmicity  

NASA Technical Reports Server (NTRS)

Recent statistical and experimental studies on the role of circadian rhythms in aircrew fatigue and aviation accidents are reviewed from a human-factors perspective, and typical data are presented in extensive graphs. Consideration is given to the biological clock and the limits of endurance, circadian desynchronization, sleep and sleepiness, short-haul and long-haul operational studies, and the potential advantages of cockpit automation.

Graeber, R. Curtis

1988-01-01

349

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.

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

2014-01-01

350

Influence of deuterium oxide on circadian activity rhythms of hamsters: role of the suprachiasmatic nuclei.  

PubMed

The period of the free-running circadian activity rhythm of Syrian hamsters was measured before and during treatment with 10% deuterium oxide (D2O). Deuteration increased period length by approximately 0.5 h per cycle both pre- and postoperatively in hamsters sustaining complete, incomplete or no unilateral lesions of the suprachiasmatic nuclei (SCN). Neither coupling between the bilaterally paired SCN, nor elimination of 50% of SCN tissue affected period length during D2O treatment. However, variability of the response to D2O was much greater in lesioned than in intact hamsters. We propose that a small percentage of the normal complement of SCN neurons is sufficient to permit full responsiveness of the circadian system to D2O and that there is substantial redundancy in the neural system that responds to deuterium. Stability of the circadian system appears to be increased by the full complement of SCN neurons. PMID:3013372

Pickard, G E; Zucker, I

1986-06-18

351

[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

352

Circadian Rhythm Sleep Disorder: Irregular Sleep Wake Rhythm Type  

PubMed Central

Irregular Sleep Wake Rhythm Disorder (ISWRD) is characterized by the relative absence of a circadian pattern in an individual’s sleep-wake cycle. Significant changes in circadian regulation occur with aging and with neurodegenerative diseases, such as Alzheimer’s disease prevalent in older adults, which are likely to contribute to the prevalence of ISWRD seen in these populations, although ISWRD is also seen in traumatic brain injury and mental retardation populations. ISWRD is thought to result from some combination of; degeneration or decreased neuronal activity of suprachiasmatic nucleus (SCN) neurons, decreased responsiveness of the circadian clock to entraining agents such as light and activity, and decreased exposure to bright light and structured social and physical activity during the day. Treatment of ISWRD seeks to consolidate sleep during the night and wakefulness during the day; primarily through restoring or enhancing exposure to the various SCN time cues, or “zeitgebers”. Studies of the effectiveness of pharmacologic treatments for ISWRD have generally yielded negative or inconsistent results. In general multi-modal non-pharmacological approaches involving increased exposure to light, increased physical and social activities and improved sleep hygiene have been the most successful therapeutic approaches.

Zee, Phyllis C.; Vitiello, Michael V.

2009-01-01

353

ISOTOPE BATTERY FOR CARDIAC PACEMAKER ISOCARD  

Microsoft Academic Search

The description concerns a miniaturized, thermoelectric converter system which is intended for use in conjunction with a Pu 238 heat source as the power supply for pacemakers. It consists of a continuous meadering line of thermocouples vapour-deposited onto a polyimide tape. The system supplies directly the necessary output voltage of 6 V. The most important stages in the production process,

Renner

1971-01-01

354

Technical Series Trends in Cardiac Pacemaker Batteries  

Microsoft Academic Search

Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads\\/electrodes have reduced energy requirements by two orders of magnitude. Micro- electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality,

Venkateswara Sarma Mallela; V. Ilankumaran; N. Srinivasa Rao

355

Intrapericardial pacemaker in a 2-kilogram newborn.  

PubMed

A 2-kilogram child had a pacemaker implanted by a subxyphoid approach with the generator located under the rectus sheath. Days later, the battery eroded the abdominal wall and the peritoneum. The whole system was removed and a new one was implanted inside the pericardium on an emergent basis. PMID:23066539

Gil-Jaurena, Juan-Miguel; Castillo, Rafael; Rubio, Lorena

2012-08-01

356

[Electrophysiological and hemodynamic consequences of pacemaker syndrome].  

PubMed

The pacemaker syndrome is a complex of adverse clinical, hemodynamic and electrophysiologic signs temporally related to the onset of ventricular pacing and having no other causes. We observed 975 patients (454 men and 251 women, mean age 67.1+/-2.4 years) who received ventricular VVI pacemakers because of sick sinus syndrome or complete atrio-ventricular block. The presence of ventriculo-atrial conduction was confirmed by transesophageal ECG. Pacemaker syndrome was diagnosed in 121 patients (12.4%) who had the following complaints: general weakness (n=82), rapid fatigability (n=51), retarded thinking (n=43), dizziness (n=75), exertional dyspnea (n=86), anginal pain at rest (n=14), or exertion (n=43), unpleasant pulsation of neck vessels (n=41), transient hypotension (n=54), syncope (n=5). Retrograde P-wave was registered in standard ECG-leads in 98 (80.9%) and only on transesophageal ECG - in 23 patients (19%). Stroke volume after stopping of ventricular pacing (mean heart rate during sinus rhythm - 52.1+/-3/min) increased in 97 (80.2%) and decreased in 24 patients (19.8%). Main method of treatment of pacemaker syndrome was restoration of atrioventricular synchrony. PMID:16234792

Medziavichius, P A; Medziavichene, V; Zhaliunas, R

2005-01-01

357

MRI-conditional pacemakers: current perspectives  

PubMed Central

Use of both magnetic resonance imaging (MRI) and pacing devices has undergone remarkable growth in recent years, and it is estimated that the majority of patients with pacemakers will need an MRI during their lifetime. These investigations will generally be denied due to the potentially dangerous interactions between cardiac devices and the magnetic fields and radio frequency energy used in MRI. Despite the increasing reports of uneventful scanning in selected patients with conventional pacemakers under close surveillance, MRI is still contraindicated in those circumstances and cannot be considered a routine procedure. These limitations prompted a series of modifications in generator and lead engineering, designed to minimize interactions that could compromise device function and patient safety. The resulting MRI-conditional pacemakers were first introduced in 2008 and the clinical experience gathered so far supports their safety in the MRI environment if certain conditions are fulfilled. With this technology, new questions and controversies arise regarding patient selection, clinical impact, and cost-effectiveness. In this review, we discuss the potential risks of MRI in patients with electronic cardiac devices and present updated information regarding the features of MRI-conditional pacemakers and the clinical experience with currently available models. Finally, we provide some guidance on how to scan patients who have these devices and discuss future directions in the field.

Ferreira, Antonio M; Costa, Francisco; Tralhao, Antonio; Marques, Hugo; Cardim, Nuno; Adragao, Pedro

2014-01-01

358

Radiation induced failures of complementary metal oxide semiconductor containing pacemakers: a potentially lethal complication  

Microsoft Academic Search

New multi-programmable pacemakers frequently employ complementary metal oxide semiconductors (CMOS). This circuitry appears more sensitive to the effects of ionizing radiation when compared to the semiconductor circuits used in older pacemakers. A case of radiation induced runaway pacemaker in a CMOS device is described. Because of this and other recent reports of radiation therapy-induced CMOS type pacemaker failure, these pacemakers

Alan A. Lewin; Christopher F. Serago; James G. Schwade; Andre A. Abitbol; Stephen C. Margolis

1984-01-01

359

Measuring pacemaker dose: a clinical perspective.  

PubMed

Recently in our clinic, we have seen an increased number of patients presenting with pacemakers and defibrillators. Precautions are taken to develop a treatment plan that minimizes the dose to the pacemaker because of the adverse effects of radiation on the electronics. Here we analyze different dosimeters to determine which is the most accurate in measuring pacemaker or defibrillator dose while at the same time not requiring a significant investment in time to maintain an efficient workflow in the clinic. The dosimeters analyzed here were ion chambers, diodes, metal-oxide-semiconductor field effect transistor (MOSFETs), and optically stimulated luminescence (OSL) dosimeters. A simple phantom was used to quantify the angular and energy dependence of each dosimeter. Next, 8 patients plans were delivered to a Rando phantom with all the dosimeters located where the pacemaker would be, and the measurements were compared with the predicted dose. A cone beam computed tomography (CBCT) image was obtained to determine the dosimeter response in the kilovoltage energy range. In terms of the angular and energy dependence of the dosimeters, the ion chamber and diode were the most stable. For the clinical cases, all the dosimeters match relatively well with the predicted dose, although the ideal dosimeter to use is case dependent. The dosimeters, especially the MOSFETS, tend to be less accurate for the plans, with many lateral beams. Because of their efficiency, we recommend using a MOSFET or a diode to measure the dose. If a discrepancy is observed between the measured and expected dose (especially when the pacemaker to field edge is <10 cm), we recommend analyzing the treatment plan to see whether there are many lateral beams. Follow-up with another dosimeter rather than repeating multiple times with the same type of dosimeter. All dosimeters should be placed after the CBCT has been acquired. PMID:21875785

Studenski, Matthew T; Xiao, Ying; Harrison, Amy S

2012-01-01

360

Resynchronization of circadian sleep-wake and temperature cycles in the squirrel monkey following phase shifts of the environmental light-dark cycle  

SciTech Connect

Circadian rhythms in physiological and behavioral functions gradually resynchronize after phase shifts in environmental time cues. In order to characterize the rate of circadian resynchronization in a diurnal primate model, the temperature, locomotor activity, and polygraphically determined sleep-wake states were monitored in squirrel monkeys before and after 8-h phase shifts of an environmental light-dark cycle of 12 h light and 12 h dark (LD 12:12). For the temperature rhythm, resynchronization took 4 d after phase delay shift and 5 d after phase advance shift; for the rest-activity cycle, resynchronization times were 3 d and 6 d, respectively. The activity acrophase shifted more rapidly than the temperature acrophase early in the post-delay shift interval, but this internal desynchronization between rhythms disappeared during the course of resynchronization. Further study of the early resynchronization process requires emphasis on identifying evoked effects and measuring circadian pacemaker function. 13 references.

Wexler, D.B.; Moore-ede, M.C.

1986-12-01

361

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

PubMed

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

2013-07-01

362

Resynchronization of circadian sleep-wake and temperature cycles in the squirrel monkey following phase shifts of the environmental light-dark cycle  

NASA Technical Reports Server (NTRS)

Circadian rhythms in physiological and behavioral functions gradually resynchronize after phase shifts in environmental time cues. In order to characterize the rate of circadian resynchronization in a diurnal primate model, the temperature, locomotor activity, and polygraphically determined sleep-wake states were monitored in squirrel monkeys before and after 8-h phase shifts of an environmental light-dark cycle of 12 h light and 12 h dark (LD 12:12). For the temperature rhythm, resynchronization took 4 d after phase delay shift and 5 d after phase advance shift; for the rest-activity cycle, resynchronization times were 3 d and 6 d, respectively. The activity acrophase shifted more rapidly than the temperature acrophase early in the post-delay shift interval, but this internal desynchronization between rhythms disappeared during the course of resynchronization. Further study of the early resynchronization process requires emphasis on identifying evoked effects and measuring circadian pacemaker function.

Wexler, D. B.; Moore-Ede, M. C.

1986-01-01

363

The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor  

PubMed Central

Post-translational modifications (such as ubiquitination) of clock proteins are critical in maintaining the precision and robustness of the evolutionarily conserved circadian clock. Ubiquitination of the core clock transcription factor BMAL1 (brain and muscle Arnt-like 1) has recently been reported. However, it remains unknown whether BMAL1 ubiquitination affects circadian pacemaking and what ubiquitin ligase(s) is involved. Here, we show that activating UBE3A (by expressing viral oncogenes E6/E7) disrupts circadian oscillations in mouse embryonic fibroblasts, measured using PER2::Luc dynamics, and rhythms in endogenous messenger ribonucleic acid and protein levels of BMAL1. Over-expression of E6/E7 reduced the level of BMAL1, increasing its ubiquitination and proteasomal degradation. UBE3A could bind to and degrade BMAL1 in a ubiquitin ligase-dependent manner. This occurred both in the presence and absence of E6/E7. We provide in vitro (knockdown/over-expression in mammalian cells) and in vivo (genetic manipulation in Drosophila) evidence for an endogenous role of UBE3A in regulating circadian dynamics and rhythmic locomotor behaviour. Together, our data reveal an essential and conserved role of UBE3A in the regulation of the circadian system in mammals and flies and identify a novel mechanistic link between oncogene E6/E7-mediated cell transformation and circadian (BMAL1) disruption.

Gossan, Nicole C.; Zhang, Feng; Guo, Baoqiang; Jin, Ding; Yoshitane, Hikari; Yao, Aiyu; Glossop, Nick; Zhang, Yong Q.; Fukada, Yoshitaka; Meng, Qing-Jun

2014-01-01

364

Multicellular Model for Intercellular Synchronization in Circadian Neural Networks  

PubMed Central

We developed a multicellular model characterized by a high degree of heterogeneity to investigate possible mechanisms that underlie circadian network synchronization and rhythmicity in the suprachiasmatic nucleus (SCN). We populated a two-dimensional grid with 400 model neurons coupled via ?-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP) neurotransmitters through a putative Ca2+ mediated signaling cascade to investigate their roles in gene expression and electrical firing activity of cell populations. As observed experimentally, our model predicted that GABA would affect the amplitude of circadian oscillations but not synchrony among individual oscillators. Our model recapitulated experimental findings of decreased synchrony and average periods, loss of rhythmicity, and reduced circadian amplitudes as VIP signaling was eliminated. In addition, simulated increases of VIP reduced periodicity and synchrony. We therefore postulated a physiological range of VIP within which the system is able to produce sustained and synchronized oscillations. Our model recapitulated experimental findings of diminished amplitudes and periodicity with decreasing intracellular Ca2+ concentrations, suggesting that such behavior could be due to simultaneous decrease of individual oscillation amplitudes and population synchrony. Simulated increases in Cl? levels resulted in increased Cl? influx into the cytosol, a decrease of inhibitory postsynaptic currents, and ultimately a shift of GABA-elicited responses from inhibitory to excitatory. The simultaneous reduction of IPSCs and increase in membrane resting potential produced GABA dose-dependent increases in firing rates across the population, as has been observed experimentally. By integrating circadian gene regulation and electrophysiology with intracellular and intercellular signaling, we were able to develop the first (to our knowledge) multicellular model that allows the effects of clock genes, electrical firing, Ca2+, GABA, and VIP on circadian system behavior to be predicted.

Vasalou, Christina; Herzog, Erik D.; Henson, Michael A.

2011-01-01

365

Multicellular model for intercellular synchronization in circadian neural networks.  

PubMed

We developed a multicellular model characterized by a high degree of heterogeneity to investigate possible mechanisms that underlie circadian network synchronization and rhythmicity in the suprachiasmatic nucleus (SCN). We populated a two-dimensional grid with 400 model neurons coupled via ?-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP) neurotransmitters through a putative Ca(2+) mediated signaling cascade to investigate their roles in gene expression and electrical firing activity of cell populations. As observed experimentally, our model predicted that GABA would affect the amplitude of circadian oscillations but not synchrony among individual oscillators. Our model recapitulated experimental findings of decreased synchrony and average periods, loss of rhythmicity, and reduced circadian amplitudes as VIP signaling was eliminated. In addition, simulated increases of VIP reduced periodicity and synchrony. We therefore postulated a physiological range of VIP within which the system is able to produce sustained and synchronized oscillations. Our model recapitulated experimental findings of diminished amplitudes and periodicity with decreasing intracellular Ca(2+) concentrations, suggesting that such behavior could be due to simultaneous decrease of individual oscillation amplitudes and population synchrony. Simulated increases in Cl(-) levels resulted in increased Cl(-) influx into the cytosol, a decrease of inhibitory postsynaptic currents, and ultimately a shift of GABA-elicited responses from inhibitory to excitatory. The simultaneous reduction of IPSCs and increase in membrane resting potential produced GABA dose-dependent increases in firing rates across the population, as has been observed experimentally. By integrating circadian gene regulation and electrophysiology with intracellular and intercellular signaling, we were able to develop the first (to our knowledge) multicellular model that allows the effects of clock genes, electrical firing, Ca(2+), GABA, and VIP on circadian system behavior to be predicted. PMID:21723810

Vasalou, Christina; Herzog, Erik D; Henson, Michael A

2011-07-01

366

CIRCADIAN GENES AND BREAST CANCER SUSCEPTIBILITY IN ROTATING SHIFT WORKERS  

PubMed Central

Rotating night shift work is associated with increased risk of breast cancer, likely via circadian disruption. We hypothesized that circadian pathway genes influence breast cancer risk, particularly in rotating night shift workers. We selected 178 common variants across 15 genes pertinent to the circadian system. Using a mixed candidate- and tag-single nucleotide polymorphism approach, we tested for associations between these variants and breast cancer risk in 1,825 women within the Nurses’ Health Study II cohort and investigated potential interactions between genotype and rotating shift-work in a subset of 1,318 women. Multiple-testing-adjusted p-values were obtained by permutation (n=10,000). None of the selected variants was significantly associated with breast cancer risk. However, when accounting for potential effect modification, rs23051560 (Ala394Thr) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2) was most strongly associated with breast cancer risk (nominal test for interaction p-value=0.0005; 10,000-permutation-based main-effects p-value among women with <24 months of shift-work=0.003). The observed multiplicative association with breast cancer risk per minor allele (A) was 0.65 (95%CI=0.51–0.82) among women with <24 months of shift-work, and 1.19 (95%CI=0.93–1.54) with ?24 months of shift-work. Women homozygous for the minor allele (AA) with ?24 months of shift-work had a 2.83-times higher breast cancer risk compared to homozygous AA women with <24 months of shift-work (95%CI=1.47–5.56). In smmary, common variation in circadian genes plays at most a small role in breast cancer risk among women of European ancestry. The impact of NPAS2 Ala394Thr in the presence of rotating shift-work requires further investigation.

Monsees, Genevieve M.; Kraft, Peter; Hankinson, Susan E.; Hunter, David J.; Schernhammer, Eva S.

2012-01-01

367

JNK regulates the photic response of the mammalian circadian clock  

PubMed Central

The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 abrogates BMAL1 phosphorylation and lengthens circadian period in fibroblasts. Mice deficient for neuron-specific isoform JNK3 have altered behavioural rhythms, with longer free-running period and compromised phase shifts to light. The locomotor rhythms are insensitive to intensity variance of constant light, deviating from Aschoff's rule. Thus, JNK regulates a core characteristic of the circadian clock by controlling the oscillation speed and the phase in response to light.

Yoshitane, Hikari; Honma, Sato; Imamura, Kiyomichi; Nakajima, Hiroto; Nishide, Shin-ya; Ono, Daisuke; Kiyota, Hiroshi; Shinozaki, Naoya; Matsuki, Hirokazu; Wada, Naoya; Doi, Hirofumi; Hamada, Toshiyuki; Honma, Ken-ichi; Fukada, Yoshitaka

2012-01-01

368

Pacemakers and implantable cardioverter defibrillators - general and anesthetic considerations.  

PubMed

A pacemaking system consists of an impulse generator and lead or leads to carry the electrical impulse to the patient's heart. Pacemaker and implantable cardioverter defibrillator codes were made to describe the type of pacemaker or implantable cardioverter defibrillator implanted. Indications for pacing and implantable cardioverter defibrillator implantation were given by the American College of Cardiologists. Certain pacemakers have magnet-operated reed switches incorporated; however, magnet application can have serious adverse effects; hence, devices should be considered programmable unless known otherwise. When a device patient undergoes any procedure (with or without anesthesia), special precautions have to be observed including a focused history/physical examination, interrogation of pacemaker before and after the procedure, emergency drugs/temporary pacing and defibrillation, reprogramming of pacemaker and disabling certain pacemaker functions if required, monitoring of electrolyte and metabolic disturbance and avoiding certain drugs and equipments that can interfere with pacemaker function. If unanticipated device interactions are found, consider discontinuation of the procedure until the source of interference can be eliminated or managed and all corrective measures should be taken to ensure proper pacemaker function should be done. Post procedure, the cardiac rate and rhythm should be monitored continuously and emergency drugs and equipments should be kept ready and consultation with a cardiologist or a pacemaker-implantable cardioverter defibrillator service may be necessary. PMID:24907883

Rapsang, Amy G; Bhattacharyya, Prithwis

2014-01-01

369

Melatonin, the Pineal Gland and Circadian Rhythms.  

National Technical Information Service (NTIS)

The rat pineal is a component of the circadian clock. Exogenous melatonin entrains the rat clock and does not require the presence of the pineal gland. The pineal gland is important for circadian rhythmicity. Pinealectomy exacerbates the disruptive effect...

V. M. Cassone

1995-01-01

370

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

371

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

372

21 CFR 870.3680 - Cardiovascular permanent or temporary pacemaker electrode.  

Code of Federal Regulations, 2010 CFR

...false Cardiovascular permanent or temporary pacemaker electrode. 870.3680 Section 870.3680...3680 Cardiovascular permanent or temporary pacemaker electrode. (a) Temporary pacemaker electrode â(1) Identification. A...

2009-04-01

373

21 CFR 870.3680 - Cardiovascular permanent or temporary pacemaker electrode.  

Code of Federal Regulations, 2010 CFR

...false Cardiovascular permanent or temporary pacemaker electrode. 870.3680 Section 870.3680...3680 Cardiovascular permanent or temporary pacemaker electrode. (a) Temporary pacemaker electrode â(1) Identification. A...

2010-04-01

374

Circadian Genes and Risk for Prostate Cancer.  

National Technical Information Service (NTIS)

We hypothesize that genetic susceptibility to prostate cancer may be in part due to variations in the core circadian genes that regulate circadian rhythms and that serum sex steroid hormone levels modify the effect that circadian gene variations have on p...

A. Hsing

2012-01-01

375

From circadian clock gene expression to pathologies  

Microsoft Academic Search

In most organisms, circadian rhythms are generated by a molecular clockwork involving so-called clock genes. These circadian clock genes participate in regulatory feedback loops, in which proteins regulate their own expression. The outcome is that ribonucleic acids (RNAs) and proteins produced from many of these genes oscillate with a circadian rhythm. Here, we describe the regulation of clock genes and

Elaine Waddington Lamont; Francine O. James; Diane B. Boivin; Nicolas Cermakian

2007-01-01

376

Pet-1 Deficiency Alters the Circadian Clock and Its Temporal Organization of Behavior  

PubMed Central

The serotonin and circadian systems are two important interactive regulatory networks in the mammalian brain that regulate behavior and physiology in ways that are known to impact human mental health. Previous work on the interaction between these two systems suggests that serotonin modulates photic input to the central circadian clock (the suprachiasmatic nuclei; SCN) from the retina and serves as a signal for locomotor activity, novelty, and arousal to shift the SCN clock, but effects of disruption of serotonergic signaling from the raphe nuclei on circadian behavior and on SCN function are not fully characterized. In this study, we examined the effects on diurnal and circadian behavior, and on ex vivo molecular rhythms of the SCN, of genetic deficiency in Pet-1, an ETS transcription factor that is necessary to establish and maintain the serotonergic phenotype of raphe neurons. Pet-1?/? mice exhibit loss of rhythmic behavioral coherence and an extended daily activity duration, as well as changes in the molecular rhythms expressed by the clock, such that ex vivo SCN from Pet-1?/? mice exhibit period lengthening and sex-dependent changes in rhythmic amplitude. Together, our results indicate that Pet-1 regulation of raphe neuron serotonin phenotype contributes to the period, precision and light/dark partitioning of locomotor behavioral rhythms by the circadian clock through direct actions on the SCN clock itself, as well as through non-clock effects.

Axley, John C.; Deneris, Evan S.; McMahon, Douglas G.

2014-01-01

377

Pacemaker explosions in crematoria: problems and possible solutions  

PubMed Central

The number of artificial cardiac pacemakers is increasing, as is the number of bodies being cremated. Because of the explosive potential of pacemakers when heated, a statutory question on the cremation form asks whether the deceased has a pacemaker and if so whether it has been removed. We sent a questionnaire to all the crematoria in the UK enquiring about the frequency, consequences and prevention of pacemaker explosions. We found that about half of all crematoria in the UK experience pacemaker explosions, that pacemaker explosions may cause structural damage and injury and that most crematoria staff are unaware of the explosive potential of implantable cardiac defibrillators. Crematoria staff rely on the accurate completion of cremation forms, and doctors who sign cremation forms have a legal obligation to provide such information.

Gale, Christopher P; Mulley, Graham P

2002-01-01

378

Circadian regulation of renal function.  

PubMed

Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids that are entrained by rest/activity and feeding/fasting cycles. However, numerous studies have shown that most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock made of a system of autoregulatory transcriptional/translational feedback loops, which have been found in all tissues studied, including the kidney. Here, we present a review of the growing evidence showing the involvement of the molecular clock in the generation of renal excretory rhythms. PMID:20664559

Firsov, Dmitri; Bonny, Olivier

2010-10-01

379

Pacemaker lead perforation causing hemopericardium eight years after implantation  

PubMed Central

The number of patients with intracardiac devices, including permanent pacemakers and implantable cardioverter-defibrillators is increasing. Lead perforation is a recognized complication which most often occurs during or shortly following pacemaker implantation. Late lead perforation occurring over 30 days after device insertion is a rare, potentially life-threatening complication. We present a case of late lead perforation unmasked greater than eight years after pacemaker implantation by initiation of anticoagulation.

Liang, Jackson J.; Killu, Ammar M.; Osborn, Michael J.; Jaffe, Allan S.

2013-01-01

380

Standards of evidence in chronobiology: critical review of a report that restoration of Bmal1 expression in the dorsomedial hypothalamus is sufficient to restore circadian food anticipatory rhythms in Bmal1-/- mice  

PubMed Central

Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibit canonical properties of circadian clock control. The molecular mechanisms and location of food-entrainable circadian oscillators hypothesized to control food anticipatory rhythms are unknown. In 2008, Fuller et al reported that food-entrainable circadian rhythms are absent in mice bearing a null mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virally-mediated restoration of Bmal1 expression in the dorsomedial nucleus of the hypothalamus (DMH) but not in the suprachiasmatic nucleus (site of the master light-entrainable circadian pacemaker). These results, taken together with controversial DMH lesion results published by the same laboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanism necessary and sufficient for food anticipatory rhythms. However, careful examination of the manuscript reveals numerous weaknesses in the evidence as presented. These problems are grouped as follows and elaborated in detail: 1. data management issues (apparent misalignments of plotted data), 2. failure of evidence to support the major conclusions, and 3. missing data and methodological details. The Fuller et al results are therefore considered inconclusive, and fail to clarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythms in rodents.

Mistlberger, Ralph E; Buijs, Ruud M; Challet, Etienne; Escobar, Carolina; Landry, Glenn J; Kalsbeek, Andries; Pevet, Paul; Shibata, Shigenobu

2009-01-01

381

Circadian Measurements of Sirtuin Biology  

PubMed Central

Many of our behavioral and physiological processes display daily oscillations that are under the control of the circadian clock. The core molecular clock network is present in both the brain and peripheral tissues and is composed of a complex series of interlocking transcriptional/translational feedback loops that oscillate with a periodicity of ?24 h. Recent evidence has implicated NAD+ biosynthesis and the sirtuin family of NAD+-dependent protein deacetylases as part of a novel feedback loop within the core clock network, findings which underscore the importance of taking circadian timing into consideration when designing and interpreting metabolic studies, particularly in regard to sirtuin biology. Thus, this chapter introduces both in vivo and in vitro circadian methods to analyze various sirtuin-related endpoints across the light–dark cycle and discusses the transcriptional, biochemical, and physiological outputs of the clock.

Ramsey, Kathryn Moynihan; Affinati, Alison H.; Peek, Clara B.; Marcheva, Biliana; Hong, Hee-Kyung; Bass, Joseph

2014-01-01

382

Primary batteries for implantable pacemakers and defibrillators  

Microsoft Academic Search

The lithium-iodine battery is established as the standard system for low-rate implantable applications, namely pacemakers because of its excellent volumetric energy density. Within defibrillators\\/cardioverters lithium-silver-oxovanadium (SVO) and lithium-manganese-dioxide (MDX) high-rate batteries are in use. The concept of a hybrid system which makes use of a high-rate battery and a low-rate battery within one application is described. Experimental results obtained from

J. Drews; G. Fehrmann; R. Staub; R. Wolf

2001-01-01

383

Software Simulation of an Implantable Pacemaker  

PubMed Central

Software simulation of a hardware system has been used as an effective tool in evaluating and testing software for microprocessor-based control systems. This paper reports on a system simulator used in the development and testing of software for an implantable pacemaker. The paper describes the functional and structural characteristics of the simulator, the user interface, run-time information that is provided from a simulation, and experiences with the system simulator.

Riley, R. E.; Rossing, M. A.

1983-01-01

384

Modulation of metabolic and clock gene mRNA rhythms by pineal and retinal circadian oscillators.  

PubMed

Avian circadian organization involves interactions between three neural pacemakers: the suprachiasmatic nuclei (SCN), pineal, and retina. Each of these structures is linked within a neuroendocrine loop to influence downstream processes and peripheral oscillations. However, the contribution of each structure to drive or synchronize peripheral oscillators or circadian outputs in avian species is largely unknown. To explore these interactions in the chick, we measured 2-deoxy[(14)C]-glucose (2DG) uptake and mRNA expression of the chick clock genes bmal1, cry1, and per3 in three brain areas and in two peripheral organs in chicks that underwent pinealectomy, enucleation, or sham surgery. We found that 2DG uptake rhythms damp under constant darkness in intact animals, while clock gene mRNA levels continue to cycle, demonstrating that metabolic rhythms are not directly driven by clock gene transcription. Moreover, 2DG rhythms are not phase-locked to rhythms of clock gene mRNA. However, pinealectomy and enucleation had similar disruptive effects on both metabolic and clock gene rhythms, suggesting that both of these oscillators act similarly to reinforce molecular and physiological rhythms in the chicken. Finally, we show that the relative phasing of at least one clock gene, cry1, varies between central and peripheral oscillators in a tissue specific manner. These data point to a complex, differential orchestration of central and peripheral oscillators in the chick, and, importantly, indicate a disconnect between canonical clock gene regulation and circadian control of metabolism. PMID:19136000

Karaganis, Stephen P; Bartell, Paul A; Shende, Vikram R; Moore, Ashli F; Cassone, Vincent M

2009-04-01

385

Modulation of metabolic and clock gene mRNA rhythms by pineal and retinal circadian oscillators  

PubMed Central

Avian circadian organization involves interactions between three neural pacemakers: the suprachiasmatic nuclei (SCN), pineal, and retina. Each of these structures is linked within a neuroendocrine loop to influence downstream processes and peripheral oscillations. However, the contribution of each structure to drive or synchronize peripheral oscillators or circadian outputs in avian species is largely unknown. To explore these interactions in the chick, we measured 2-deoxy[14C]-glucose (2DG) uptake and mRNA expression of the chick clock genes bmal1, cry1, and per3 in three brain areas and in two peripheral organs in chicks that underwent pinealectomy, enucleation, or sham surgery. We found that 2DG uptake rhythms damp under constant darkness in intact animals, while clock gene mRNA levels continue to cycle, demonstrating that metabolic rhythms are not directly driven by clock gene transcription. Moreover, 2DG rhythms are not phase-locked to rhythms of clock gene mRNA. However, pinealectomy and enucleation had similar disruptive effects on both metabolic and clock gene rhythms, suggesting that both of these oscillators act similarly to reinforce molecular and physiological rhythms in the chicken. Finally, we show that the relative phasing of at least one clock gene, cry1, varies between central and peripheral oscillators in a tissue specific manner. These data point to a complex, differential orchestration of central and peripheral oscillators in the chick, and, importantly, indicate a disconnect between canonical clock gene regulation and circadian control of metabolism.

Karaganis, Stephen P.; Bartell, Paul A.; Shende, Vikram R.; Moore, Ashli F.; Cassone, Vincent M.

2009-01-01

386

Effects of restricted feeding schedules on circadian organization in squirrel monkeys  

NASA Technical Reports Server (NTRS)

Free running circadian rhythms of motor activity, food-motivated lever-pressing, and either drinking (N = 7) or body temperature (N = 3) were recorded from 10 squirrel monkeys maintained in constant illumination with unlimited access to food. Food availability was then restricted to a single unsignaled 3-hour interval each day. The feeding schedule failed to entrain the activity rhythms of 8 monkeys, which continued to free-run. Drinking was almost completely synchronized by the schedule, while body temperature showed a feeding-induced rise superimposed on a free-running rhythm. Nonreinforced lever-pressing showed both a free-running component and a 24-hour component that anticipated the time of feeding. At the termination of the schedule, all recorded variables showed free-running rhythms, but in 3 animals the initial phase of the postschedule rhythms was advanced by several hours, suggesting relative coordination. Of the remaining 2 animals, one exhibited stable entrainment of all 3 recorded rhythms, while the other appeared to entrain temporarily to the feeding schedule. These results indicate that restricted feeding schedules are only a weak zeitgeber for the circadian pacemaker generating free-running rhythms in the squirrel monkey. Such schedules, however, may entrain a separate circadian system responsible for the timing of food-anticipatory changes in behavior and physiology.

Boulos, Z.; Frim, D. M.; Dewey, L. K.; Moore-Ede, M. C.

1989-01-01

387

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.

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

2013-01-01

388

Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine  

PubMed Central

Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their entrainment to a light-dark (LD) cycle, by using transgenic mice in which Tat expression in the brain was induced via a doxycycline (DOX)-sensitive, glial fibrillary-associated, protein-restricted promoter. Because opiate substance abuse, which shares comorbidity with HIV infection, also disrupts sleep, a final experiment assessed the effects of morphine exposure on circadian rhythms in wild-type and Tat transgenic mice. Mice housed in cages equipped with running wheels were fed chow with or without DOX. Experiment 1 revealed a small but significant (P < 0.05) difference between groups in the phase angle of entrainment and a 15% decrease in the wheel running in the DOX group (P < 0.005). During exposure to constant darkness, DOX did not alter the endogenous period length of the circadian rhythm. Experiment 2 investigated the effect of DOX on circadian rhythms in wild-type and Tat(+) mice during exposure to a normal or phase-shifted LD cycle, or morphine treatment without any change in the LD cycle. Tat induction significantly decreased wheel running but did not affect entrainment to the normal or shifted LD cycle. Morphine decreased wheel running without altering the phase angle of entrainment, and the drug's effects were independent of Tat induction. In conclusion, these findings suggest that chronic brain expression of Tat decreases locomotor activity and the amplitude of circadian rhythms, but does not affect photic entrainment or reentrainment of the murine circadian pacemaker.

Duncan, Marilyn J.; Bruce-Keller, Annadora J.; Conner, Clayton; Knapp, Pamela E.; Xu, Ruquiang; Nath, Avindra; Hauser, Kurt F.

2008-01-01

389

Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine.  

PubMed

Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their entrainment to a light-dark (LD) cycle, by using transgenic mice in which Tat expression in the brain was induced via a doxycycline (DOX)-sensitive, glial fibrillary-associated, protein-restricted promoter. Because opiate substance abuse, which shares comorbidity with HIV infection, also disrupts sleep, a final experiment assessed the effects of morphine exposure on circadian rhythms in wild-type and Tat transgenic mice. Mice housed in cages equipped with running wheels were fed chow with or without DOX. Experiment 1 revealed a small but significant (P < 0.05) difference between groups in the phase angle of entrainment and a 15% decrease in the wheel running in the DOX group (P < 0.005). During exposure to constant darkness, DOX did not alter the endogenous period length of the circadian rhythm. Experiment 2 investigated the effect of DOX on circadian rhythms in wild-type and Tat(+) mice during exposure to a normal or phase-shifted LD cycle, or morphine treatment without any change in the LD cycle. Tat induction significantly decreased wheel running but did not affect entrainment to the normal or shifted LD cycle. Morphine decreased wheel running without altering the phase angle of entrainment, and the drug's effects were independent of Tat induction. In conclusion, these findings suggest that chronic brain expression of Tat decreases locomotor activity and the amplitude of circadian rhythms, but does not affect photic entrainment or reentrainment of the murine circadian pacemaker. PMID:18784333

Duncan, Marilyn J; Bruce-Keller, Annadora J; Conner, Clayton; Knapp, Pamela E; Xu, Ruquiang; Nath, Avindra; Hauser, Kurt F

2008-11-01

390

Analysis of core circadian feedback loop in suprachiasmatic nucleus of mCry1-luc transgenic reporter mouse  

PubMed Central

The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of Period (Per) and Cryptochrome (Cry) genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences in Per and Cry to inhibit their transactivation by CLOCK/BMAL1 heterodimers. To function effectively, these closed intracellular loops need to be synchronized between SCN cells and to the light/dark cycle. For Per expression, this is mediated by neuropeptidergic and glutamatergic extracellular cues acting via cAMP/calcium-responsive elements (CREs) in Per genes. Cry genes, however, carry no CREs, and how CRY-dependent SCN pacemaking is synchronized remains unclear. Furthermore, whereas reporter lines are available to explore Per circadian expression in real time, no Cry equivalent exists. We therefore created a mouse, B6.Cg-Tg(Cry1-luc)01Ld, carrying a transgene (mCry1-luc) consisting of mCry1 elements containing an E-box and E?-box driving firefly luciferase. mCry1-luc organotypic SCN slices exhibited stable circadian bioluminescence rhythms with appropriate phase, period, profile, and spatial organization. In SCN lacking vasoactive intestinal peptide or its receptor, mCry1 expression was damped and desynchronized between cells. Despite the absence of CREs, mCry1-luc expression was nevertheless (indirectly) sensitive to manipulation of cAMP-dependent signaling. In mPer1/2-null SCN, mCry1-luc bioluminescence was arrhythmic and no longer suppressed by elevation of cAMP. Finally, an SCN graft procedure showed that PER-independent as well as PER-dependent mechanisms could sustain circadian expression of mCry1. The mCry1-luc mouse therefore reports circadian mCry1 expression and its interactions with vasoactive intestinal peptide, cAMP, and PER at the heart of the SCN pacemaker.

Maywood, Elizabeth S.; Drynan, Lesley; Chesham, Johanna E.; Edwards, Mathew D.; Dardente, Hugues; Fustin, Jean-Michel; Hazlerigg, David G.; O'Neill, John S.; Codner, Gemma F.; Smyllie, Nicola J.; Brancaccio, Marco; Hastings, Michael H.

2013-01-01

391

Analysis of core circadian feedback loop in suprachiasmatic nucleus of mCry1-luc transgenic reporter mouse.  

PubMed

The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of Period (Per) and Cryptochrome (Cry) genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences in Per and Cry to inhibit their transactivation by CLOCK/BMAL1 heterodimers. To function effectively, these closed intracellular loops need to be synchronized between SCN cells and to the light/dark cycle. For Per expression, this is mediated by neuropeptidergic and glutamatergic extracellular cues acting via cAMP/calcium-responsive elements (CREs) in Per genes. Cry genes, however, carry no CREs, and how CRY-dependent SCN pacemaking is synchronized remains unclear. Furthermore, whereas reporter lines are available to explore Per circadian expression in real time, no Cry equivalent exists. We therefore created a mouse, B6.Cg-Tg(Cry1-luc)01Ld, carrying a transgene (mCry1-luc) consisting of mCry1 elements containing an E-box and E'-box driving firefly luciferase. mCry1-luc organotypic SCN slices exhibited stable circadian bioluminescence rhythms with appropriate phase, period, profile, and spatial organization. In SCN lacking vasoactive intestinal peptide or its receptor, mCry1 expression was damped and desynchronized between cells. Despite the absence of CREs, mCry1-luc expression was nevertheless (indirectly) sensitive to manipulation of cAMP-dependent signaling. In mPer1/2-null SCN, mCry1-luc bioluminescence was arrhythmic and no longer suppressed by elevation of cAMP. Finally, an SCN graft procedure showed that PER-independent as well as PER-dependent mechanisms could sustain circadian expression of mCry1. The mCry1-luc mouse therefore reports circadian mCry1 expression and its interactions with vasoactive intestinal peptide, cAMP, and PER at the heart of the SCN pacemaker. PMID:23690615

Maywood, Elizabeth S; Drynan, Lesley; Chesham, Johanna E; Edwards, Mathew D; Dardente, Hugues; Fustin, Jean-Michel; Hazlerigg, David G; O'Neill, John S; Codner, Gemma F; Smyllie, Nicola J; Brancaccio, Marco; Hastings, Michael H

2013-06-01

392

Mind your rhythms: an important role for circadian genes in neuroprotection  

PubMed Central

Circadian rhythms govern nearly every physiological process in our brains and bodies. At the most basic level, the molecular clockwork in each cell interacts with metabolic cycles to influence the redox state, allowing for increased cellular activity at specific times of day. In this issue of the JCI, Musiek et al. show that genetic disruptions in the positive arm of the molecular clock can lead to severe astrogliosis, which likely occurs through disruptions in output genes that keep oxidative stress in check. This study demonstrates the importance of proper circadian protein function in the maintenance of neuronal integrity.

McClung, Colleen A.

2013-01-01

393

Metabolism and the circadian clock converge.  

PubMed

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; Sassone-Corsi, Paolo

2013-01-01

394

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.

Eckel-Mahan, Kristin

2013-01-01

395

CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP  

Microsoft Academic Search

DBP, the founding member of the PAR leucine zipper transcription factor family, is expressed according to a robust daily rhythm in the suprachiasmatic nucleus and several peripheral tissues. Previous studies with mice deleted for the Dbp gene have established that DBP participates in the regulation of several clock outputs, including locomotor activity, sleep distribution, and liver gene expression. Here we

Jurgen A. Ripperger; Lauren P. Shearman; Steven M. Reppert; Ueli Schibler

2000-01-01

396

Clinical Trial of the Effect of Exercise on Resetting of the Endogenous Circadian Pacemaker.  

National Technical Information Service (NTIS)

The objectives of the research effort have not changed; they remain as follows: Specific Aim 1: test the hypothesis that a 9-hr phase delay shift of the duty-rest schedule, such as that required for either transmeridian travel or night operations, will in...

C. A. Czeisler R. J. Hughes

2000-01-01

397

Dipper and non-dipper blood pressure 24-hour patterns: circadian rhythm-dependent physiologic and pathophysiologic mechanisms.  

PubMed

Neuroendocrine mechanisms are major determinants of the normal 24-h blood pressure (BP) pattern. At the central level, integration of the major driving factors of this temporal variability is mediated by circadian rhythms of monoaminergic systems in conjunction with those of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, plus endothelial systems and specific vasoactive peptides. Humoral secretions are typically episodic, coupled either to sleep and/or the circadian endogenous (suprachiasmatic nucleus) central pacemaker clock, but exhibiting also weekly, monthly, seasonal, and annual periodicities. Sleep induction and arousal are influenced also by many hormones and chemical substances that exhibit 24-h variation, e.g., arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, corticotropin-releasing factor, adrenocorticotropic hormone, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin E2, all with established effects on the cardiovascular system. As a consequence, physical, mental, and pathologic stimuli that activate or inhibit neuroendocrine effectors of biological rhythmicity may also interfere with, or modify, the temporal BP structure. Moreover, immediate adjustment to exogenous components/environment demands by BP rhythms is modulated by the circadian-time-dependent responsiveness of biological oscillators and their neuroendocrine effectors. This knowledge contributes to a better understanding of the pathophysiology of abnormalities of the 24-h BP pattern and level and their correction through circadian rhythm-based chronotherapeutic strategies. PMID:23002916

Fabbian, Fabio; Smolensky, Michael H; Tiseo, Ruana; Pala, Marco; Manfredini, Roberto; Portaluppi, Francesco

2013-03-01

398

Dynamics of the human EEG during prolonged wakefulness: evidence for frequency-specific circadian and homeostatic influences.  

PubMed

The electroencephalogram (EEG) of nine healthy individuals was recorded at half-hourly intervals during approximately 40 h of sustained wakefulness in a constant routine protocol. EEG power density in the 0.75-9.0 Hz range exhibited a global increasing trend, and a local trough in the evening, centered approximately 6 h prior to the temperature minimum. The former could be attributed to a wake-dependent influence, and the latter to a circadian influence. Power density in the 9.25-12.0 Hz band showed a circadian modulation, the trough coinciding with the minimum of the endogenous rhythm of body temperature, whereas a wake-dependent influence was not evident. Power density in the 12.25-25.0 Hz range exhibited a wake-dependent increase, whereas a circadian modulation was absent. It is concluded that the circadian pacemaker and the wake-dependent (i.e. homeostatic) process affect the waking EEG in a frequency-specific manner. PMID:9469671

Aeschbach, D; Matthews, J R; Postolache, T T; Jackson, M A; Giesen, H A; Wehr, T A

1997-12-19

399

Overexpression of the human VPAC2 receptor in the suprachiasmatic nucleus alters the circadian phenotype of mice  

PubMed Central

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) belong to a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, and growth hormone-releasing hormone. Microinjection of VIP or PACAP into the rodent suprachiasmatic nucleus (SCN) phase shifts the circadian pacemaker and VIP antagonists, and antisense oligodeoxynucleotides have been shown to disrupt circadian function. VIP and PACAP have equal potency as agonists of the VPAC2 receptor (VPAC2R), which is expressed abundantly in the SCN, in a circadian manner. To determine whether manipulating the level of expression of the VPAC2R can influence the control of the circadian clock, we have created transgenic mice overexpressing the human VPAC2R gene from a yeast artificial chromosome (YAC) construct. The YAC was modified by a strategy using homologous recombination to introduce (i) the HA epitope tag sequence (from influenza virus hemagglutinin) at the carboxyl terminus of the VPAC2R protein, (ii) the lacZ reporter gene, and (iii) a conditional centromere, enabling YAC DNA to be amplified in culture in the presence of galactose. High levels of lacZ expression were detected in the SCN, habenula, pancreas, and testis of the transgenic mice, with lower levels in the olfactory bulb and various hypothalamic areas. Transgenic mice resynchronized more quickly than wild-type controls to an advance of 8 h in the light-dark (LD) cycle and exhibited a significantly shorter circadian period in constant darkness (DD). These data suggest that the VPAC2R can influence the rhythmicity and photic entrainment of the circadian clock.

Shen, Sanbing; Spratt, Christopher; Sheward, W. John; Kallo, Imre; West, Katrine; Morrison, Christine F.; Coen, Clive W.; Marston, Hugh M.; Harmar, Anthony J.

2000-01-01

400

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

401

A Portable Miniature Transistorized Radio-Frequency Coupled Cardiac Pacemaker  

Microsoft Academic Search

A miniature, transistorized radio-frequency-coupled cardiac pacemaker was developed to eliminate wires penetrating the skin when electrodes are placed on the heart to drive it. The design also eliminates the need for totally implanting a pacemaker with its batteries. The stimulating impulse is transmitted via amplitude modulation to a tuned circuit and detector assembly implanted below the skin. The output of

D. M. Hickman; L. A. Geddes; H. E. Hoff; M. Hinds; A. G. Moore; C. K. Francis; T. Engen

1961-01-01

402

Microgenerators for Energy Autarkic Pacemakers and Defibrillators: Fact or Fiction?  

Microsoft Academic Search

Background: Implantable devices for medical use like permanent pacemakers, defibrillators, and fluid pumps depend on an energy provided by batteries. Unfortunately, the battery usually determines the duration of life of these devices, while technical problems occur infrequent. Device replacement for battery exhaustion requires surgical procedures and account for up to 1\\/3 of all pacemakers sold. Attempts to provide unlimited power

Günter Görge; Michael Kirstein; Raimund Erbel

2001-01-01

403

Laser welding in the manufacture of heart pacemakers  

NASA Astrophysics Data System (ADS)

Laser welding has become a key process in the manufacture of pacemakers but there are more powerful arguments than that for the use of lasers: (1) The laser is a most refined welding tool; (2) The laser simplifies pacemaker design; and (3) Laser welding is readily adapted to CNC control.