Sample records for circadian pacemaker neurons

  1. A mechanism for circadian control of pacemaker neuron excitability

    PubMed Central

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

    2014-01-01

    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. PMID:23010658

  2. Circadian Activators Are Expressed Days before They Initiate Clock Function in Late Pacemaker Neurons from Drosophila.

    PubMed

    Liu, Tianxin; Mahesh, Guruswamy; Houl, Jerry H; Hardin, Paul E

    2015-06-01

    Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. PMID:26041931

  3. Phase resetting of the mammalian circadian clock relies on a rapid shift of a small population of pacemaker neurons.

    PubMed

    Rohling, Jos H T; vanderLeest, Henk Tjebbe; Michel, Stephan; Vansteensel, Mariska J; Meijer, Johanna H

    2011-01-01

    The circadian pacemaker of the suprachiasmatic nuclei (SCN) contains a major pacemaker for 24 h rhythms that is synchronized to the external light-dark cycle. In response to a shift in the external cycle, neurons of the SCN resynchronize with different pace. We performed electrical activity recordings of the SCN of rats in vitro following a 6 hour delay of the light-dark cycle and observed a bimodal electrical activity pattern with a shifted and an unshifted component. The shifted component was relatively narrow as compared to the unshifted component (2.2 h and 5.7 h, respectively). Curve fitting and simulations predicted that less than 30% of the neurons contribute to the shifted component and that their phase distribution is small. This prediction was confirmed by electrophysiological recordings of neuronal subpopulations. Only 25% of the neurons exhibited an immediate shift in the phase of the electrical activity rhythms, and the phases of the shifted subpopulations appeared significantly more synchronized as compared to the phases of the unshifted subpopulations (p<0.05). We also performed electrical activity recordings of the SCN following a 9 hour advance of the light-dark cycle. The phase advances induced a large desynchrony among the neurons, but consistent with the delays, only 19% of the neurons peaked at the mid of the new light phase. The data suggest that resetting of the central circadian pacemaker to both delays and advances is brought about by an initial shift of a relatively small group of neurons that becomes highly synchronized following a shift in the external cycle. The high degree of synchronization of the shifted neurons may add to the ability of this group to reset the pacemaker. The large desynchronization observed following advances may contribute to the relative difficulty of the circadian system to respond to advanced light cycles. PMID:21966529

  4. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms.

    PubMed

    Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu; Shan, Yongli; Fan, Junmei; Izumo, Mariko; Ikeda, Yuichi; Motoike, Toshiyuki; Dixon, Shelley; Seinfeld, Jeffrey E; Takahashi, Joseph S; Yanagisawa, Masashi

    2015-03-01

    Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. PMID:25741729

  5. Phase-shifting of a neuronal circadian pacemaker in Bulla gouldiana by pentylenetetrazol.

    PubMed

    Khalsa, S B; Block, G D

    1992-04-01

    1. The convulsant agent pentylenetetrazol generates compound action potential activity from the circadian pacemaker cells in the Bulla retina. 2. The phase response curve to 3 hr pulses of pentylenetetrazol consists of only phase delays which occur following pulses delivered in the early subjective night. 3. Phase shifts to pentylenetetrazol are independent of extracellular calcium since they persist in a low-calcium EGTA solution. PMID:1354133

  6. Light affects the branching pattern of peptidergic circadian pacemaker neurons in the brain of the cockroach Leucophaea maderae.

    PubMed

    Wei, Hongying; Stengl, Monika

    2011-12-01

    Pigment-dispersing factor-immunoreactive neurons anterior to the accessory medulla (aPDFMes) in the optic lobes of insects are circadian pacemaker neurons in cockroaches and fruit flies. The authors examined whether any of the aPDFMes of the cockroach Leucophaea maderae are sensitive to changes in period and photoperiod of light/dark (LD) cycles as a prerequisite to adapt to changes in external rhythms. Cockroaches were raised in LD cycles of 11:11, 13:13, 12:12, 6:18, or 18:6 h, and the brains of the adults were examined with immunocytochemistry employing antisera against PDF and orcokinin. Indeed, in 11:11 LD cycles, only the number of medium-sized aPDFMes specifically decreased, while it increased in 13:13. In addition, 18:6 LD cycles increased the number of large- and medium-sized aPDFMes, as well as the posterior pPDFMes, while 6:18 LD cycles only decreased the number of medium-sized aPDFMes. Furthermore, PDF-immunoreactive fibers in the anterior optic commissure and orcokinin-immunoreactive fibers in both the anterior and posterior optic commissures were affected by different lengths of light cycles. Thus, apparently different groups of the PDFMes, most of all the medium-sized aPDFMes, which colocalize orcokinin, respond to changes in period and photoperiod and could possibly allow for the adjustment to different photoperiods. PMID:22215609

  7. Mechanisms of clock output in the Drosophila circadian pacemaker system.

    PubMed

    Taghert, Paul H; Shafer, Orie T

    2006-12-01

    Molecular oscillations that underlie the circadian clock are coupled to different output signals by which daily rhythms in downstream events are evoked and/or synchronized. Here the authors review the literature that describes circadian output mechanisms in Drosophila. They begin at the most proximal level, within oscillator cells themselves, by surveying studies of rhythmic gene expression within Drosophila heads. Next the authors describe the several neuron groups that compose the circadian pacemaker network underlying rhythmic locomotor activity, and they detail current models of how that network is organized and coordinated. The authors outline the body of evidence that describes a role for the neuropeptide pigment dispersing factor (PDF) as a circadian transmitter in the fly brain. Finally, in the context of PDF, they consider studies that address mechanisms of signaling from the circadian pacemaker network to downstream neurons and nonneuronal cells that directly control rhythmic outputs. PMID:17107935

  8. Pacemaking Kisspeptin Neurons

    PubMed Central

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

    2013-01-01

    Kisspeptin (Kiss1) neurons are vital for reproduction. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. As such Kiss1 neurons may be the pre-synaptic 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 participate 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 behavior. 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. Under voltage clamp conditions, these channels produce distinct currents that under current clamp conditions can generate burst firing behavior. 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 and hence reproduction. PMID:23884368

  9. Circadian Pacemaking in Cells and Circuits of the Suprachiasmatic Nucleus

    PubMed Central

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

    2014-01-01

    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. PMID:24329967

  10. Reentrainment of the Circadian Pacemaker through Three Distinct Stages

    Microsoft Academic Search

    Tiecheng Liu; Jimo Borjigin

    2005-01-01

    Circadian rhythms are endogenously generated by a central pacemaker and are synchronized to the environmental LD cycle. The rhythms can be resynchronized, or reentrained, after a shift of the LD cycle, as in traveling across time zones. The authors have performed high-resolution mapping of the pacemaker to analyze the reentrainment process using rat pineal melatonin onset (MTon) and melatonin offset

  11. Differentially timed extracellular signals synchronize pacemaker neuron clocks.

    PubMed

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

    2014-09-01

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

  12. Differentially Timed Extracellular Signals Synchronize Pacemaker Neuron Clocks

    PubMed Central

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

    2014-01-01

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

  13. Physiological effects of light on the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

  14. Cellular circadian pacemaking and the role of cytosolic rhythms.

    PubMed

    Hastings, Michael H; Maywood, Elizabeth S; O'Neill, John S

    2008-09-01

    The daily rhythms that adapt organisms to the solar cycle are driven by internal circadian clocks. The hypothesis that the core pacemakers of these clocks consist of auto-regulatory transcriptional/post-translational feedback loops (TTFLs) was first developed in flies and fungi and has now been extended successfully to describe circadian timing mechanisms in mammals and plants. TTFL models revolve around the protein products of 'clock' genes that feedback periodically to regulate their own expression. From this simple beginning, the models have been expanded to encompass multiple, interlinked loops. However, experimental data now highlight the limitations of the TTFL model. Until recently, the focus on transcription caused rhythms in cytosolic signalling pathways to be viewed as outputs of the 'core' transcriptional clockwork, or else as a mechanism for its entrainment by extra-cellular stimuli. Recent work in Arabidopsis thaliana, Drosophila melanogaster and mammals now reveals that cytosolic rhythms in small signalling molecules have a central role within the circadian pacemaker. The logic is consistent across taxa: oscillatory cytoplasmic elements integrate with transcriptional feedback loops to sustain them and determine their rhythmic properties. Thus, clock outputs can constitute inputs to subsequent cycles and so become indistinguishable from a core mechanism. This emphasises the interdependence of nuclear and cytoplasmic processes in circadian pacemaking, such that the pacemakers of some species might encompass the entire cell and its intercellular environment. PMID:18786386

  15. The neurochemical basis of photic entrainment of the circadian pacemaker

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

    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.

  16. Cellular mechanisms of circadian pacemaking: beyond transcriptional loops.

    PubMed

    O'Neill, John S; Maywood, Elizabeth S; Hastings, Michael H

    2013-01-01

    Circadian clocks drive the daily rhythms in our physiology and behaviour that adapt us to the 24-h solar and social worlds. Because they impinge upon every facet of metabolism, their acute or chronic disruption compromises performance (both physical and mental) and systemic health, respectively. Equally, the presence of such rhythms has significant implications for pharmacological dynamics and efficacy, because the fate of a drug and the state of its therapeutic target will vary as a function of time of day. Improved understanding of the cellular and molecular biology of circadian clocks therefore offers novel approaches for therapeutic development, for both clock-related and other conditions. At the cellular level, circadian clocks are pivoted around a transcriptional/post-translational delayed feedback loop (TTFL) in which the activation of Period and Cryptochrome genes is negatively regulated by their cognate protein products. Synchrony between these, literally countless, cellular clocks across the organism is maintained by the principal circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. Notwithstanding the success of the TTFL model, a diverse range of experimental studies has shown that it is insufficient to account for all properties of cellular pacemaking. Most strikingly, circadian cycles of metabolic status can continue in human red blood cells, devoid of nuclei and thus incompetent to sustain a TTFL. Recent interest has therefore focused on the role of oscillatory cytosolic mechanisms as partners to the TTFL. In particular, cAMP- and Ca²?-dependent signalling are important components of the clock, whilst timekeeping activity is also sensitive to a series of highly conserved kinases and phosphatases. This has led to the view that the 'proto-clock' may have been a cytosolic, metabolic oscillation onto which evolution has bolted TTFLs to provide robustness and amplify circadian outputs in the form of rhythmic gene expression. This evolutionary ascent of the clock has culminated in the SCN, a true pacemaker to the innumerable clock cells distributed across the body. On the basis of findings from our own and other laboratories, we propose a model of the SCN pacemaker that synthesises the themes of TTFLs, intracellular signalling, metabolic flux and interneuronal coupling that can account for its unique circadian properties and pre-eminence. PMID:23604476

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

    PubMed Central

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

    2013-01-01

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

  18. Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans.

    PubMed

    Lewy, A J; Sack, R L; Blood, M L; Bauer, V K; Cutler, N L; Thomas, K H

    1995-01-01

    Measuring the dim light melatonin onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This 'phase response curve' (PRC) to light has been applied in the treatment of winter depression, jet lag and shift work, as well as circadian phase sleep disorders. Exogenous melatonin has phase-shifting effects described by a PRC that is about 12 h out of phase with the PRC to light. That is, melatonin administration in the morning causes phase delays and in the afternoon causes phase advances. All of the circadian phase disorders that have been successfully treated with appropriately timed exposure to bright light can be treated with appropriately scheduled melatonin administration. Melatonin administration is more convenient and therefore may be the preferred treatment. PMID:7656692

  19. Metabolic aspects of the rhythmogenesis in Aplysia pacemaker neurons

    Microsoft Academic Search

    C. F. Chen; R. Baumgarten; O. Harth

    1973-01-01

    Completely isolatedAplysia pacemaker neurons were used to investigate mechanisms of endogenous electrical rhythmicity. This preparation allows the study of pure pacemaker activity free from synaptic, ephaptic and\\/or humoral influences from the surrounding cells. The effect of some substances quite different in their mode of biochemical action were tested: sodium iodoacetate, phloridzin, dinitrophenol, heavy water, and ouabain. Each of these substances

  20. Role of Neuronal Membrane Events in Circadian Rhythm Generation

    Microsoft Academic Search

    Gabriella B. Lundkvist; Gene D. Block

    2005-01-01

    Circadian clock systems are composed of an input or “entrainment” pathway by which synchronization to the external environment occurs, a pacemaker responsible for generating rhythmicity, and an output or “expression” pathway through which rhythmic signals act to modulate physiology and behavior. The circadian pacemaker contains molecular feedback loops of rhythmically expressed genes and their protein products, which, through interactions, generate

  1. Computational Model of Electrically Coupled, Intrinsically Distinct Pacemaker Neurons

    PubMed Central

    Soto-Treviño, Cristina; Rabbah, Pascale; Marder, Eve; Nadim, Farzan

    2005-01-01

    Electrical coupling between neurons with similar properties is often studied. Nonetheless, the role of electrical coupling between neurons with widely different intrinsic properties also occurs, but is less well understood. Inspired by the pacemaker group of the crustacean pyloric network, we developed a multicompartment, conductance-based model of a small network of intrinsically distinct, electrically coupled neurons. In the pyloric network, a small intrinsically bursting neuron, through gap junctions, drives 2 larger, tonically spiking neurons to reliably burst in-phase with it. Each model neuron has 2 compartments, one responsible for spike generation and the other for producing a slow, large-amplitude oscillation. We illustrate how these compartments interact and determine the dynamics of the model neurons. Our model captures the dynamic oscillation range measured from the isolated and coupled biological neurons. At the network level, we explore the range of coupling strengths for which synchronous bursting oscillations are possible. The spatial segregation of ionic currents significantly enhances the ability of the 2 neurons to burst synchronously, and the oscillation range of the model pacemaker network depends not only on the strength of the electrical synapse but also on the identity of the neuron receiving inputs. We also compare the activity of the electrically coupled, distinct neurons with that of a network of coupled identical bursting neurons. For small to moderate coupling strengths, the network of identical elements, when receiving asymmetrical inputs, can have a smaller dynamic range of oscillation than that of its constituent neurons in isolation. PMID:15728775

  2. Lability of circadian pacemaker amplitude in chick pineal cells: a temperature-dependent process.

    PubMed

    Barrett, R K; Takahashi, J S

    1997-08-01

    Temperature is a major regulator of circadian rhythms. The authors report here three lines of evidence that temperature modulates the amplitude of the circadian pacemaker that drives rhythmic melatonin production in chick pineal cells. (1) The melatonin rhythm persists longer in constant conditions at 40 degrees C than at 37 degrees C. (2) the phase response curve to low-intensity (0.15 microW/cm2) light pulses of 6-h duration has a higher amplitude at 37 degrees C than at 40 degrees C; a nonphotic stimulus, anisomycin, also causes larger shifts at 37 degrees C than at 40 degrees C. These results suggest a general increase in sensitivity to phase-shifting stimuli as temperature decreases. (3) The light intensity necessary for a critical pulse that causes arrhythmicity is lower at 37 degrees C than at 40 degrees C. All three of these effects of temperature can be explained in a unified manner by a limit cycle model in which temperature increases circadian pacemaker amplitude. The use of critical pulse experiments provides a novel method for estimating relative circadian pacemaker amplitude under different conditions. PMID:9438879

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

    NASA Technical Reports Server (NTRS)

    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

    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.

  4. Nicotine phase-advances the circadian neuronal activity rhythm in rat suprachiasmatic nuclei explants.

    PubMed

    Trachsel, L; Heller, H C; Miller, J D

    1995-04-01

    In vivo studies reported that cholinergic agents affect mammalian circadian rhythmicity. To study phase resetting properties of cholinergic compounds more directly, we carried out experiments in rat suprachiasmatic nuclei slices. Compounds were added to the perfusate for 1 h at specific phases of the circadian cycle. On the following day, the time of peak neuronal activity, a measure of the phase of the endogenous circadian pacemaker, was assessed by means of extracellular recording in the suprachiasmatic nuclei. The peak of neuronal activity occurred at circadian time 5.8 +/- 0.7 (mean +/- 95% confidence limits) in the control slice (circadian time 0: lights-on). Ten-micromolar carbachol had no effect on the phase of the circadian rhythm when given at circadian times 6 and 15, while at circadian time 21 a phase advance of one hour was observed. By contrast, 10 microM nicotine significantly phase advanced (> 1 h) the neuronal circadian rhythm at all but one experimental circadian phase. The circadian times of maximal nicotinic phase advances were 15 (+2.6 h) and 21 (+2.8 h). A concentration response curve for nicotine was generated and pharmacological blocking experiments were performed at circadian time 15. The estimated maximum response of nicotine was 3.4 h, and the estimated concentration for half maximal response was 5 microM. The Hill coefficient (= 1.08) indicated that the effects of nicotine may be explained by a single receptor occupancy model. Mecamylamine (20 microM) almost completely antagonized the nicotinic phase-advances, whereas tetrodotoxin (1 microM) or high Mg2+ (10 mM) did not significantly attenuate the nicotinic phase-advances.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7609878

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

    NASA Technical Reports Server (NTRS)

    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

    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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24643294

  7. Central Control of Circadian Phase in Arousal-Promoting Neurons

    PubMed Central

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

    2013-01-01

    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

  8. Photoperiodic plasticity in circadian clock neurons in insects

    PubMed Central

    Shiga, Sakiko

    2013-01-01

    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. PMID:23986711

  9. Glycinergic pacemaker neurons in preBötzinger complex of neonatal mouse.

    PubMed

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

    2010-03-10

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

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

    PubMed Central

    Tohidi, Vahid; Nadim, Farzan

    2009-01-01

    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. PMID:19458214

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

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

    PubMed

    Damulewicz, Milena; Rosato, Ezio; Pyza, Elzbieta

    2013-01-01

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

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

    PubMed

    Underwood, H

    1983-06-01

    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

  14. The visual input stage of the mammalian circadian pacemaking system: I. Is there a clock in the mammalian eye?

    PubMed

    Remé, C E; Wirz-Justice, A; Terman, M

    1991-01-01

    Threads of evidence from recent experimentation in retinal morphology, neurochemistry, electrophysiology, and visual perception point toward rhythmic ocular processes that may be integral components of circadian entrainment in mammals. Components of retinal cell biology (rod outer-segment disk shedding, inner-segment degradation, melatonin and dopamine synthesis, electrophysiological responses) show self-sustaining circadian oscillations whose phase can be controlled by light-dark cycles. A complete phase response curve in visual sensitivity can be generated from light-pulse-induced phase shifting. Following lesions of the suprachiasmatic nuclei, circadian rhythms of visual detectability and rod outer-segment disk shedding persist, even though behavioral activity becomes arrhythmic. We discuss the converging evidence for an ocular circadian timing system in terms of interactions between rhythmic retinal processes and the central suprachiasmatic pacemaker, and propose that retinal phase shifts to light provide a critical input signal. PMID:1773080

  15. Computational Modeling of the Regulation of Pacemaker Frequency in Dopamine Neurons Marco Huertas and Carmen Canavier

    E-print Network

    Ullmer, Brygg

    the electrical activity of dopamine neurons with spatially extended dendritic processes the native fast sodium conductance and replacing it with a virtual conductance using that the subthreshold component of the sodium current contributes to setting the pacemaking rate

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

    Microsoft Academic Search

    Helena Illnerová; Ji?í Van??ek

    1982-01-01

    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

  17. Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

    PubMed Central

    Görlich, Andreas; Antolin-Fontes, Beatriz; Ables, Jessica L.; Frahm, Silke; ?limak, Marta A.; Dougherty, Joseph D.; Ibañez-Tallon, Inés

    2013-01-01

    The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula–interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for ?3, ?4, and ?5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2–10 Hz generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, ?3?4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse. PMID:24082085

  18. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling

    Microsoft Academic Search

    Elizabeth S. Maywood; Akhilesh B. Reddy; Gabriel K. Y. Wong; John S. O'Neill; John A. O'Brien; Douglas G. McMahon; Anthony J. Harmar; Hitoshi Okamura; Michael H. Hastings

    2006-01-01

    Circadian timekeeping in mammals is driven by transcriptional\\/posttranslational feedback loops that are active within both peripheral tissues and the circadian pacemaker of the suprachiasmatic nuclei (SCN). Spontaneous synchronization of these molecular loops between SCN neurons is a primary requirement of its pacemaker role and distinguishes it from peripheral tissues, which require extrinsic, SCN-dependent cues to impose cellular synchrony. Vasoactive intestinal

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

    E-print Network

    Zucker, Robert S.

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

  20. Pacemaker rate and depolarization block in nigral dopamine neurons: a somatic sodium channel balancing act

    PubMed Central

    Tucker, Kristal R.; Huertas, Marco A.; Horn, John P.; Canavier, Carmen C.; Levitan, Edwin S.

    2012-01-01

    Midbrain dopamine (DA) neurons are slow intrinsic pacemakers that undergo depolarization (DP) block upon moderate stimulation. Understanding DP block is important because it has been correlated with the clinical efficacy of chronic antipsychotic drug treatment. Here we describe how voltage-gated sodium (NaV) channels regulate DP block and pacemaker activity in DA neurons of the substantia nigra using rat brain slices. The distribution, density and gating of NaV currents were manipulated by blocking native channels with tetrodotoxin and by creating virtual channels and anti-channels with dynamic clamp. Although action potentials initiate in the axon initial segment (AIS) and NaV channels are distributed in multiple dendrites, selective reduction of NaV channel activity in the soma was sufficient to decrease pacemaker frequency and increase susceptibility to DP block. Conversely, increasing somatic NaV current density raised pacemaker frequency and lowered susceptibility to DP block. Finally, when NaV currents were restricted to the soma, pacemaker activity occurred at abnormally high rates due to excessive local subthreshold NaV current. Together with computational simulations, these data show that both the slow pacemaker rate and the sensitivity to DP block that characterizes DA neurons result from the low density of somatic NaV channels. More generally, we conclude that the somatodendritic distribution of NaV channels is a major determinant of repetitive spiking frequency. PMID:23077037

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

    E-print Network

    Menger, Gus John, III

    2009-05-15

    , neuronal activity, cell division and numerous facets of gene expression (e.g., chromatin modification, mRNA abundance, translation and post-translational regulation) have been shown to exhibit circadian rhythms (120, 137, 44, 34, 76, 63, 158, 96, 20, 107... are then transmitted to other regions of the SCN, through neuronal and diffusible factors, to facilitate synchrony between the cellular activities of the SCN and the progression of the daily solar cycle. Lastly, through neuronal and diffusible output pathways, SCN...

  2. The Nonlinear Phase Response Curve of the Human Circadian Pacemaker and How Complex Behaviors Might Arise in Nature

    NASA Astrophysics Data System (ADS)

    Leder, Ron S.

    2002-08-01

    Our example from nature is two groups of about 10,000 cells in the brain called Suprachiasmatic Nuclei (SCN) and how light can entrain free running endogenous periodic behavior via the retina's connection to the SCN. Our major question is how a complex behavior like this can arise in nature. Finally presented is a mathematical model and simulation showing how simple periodic signals can be coupled to produce spatio-temporal chaotic behavior and how two complex signals can combine to produce simple coherent behavior with a hypothetical analogy to phase resetting in biological circadian pacemakers.

  3. Circadian rhythms, diet, and neuronal excitability.

    PubMed

    Allen, Charles N

    2008-11-01

    Many aspects of normal biological function are governed by circadian rhythms, including metabolism, ingestive behaviors, and sleep-wake cycles. Certain pathological processes as well are also affected by the circadian rhythms. For example, it is well known that seizure occurrence can be influenced by the sleep-wake cycle. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with proven efficacy in the treatment of intractable epilepsies. While the mechanisms underlying the clinical effects of the KD remain unclear, there are emerging links between circadian rhythms and KD action. Such factors should be considered when planning and administering the KD to patients. PMID:19049609

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

    PubMed

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

    2011-12-01

    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. PMID:22225376

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

    Microsoft Academic Search

    S. I. Alekseev; N. V. Kochetkova; M. C. Ziskin; M. A. Bolshakov

    1997-01-01

    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

  6. Activation of three types of membrane currents by various divalent cations in identified molluscan pacemaker neurons

    Microsoft Academic Search

    T. H. Muller; D. SWANDULLA; H. D. Lux

    1989-01-01

    We investigated membrane currents activated by intracellular diva- lent cations in two types of molluscan pacemaker neurons. A fast and quantitative pressure injection technique was used to apply Ca ~+ and other divalent cations. Ca 2§ was most effective in activating a nonspecific cation current and two types of K § currents found in these cells. One type of outward

  7. The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude.

    PubMed

    Vitaterna, Martha Hotz; Ko, Caroline H; Chang, Anne-Marie; Buhr, Ethan D; Fruechte, Ethan M; Schook, Andrew; Antoch, Marina P; Turek, Fred W; Takahashi, Joseph S

    2006-06-13

    The mouse Clock gene encodes a basic helix-loop-helix-PAS transcription factor, CLOCK, that acts in concert with BMAL1 to form the positive elements of the circadian clock mechanism in mammals. The original Clock mutant allele is a dominant negative (antimorphic) mutation that deletes exon 19 and causes an internal deletion of 51 aa in the C-terminal activation domain of the CLOCK protein. Here we report that heterozygous Clock/+ mice exhibit high-amplitude phase-resetting responses to 6-h light pulses (Type 0 resetting) as compared with wild-type mice that have low amplitude (Type 1) phase resetting. The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation. However, the amplitude of the circadian rhythms of Per gene expression are significantly reduced in Clock homozygous and heterozygous mutants. Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in Clock heterozygotes. The phase-response curves to changes in culture medium are Type 0 in Clock heterozygotes, but Type 1 in wild types, similar to that seen for light in vivo. The increased efficacy of resetting stimuli and decreased PER expression amplitude can be explained in a unified manner by a model in which the Clock mutation reduces circadian pacemaker amplitude in the suprachiasmatic nuclei. PMID:16754844

  8. Synergistic Interactions between the Molecular and Neuronal Circadian Networks Drive Robust Behavioral Circadian Rhythms in Drosophila melanogaster

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

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

    2014-04-01

    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

  10. 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

    Derk-Jan Dijk; Charles A. Czeisler

    1995-01-01

    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

  11. Influences of the circadian clock on neuronal susceptibility to excitotoxicity

    PubMed Central

    Karmarkar, Sumedha W.; Tischkau, Shelley A.

    2013-01-01

    Stroke is the third leading cause of death and the primary cause of morbidity in the United States, thus posing an enormous burden on the healthcare system. The factors that determine the risk of an individual toward precipitation of an ischemic event possess a strong circadian component as does the ischemic event itself. This predictability provided a window of opportunity toward the development of chronopharmaceuticals which provided much better clinical outcomes. Experiments from our lab showed for the first time that neuronal susceptibility to ischemic events follows a circadian pattern; hippocampal neurons being most susceptible to an ischemic insult occurring during peak activity in a rodent model of global cerebral ischemia. We also demonstrated that the SCN2.2 cells (like their in vivo counterpart) are resistant to excitotoxicity by glutamate and that this was dependent on activation of ERK signaling. We are currently working on elucidating the complete neuroprotective pathway that provides a barricade against glutamate toxicity in the SCN2.2 cells. Our future experiments will be engaged in hijacking the neuroprotective mechanism in the SCN2.2 cells and applying it to glutamate-susceptible entities in an effort to prevent their death in the presence of excitotoxicity. Despite the advancement in chronopharmaceuticals, optimal clinical outcome with minimal adverse events are difficult to come by at an affordable price. Superior treatment options require a better understanding of molecular mechanisms that define the disease, including the role of the circadian clock. PMID:24204346

  12. Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking

    PubMed Central

    Lei, Ming; Jones, Sandra A; Liu, Jie; Lancaster, Matthew K; Fung, Simon S-M; Dobrzynski, Halina; Camelliti, Patrizia; Maier, Sebastian K G; Noble, Denis; Boyett, Mark R

    2004-01-01

    The majority of Na+ channels in the heart are composed of the tetrodotoxin (TTX)-resistant (KD, 2–6 ?m) Nav1.5 isoform; however, recently it has been shown that TTX-sensitive (KD, 1–10 nm) neuronal Na+ channel isoforms (Nav1.1, Nav1.3 and Nav1.6) are also present and functionally important in the myocytes of the ventricles and the sinoatrial (SA) node. In the present study, in mouse SA node pacemaker cells, we investigated Na+ currents under physiological conditions and the expression of cardiac and neuronal Na+ channel isoforms. We identified two distinct Na+ current components, TTX resistant and TTX sensitive. At 37°C, TTX-resistant iNa and TTX-sensitive iNa started to activate at ??70 and ??60 mV, and peaked at ?30 and ?10 mV, with a current density of 22 ± 3 and 18 ± 1 pA pF?1, respectively. TTX-sensitive iNa inactivated at more positive potentials as compared to TTX-resistant iNa. Using action potential clamp, TTX-sensitive iNa was observed to activate late during the pacemaker potential. Using immunocytochemistry and confocal microscopy, different distributions of the TTX-resistant cardiac isoform, Nav1.5, and the TTX-sensitive neuronal isoform, Nav1.1, were observed: Nav1.5 was absent from the centre of the SA node, but present in the periphery of the SA node, whereas Nav1.1 was present throughout the SA node. Nanomolar concentrations (10 or 100 nm) of TTX, which block TTX-sensitive iNa, slowed pacemaking in both intact SA node preparations and isolated SA node cells without a significant effect on SA node conduction. In contrast, micromolar concentrations (1–30 ?m) of TTX, which block TTX-resistant iNa as well as TTX-sensitive iNa, slowed both pacemaking and SA node conduction. It is concluded that two Na+ channel isoforms are important for the functioning of the SA node: neuronal (putative Nav1.1) and cardiac Nav1.5 isoforms are involved in pacemaking, although the cardiac Nav1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle. PMID:15254155

  13. Fentanyl, a upsilon-opioid receptor agonist, phase shifts the hamster circadian pacemaker.

    PubMed

    Meijer, J H; Ruijs, A C; Albus, H; van de Geest, B; Duindam, H; Zwinderman, A H; Dahan, A

    2000-06-16

    The phase-shifting effects of the mu-opioid receptor agonist fentanyl on the circadian timing system were investigated in the hamster. Fentanyl injections during the mid-subjective day induced phase advances of the hamsters' wheel-running activity rhythm. The shifts were not accompanied by an increase in locomotor activity but instead a decrease of activity was often observed. A dose-response curve indicated that with increasing dosage, the response probability increased, while the magnitude of the induced shift remained stable. The present data suggest that there is some role for opioid regulation of the circadian system. PMID:10841898

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

    Microsoft Academic Search

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

    1995-01-01

    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,

  15. CENTRAL AND PERIPHERAL CIRCADIAN CLOCKS IN MAMMALS

    PubMed Central

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

    2013-01-01

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

  16. Dual regulation of clock gene Per2 expression in discrete brain areas by the circadian pacemaker and methamphetamine-induced oscillator in rats.

    PubMed

    Natsubori, Akiyo; Honma, Ken-ichi; Honma, Sato

    2014-01-01

    Behavioral rhythms induced by methamphetamine (MAP) treatment in rats are independent of the circadian pacemaker in the suprachiasmatic nucleus (SCN). To know the site and mechanism of an underlying oscillation (MAP-induced oscillator; MAO), extra-SCN circadian rhythms in the discrete brain areas were examined in rats with and without the SCN. To fix the phase of MAO, MAP was supplied in drinking water at a restricted time of day for 14 days (R-MAP) and subsequently given ad libitum (ad-MAP). Plain water was given to the controls at the same restricted time (R-Water). Clock gene Per2 expression was measured by a bioluminescence reporter in cultured brain tissues. In SCN-intact rats, MAO was induced by R-MAP and behavioral rhythms were phase-delayed from the restricted time under ad-MAP with relative coordination. Circadian Per2 rhythms in R-MAP rats were not affected in the SCN but were slightly phase-advanced in the olfactory bulb (OB), caudate-putamen (CPU) and substantia nigra (SN) as compared with R-Water rats. Following SCN lesion, R-MAP-induced MAO phase-shifted more slowly and did not show a sign of relative coordination. In these rats, circadian Per2 rhythms were significantly phase-shifted in the OB and SN as compared with SCN-intact rats. These findings indicate that MAO was induced by MAP given at a restricted time of day in association with phase-shifts of the extra-SCN circadian oscillators in the brain dopaminergic areas. The findings also suggest that these extra-SCN oscillators are the components of MAO and receive dual regulation by MAO and the SCN circadian pacemaker. PMID:24438490

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

    PubMed Central

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

    2014-01-01

    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 PMID:24939987

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

    PubMed

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

    2014-01-01

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

  19. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1

    PubMed Central

    Guzman, Jaime N.; Sanchez-Padilla, Javier; Wokosin, David; Kondapalli, Jyothisri; Ilijic, Ema; Schumacker, Paul T.; Surmeier, D. James

    2015-01-01

    Parkinson's disease (PD) is a pervasive, aging-related neurodegenerative disease whose cardinal motor symptoms reflect the loss of a small group of neurons – dopaminergic neurons in the substantia nigra pars compacta (SNc)1. Mitochondrial oxidant stress is widely viewed as responsible for this loss2, but why these particular neurons should be stressed is a mystery. Using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, it was discovered that the unusual engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. This stress engaged defenses that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, antagonists of cloned uncoupling proteins. Knocking out DJ-1, a gene associated with an early onset form of PD, down-regulated the expression of two uncoupling proteins (UCP4, 5), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of PD. PMID:21068725

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

    E-print Network

    Menger, Gus John, III

    2009-05-15

    Diverse forms of life have evolved 24-hour or circadian timekeeping systems serving to coordinate internal biological events with the daily solar cycle. The generation of circadian rhythms by this timekeeping system ensures that internal processes...

  1. Neuronal circadian rhythm: phase shifting by a protein synthesis inhibitor.

    PubMed

    Jacklet, J W

    1977-10-01

    A potent inhibitor of protein synthesis, anisomycin, was applied (10(-6)M) in 6-hour pulses at specific phases in the circadian rhythm of endogenous compound action potential (CAP) activity recorded from the eye of Aplysia in vitro. The phase of the circadian rhythm was systematically advanced or delayed (up to 15 hours) depending on the specific phase at which the pulse was applied. The resultant phase response curve implicates protein synthesis on the eukaryotic ribosome as a fundamental part of the controlling processes that constitutes the circadian clock. PMID:897685

  2. Setting Clock Speed in Mammals: The CK1? tau Mutation in Mice Accelerates Circadian Pacemakers by Selectively Destabilizing PERIOD Proteins

    Microsoft Academic Search

    Qing-Jun Meng; Larisa Logunova; Elizabeth S. Maywood; Monica Gallego; Jake Lebiecki; Timothy M. Brown; Martin Sládek; Andrei S. Semikhodskii; Nicholas R. J. Glossop; Hugh D. Piggins; Johanna E. Chesham; David A. Bechtold; Seung-Hee Yoo; Joseph S. Takahashi; David M. Virshup; Raymond P. Boot-Handford; Michael H. Hastings; Andrew S. I. Loudon

    2008-01-01

    SUMMARY The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mech- anisms whereby casein kinase1 (CK1) determines cir- cadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period length- ened in CK13? \\/? , whereas CK13tau\\/tau shortened circa- dian period of behavior in vivo and suprachiasmatic nucleus firing

  3. Circadian Rhythm of Redox State Regulates Excitability in Suprachiasmatic Nucleus Neurons

    PubMed Central

    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

    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. PMID:22859819

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

    Microsoft Academic Search

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

    2004-01-01

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

  5. Neuropeptidergic input pathways to the circadian pacemaker center of the Madeira cockroach analysed with an improved injection technique.

    PubMed

    Schulze, Julia; Schendzielorz, Thomas; Neupert, Susanne; Predel, Reinhard; Stengl, Monika

    2013-09-01

    Light entrainment pathways synchronize the circadian clock of almost all species of the animal and plant kingdom to the daily light dark cycle. In the Madeira cockroach Rhyparobia (Leucophaea) maderae, the circadian clock is located in the accessory medulla of the brain's optic lobes. The clock has abundant neuropeptides with unknown functions. Previous studies suggested that myoinhibitory peptides (MIPs), orcokinins (ORCs), and allatotropin (AT) take part in light input pathways to the circadian clock. As the sequences of AT and ORCs of R. maderae have not yet been determined, with matrix-assisted laser desorption/ionization-time of flight mass spectrometry, the respective Rhyparobia peptides were characterized. To search for light-like phase-shifting inputs to the circadian clock, Rhyparobia-MIP-1, Rhyparobia-AT, and Rhyparobia-ORC were injected at different circadian times, combined with locomotor activity assays. An improved, less invasive injection method was developed that allowed for the analysis of peptide effects within <2 weeks after injection. Rhyparobia-MIP-1 and Rhyparobia-AT injections resulted in dose-dependent monophasic phase response curves with maximum delays at the beginning of the subjective night, similar to light-dependent phase delays. In contrast to Manduca sexta-AT, Rhyparobia-AT did not phase advance locomotor activity rhythms. Only injections of Rhyparobia-ORCs resulted in a biphasic light-like phase response curve. Thus, it is hypothesized that Rhyparobia-MIP-1 and -AT are candidates for relaying light-dependent delays and/or non-photic inputs to the clock, whereas Rhyparobia-ORCs might be part of the light-entrainment pathways relaying phase delays and advances to the circadian clock of the Madeira cockroach. PMID:23802608

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

    PubMed

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

    2015-02-11

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

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

    PubMed

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

    2012-04-01

    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

  8. Circadian rhythms in the morphology of neurons in Drosophila

    Microsoft Academic Search

    Kerstin I. Mehnert; Rafael Cantera

    2011-01-01

    Neurons have an enormous capacity to adapt to changing conditions through the regulation of gene expression, morphology, and\\u000a physiology. In the fruit fly Drosophila melanogaster, this plasticity includes recurrent changes taking place within intervals of a few hours during the day. The rhythmic alterations\\u000a in the morphology of neurons described so far include changes in axonal diameter, branching complexity, synapse

  9. The circadian system: plasticity at many levels.

    PubMed

    Muraro, N I; Pírez, N; Ceriani, M F

    2013-09-01

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

  10. Interaction of circadian and stress systems in the regulation of adipose physiology.

    PubMed

    Tsang, Anthony H; Kolbe, Isa; Seemann, Julia; Oster, Henrik

    2014-08-01

    Endogenous circadian clocks facilitate the adaptation of physiology and behavior to recurring environmental changes brought about by the Earth's rotation around its axis. Adipose tissues harbor intrinsic circadian oscillators based on interlocked transcriptional-translational feedback loops built from a set of clock genes that regulate important aspects of lipid metabolism and adipose endocrine function. These adipocyte clocks are reset via neuronal and endocrine pathways originating from a master circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus. One important mediator of circadian output is the stress hormone cortisol, which, at the same time, is one of the major regulators of adipose physiology. In this review we summarize recent findings on the interaction between circadian and stress systems in the regulation of adipose physiology and discuss the implications of this crosstalk for the development of metabolic disorders associated with circadian disruption and/or chronic stress, for example in shift workers. PMID:25390019

  11. A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits.

    PubMed

    Maywood, Elizabeth S; Chesham, Johanna E; O'Brien, John A; Hastings, Michael H

    2011-08-23

    The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of mammals, coordinating daily rhythms of behavior and metabolism. Circadian timekeeping in SCN neurons revolves around transcriptional/posttranslational feedback loops, in which Period (Per) and Cryptochrome (Cry) genes are negatively regulated by their protein products. Recent studies have revealed, however, that these "core loops" also rely upon cytosolic and circuit-level properties for sustained oscillation. To characterize interneuronal signals responsible for robust pacemaking in SCN cells and circuits, we have developed a unique coculture technique using wild-type (WT) "graft" SCN to drive pacemaking (reported by PER2::LUCIFERASE bioluminescence) in "host" SCN deficient either in elements of neuropeptidergic signaling or in elements of the core feedback loop. We demonstrate that paracrine signaling is sufficient to restore cellular synchrony and amplitude of pacemaking in SCN circuits lacking vasoactive intestinal peptide (VIP). By using grafts with mutant circadian periods we show that pacemaking in the host SCN is specified by the genotype of the graft, confirming graft-derived factors as determinants of the host rhythm. By combining pharmacological with genetic manipulations, we show that a hierarchy of neuropeptidergic signals underpins this paracrine regulation, with a preeminent role for VIP augmented by contributions from arginine vasopressin (AVP) and gastrin-releasing peptide (GRP). Finally, we show that interneuronal signaling is sufficiently powerful to maintain circadian pacemaking in arrhythmic Cry-null SCN, deficient in essential elements of the transcriptional negative feedback loops. Thus, a hierarchy of paracrine neuropeptidergic signals determines cell- and circuit-level circadian pacemaking in the SCN. PMID:21788520

  12. Spike firing pattern of output neurons of the Limulus circadian clock.

    PubMed

    Liu, Jiahui S; Passaglia, Christopher L

    2011-08-01

    The lateral eyes of the horseshoe crab (Limulus polyphemus) show a daily rhythm in visual sensitivity that is mediated by efferent nerve signals from a circadian clock in the crab's brain. How these signals communicate circadian messages is not known for this or other animals. Here the authors describe in quantitative detail the spike firing pattern of clock output neurons in living horseshoe crabs and discuss its possible significance to clock organization and function. Efferent fiber spike trains were recorded extracellularly for several hours to days, and in some cases, the electroretinogram was simultaneously acquired to monitor eye sensitivity. Statistical features of single- and multifiber recordings were characterized via interval distribution, serial correlation, and power spectral analysis. The authors report that efferent feedback to the eyes has several scales of temporal structure, consisting of multicellular bursts of spikes that group into clusters and packets of clusters that repeat throughout the night and disappear during the day. Except near dusk and dawn, the bursts occur every 1 to 2 sec in clusters of 10 to 30 bursts separated by a minute or two of silence. Within a burst, each output neuron typically fires a single spike with a preferred order, and intervals between bursts and clusters are positively correlated in length. The authors also report that efferent activity is strongly modulated by light at night and that just a brief flash has lasting impact on clock output. The multilayered firing pattern is likely important for driving circadian rhythms in the eye and other target organs. PMID:21775292

  13. Genetics of Circadian Rhythms in Mammalian Model Organisms

    PubMed Central

    Lowrey, Phillip L.; Takahashi, Joseph S.

    2013-01-01

    The mammalian circadian system is a complex hierarchical temporal network which is organized around an ensemble of uniquely coupled cells comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus. This central pacemaker is entrained each day by the environmental light/dark cycle and transmits synchronizing cues to cell-autonomous oscillators in tissues throughout the body. Within cells of the central pacemaker and the peripheral tissues, the underlying molecular mechanism by which oscillations in gene expression occur involves interconnected feedback loops of transcription and translation. Over the past 10 years we have learned much regarding the genetics of this system, including how it is particularly resilient when challenged by single-gene mutations, how accessory transcriptional loops enhance the robustness of oscillations, how epigenetic mechanisms contribute to the control of circadian gene expression, and how, from coupled neuronal networks, emergent clock properties arise. Here we will explore the genetics of the mammalian circadian system from cell-autonomous molecular oscillations, to interactions among central and peripheral oscillators and ultimately, to the daily rhythms of behavior observed in the animal. PMID:21924978

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

    PubMed Central

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

    2013-01-01

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

  15. Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health

    PubMed Central

    Ramkisoensing, Ashna; Meijer, Johanna H.

    2015-01-01

    In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude of the SCN’s electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise) has a positive effect on amplitude. Given that the amplitude of the SCN’s electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-h rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders.

  16. PREBOTZINGER COMPLEX AND PACEMAKER NEURONS: Hypothesized Site and Kernel for Respiratory Rhythm Generation

    Microsoft Academic Search

    Jens C. Rekling; Jack L. Feldman

    1998-01-01

    Identification of the sites and mechanisms underlying the generation of respiratory rhythm is of longstanding interest to physiologists and neurobiologists. Recently, with the development of novel experimental preparations, especially in vitro en bloc and slice preparations of rodent brainstem, progress has been made. In particular, a site in the ventrolateral medulla, the preBotzinger Complex, is hypothesized to contain neuronal circuits

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

    PubMed Central

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

    2013-01-01

    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. PMID:23318870

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

    PubMed

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

    2013-04-01

    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

  19. Programmable Pacemaker

    NASA Technical Reports Server (NTRS)

    1980-01-01

    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.

  20. NAT1/DAP5/p97 and atypical translational control in the Drosophila Circadian Oscillator.

    PubMed

    Bradley, Sean; Narayanan, Siddhartha; Rosbash, Michael

    2012-11-01

    Circadian rhythms are driven by gene expression feedback loops in metazoans. Based on the success of genetic screens for circadian mutants in Drosophila melanogaster, we undertook a targeted RNAi screen to study the impact of translation control genes on circadian locomotor activity rhythms in flies. Knockdown of vital translation factors in timeless protein-positive circadian neurons caused a range of effects including lethality. Knockdown of the atypical translation factor NAT1 had the strongest effect and lengthened circadian period. It also dramatically reduced PER protein levels in pigment dispersing factor (PDF) neurons. BELLE (BEL) protein was also reduced by the NAT1 knockdown, presumably reflecting a role of NAT1 in belle mRNA translation. belle and NAT1 are also targets of the key circadian transcription factor Clock (CLK). Further evidence for a role of NAT1 is that inhibition of the target of rapamycin (TOR) kinase increased oscillator activity in cultured wings, which is absent under conditions of NAT1 knockdown. Moreover, the per 5'- and 3'-UTRs may function together to facilitate cap-independent translation under conditions of TOR inhibition. We suggest that NAT1 and cap-independent translation are important for per mRNA translation, which is also important for the circadian oscillator. A circadian translation program may be especially important in fly pacemaker cells. PMID:22904033

  1. Circadian dysfunction in a mouse model of Parkinson's disease.

    PubMed

    Kudo, Takashi; Loh, Dawn H; Truong, Danny; Wu, Yingfei; Colwell, Christopher S

    2011-11-01

    Many Parkinson's disease (PD) patients exhibit sleep disorders as part of their symptoms with evidence suggesting that REM sleep disorders may be intimately associated with this disease. Possible dysfunction in the circadian system in PD has received less attention, yet problems in circadian timing are common in neurodegenerative diseases. In the present study, we examined the expression of daily and circadian rhythms in the alpha-synuclein overexpressing (ASO) transgenic line. We found selective deficits in the expression of circadian rhythms of locomotor activity, including lower night-time activity and greater fragmentation in the wheel-running activity in this PD model. These alterations were prominent in young adult (3-4 mo) ASO mice and worsened progressively with age, consistent with prior reports of age-related loss of motor skills. The temporal distribution of sleep was also altered in the ASO mice compared to littermate controls. In the ASO mice, the peak/trough expression of the clock gene PERIOD2 was normal in the master pacemaker of the circadian system: the suprachiasmatic nucleus (SCN); however, the daytime firing rate of SCN neurons was reduced in the mutant mice. Together, this data raises the possibility that a weakening of circadian output is a core feature of PD. The reduction in magnitude of circadian output would be expected to have functional consequences throughout the body. PMID:21864527

  2. [Dyslipidemia induced disorder of circadian rhythm].

    PubMed

    Shimba, Shigeki

    2013-12-01

    Several epidemiological studies have suggested that the perturbation of circadian rhythm has adverse metabolic consequences (e.g., dyslipidemia) in humans. At the molecular level, circadian rhythms are encoded by an autoregulatory loop composed of a set of transcription activators (BMAL1/CLOCK) that induce expression of repressors (PER/CRY). The mammalian molecular clock is not only expressed within the master suprachiasmatic nucleus pacemaker neurons, but also within nearly all cells. In addition to this core loop, BMAL1/CLOCK also induce expression of the orphan nuclear hormone receptor, which modulates Bmal1 transcription. Disruption of clock genes results in metabolic deregulation in mice. In this article, the roles of clock genes in the regulation of metabolism were summarized based on the phenotypes of the knockout mice. PMID:24437265

  3. The Tau mutation of casein kinase 1? sets the period of the mammalian pacemaker via regulation of Period1 or Period2 clock proteins.

    PubMed

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

    2014-04-01

    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

  4. Advanced Pacemaker

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Synchrony, developed by St. Jude Medical's Cardiac Rhythm Management Division (formerly known as Pacesetter Systems, Inc.) is an advanced state-of-the-art implantable pacemaker that closely matches the natural rhythm of the heart. The companion element of the Synchrony Pacemaker System is the Programmer Analyzer APS-II which allows a doctor to reprogram and fine tune the pacemaker to each user's special requirements without surgery. The two-way communications capability that allows the physician to instruct and query the pacemaker is accomplished by bidirectional telemetry. APS-II features 28 pacing functions and thousands of programming combinations to accommodate diverse lifestyles. Microprocessor unit also records and stores pertinent patient data up to a year.

  5. Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons.

    PubMed

    Farajnia, Sahar; Meijer, Johanna H; Michel, Stephan

    2015-06-01

    Aging impairs the function of the suprachiasmatic nucleus (SCN, the central mammalian clock), leading to a decline in the circadian rhythm of many physiological processes, including sleep-wake rhythms. Recent studies have found evidence of age-related changes in the circadian regulation of potassium currents; these changes presumably lead to a decrease in the SCN's electrical rhythm amplitude. Current through large-conductance Ca(2+)-activated K(+) (BK) channels promote rhythmicity in both SCN neuronal activity and behavior. In many neuron types, changes in BK activity are correlated with changes in intracellular Ca(2+) concentration ([Ca(2+)]i). We performed patch-clamp recordings of SCN neurons in aged mice and observed that the circadian modulation of BK channel activity was lost because of a reduction in BK currents during the night. This reduced current diminished the afterhyperpolarization, depolarized the resting membrane potential, widened the action potential, and increased [Ca(2+)]i. These data suggest that reduced BK current increases [Ca(2+)]i by altering the action potential waveform, possibly contributing to the observed age-related phenotype. PMID:25735218

  6. Fast delayed rectifier potassium current is required for circadian neural activity.

    PubMed

    Itri, Jason N; Michel, Stephan; Vansteensel, Mariska J; Meijer, Johanna H; Colwell, Christopher S

    2005-05-01

    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). The ionic mechanisms that underlie these rhythms are largely unknown. Using the mouse brain slice preparation, we show that the magnitude of fast delayed rectifier (FDR) potassium currents has a diurnal rhythm that peaks during the day. Notably, this rhythm continues in constant darkness, providing the first demonstration of the circadian regulation of an intrinsic voltage-gated current in mammalian cells. Blocking this current prevented the daily rhythm in firing rate in SCN neurons. Kv3.1b and Kv3.2 potassium channels were widely distributed within the SCN, with higher expression during the day. We conclude that the FDR is necessary for the circadian modulation of electrical activity in SCN neurons and represents an important part of the ionic basis for the generation of rhythmic output. PMID:15852012

  7. Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus

    PubMed Central

    Bernard, Samuel; Gonze, Didier; ?ajavec, Branka; Herzel, Hanspeter; Kramer, Achim

    2007-01-01

    The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides coordinating cells, the synchronization factors play a crucial role in the sustenance of intrinsic cellular rhythmicity. Disruption of intercellular signaling abolishes sustained rhythmicity in a majority of neurons and desynchronizes the remaining rhythmic neurons. Based on these observations, the authors propose a model for the synchronization of circadian oscillators that combines intracellular and intercellular dynamics at the single-cell level. The model is a heterogeneous network of circadian neuronal oscillators where individual oscillators are damped rather than self-sustained. The authors simulated different experimental conditions and found that: (1) in normal, constant conditions, coupled circadian oscillators quickly synchronize and produce a coherent output; (2) in large populations, such oscillators either synchronize or gradually lose rhythmicity, but do not run out of phase, demonstrating that rhythmicity and synchrony are codependent; (3) the number of oscillators and connectivity are important for these synchronization properties; (4) slow oscillators have a higher impact on the period in mixed populations; and (5) coupled circadian oscillators can be efficiently entrained by light–dark cycles. Based on these results, it is predicted that: (1) a majority of SCN neurons needs periodic synchronization signal to be rhythmic; (2) a small number of neurons or a low connectivity results in desynchrony; and (3) amplitudes and phases of neurons are negatively correlated. The authors conclude that to understand the orchestration of timekeeping in the SCN, intracellular circadian clocks cannot be isolated from their intercellular communication components. PMID:17432930

  8. Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei

    PubMed Central

    Landgraf, Dominic; Koch, Christiane E.; Oster, Henrik

    2014-01-01

    In most species, self-sustained molecular clocks regulate 24-h rhythms of behavior and physiology. In mammals, a circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN) receives photic signals from the retina and synchronizes subordinate clocks in non-SCN tissues. The emergence of circadian rhythmicity during development has been extensively studied for many years. In mice, neuronal development in the presumptive SCN region of the embryonic hypothalamus occurs on days 12–15 of gestation. Intra-SCN circuits differentiate during the following days and retinal projections reach the SCN, and thus mediate photic entrainment, only after birth. In contrast the genetic components of the clock gene machinery are expressed much earlier and during midgestation SCN explants and isolated neurons are capable of generating molecular oscillations in culture. In vivo metabolic rhythms in the SCN, however, are observed not earlier than the 19th day of rat gestation, and rhythmic expression of clock genes is hardly detectable until after birth. Together these data indicate that cellular coupling and, thus, tissue-wide synchronization of single-cell rhythms, may only develop very late during embryogenesis. In this mini-review we describe the developmental origin of the SCN structure and summarize our current knowledge about the functional initiation and entrainment of the circadian pacemaker during embryonic development. PMID:25520627

  9. Disruption of the Activity–Rest Cycle by MAOI Treatment: Dependence on Light and a Secondary Visual Pathway to the Circadian Pacemaker

    Microsoft Academic Search

    W. C Duncan; K. A Johnson; E Sutin; T. A Wehr

    1998-01-01

    The disruptive effects on the activity–rest cycle of the monoamine oxidase inhibitor (MAOI) clorgyline and of continuous light were examined in Syrian hamsters. When administered in dim and moderate light intensities, clorgyline delayed the daily onset of wheel-running. When administered in bright light, it dissociated the circadian rhythm of wheel-running. This dissociation was prevented by lesions of the intergeniculate leaflet

  10. A simple model for circadian timing by mammals.

    PubMed

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

    2009-01-01

    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

  11. Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis

    Microsoft Academic Search

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

    2008-01-01

    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

  12. Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus

    PubMed Central

    Doi, Masao; Ishida, Atsushi; Miyake, Akiko; Sato, Miho; Komatsu, Rie; Yamazaki, Fumiyoshi; Kimura, Ikuo; Tsuchiya, Soken; Kori, Hiroshi; Seo, Kazuyuki; Yamaguchi, Yoshiaki; Matsuo, Masahiro; Fustin, Jean-Michel; Tanaka, Rina; Santo, Yasuko; Yamada, Hiroyuki; Takahashi, Yukari; Araki, Michihiro; Nakao, Kazuki; Aizawa, Shinichi; Kobayashi, Masaki; Obrietan, Karl; Tsujimoto, Gozoh; Okamura, Hitoshi

    2011-01-01

    Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell–cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate G?i, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24?h rhythm in behaviour. PMID:21610730

  13. Computational modeling of synchronization process of the circadian timing system of mammals.

    PubMed

    Cardoso, Francisco Roberto Gomes; de Oliveira Cruz, Frederico Alan; Silva, Dílson; Cortez, Célia Martins

    2009-05-01

    This paper presents a model for the circadian temporization system of mammals which associates the synchronization dynamics of coupling oscillators to a set of equations able to reproduce the synaptic characteristics of somatodendritic membrane of neurons. The circadian timing system is organized in a way to receive information from the external and internal environments, and its function is the timing organization of physiological and behavioral processes in a circadian pattern. Circadian timing system in mammals is constituted by a group of structures which includes the suprachiasmatic nucleus, the intergeniculate leaflet and the pineal gland. In suprachiasmatic nucleus are found neuron groups working as a biological pacemaker-the so-called biological master clock. By means of numerical simulations using the Kuramoto model, we simulated the dynamics behavior of the biological pacemaker. For this we used a set of 1,000 coupled oscillators with long-range coupling, which were distributed on a 10 x 10 x 10 spherical lattice, and a new method to estimate the order parameter, which characterizes the degree of synchronization of oscillator system. Our model has been able to produce frequency responses in accordance with physiological patterns, and to reproduce two fundamental characteristics of biological rhythms: the endogenous generation and synchronization to the light-dark cycle. PMID:19367410

  14. Djungarian hamsters: a species with a labile circadian pacemaker? Arrhythmicity under a light-dark cycle induced by short light pulses.

    PubMed

    Steinlechner, Stephan; Stieglitz, Ariane; Ruf, Thomas

    2002-06-01

    In most cases, phase-shifting effects of light pulses are studied in animals kept in constant darkness (DD) or in animals released into DD following the stimulus. In this study, the authors exposed Djungarian hamsters (Phodopus sungorus) to short light pulses during the dark phase of a 16:8 light-dark (LD) cycle and thus obtained a type VI phase response curve. Light pulses early in the night caused phase delays of the activity onset as well as phase advances of the activity offset, whereas light pulses later in the night resulted in phase advances of the activity offset only. A combination of two 15-min light pulses-the first one given late in the scotophase and the second given early in the dark phase of the following night-led to a strong compression of the activity phase alpha. In 75% of all animals, daily rhythms were no longer visible after complete alpha compression, and long-term arrhythmicity (up to 145 days) persisted despite continued exposure to an LD cycle. Because three independent output rhythms of the clock (i.e., activity, body temperature, and melatonin rhythms) were equally affected, the authors conclude that overt arrhythmicity was due not merely to disrupted output pathways but to an altered state of the central pacemaker. The authors suggest a qualitative two-oscillator model to explain this phenomenon. Their hypothesis assumes that, due to loose coupling, the pacemaker of Djungarian hamsters can be driven to a state of zero phase difference between the two oscillators, with zero amplitude of their outputs. PMID:12054196

  15. Wavelet Measurement Suggests Cause of Period Instability in Mammalian Circadian Neurons

    Microsoft Academic Search

    Kirsten Meeker; Richard Harang; Alexis B. Webb; David K. Welsh; Francis J. Doyle; Guillaume Bonnet; Erik D. Herzog; Linda R. Petzold

    2011-01-01

    Cells in the suprachiasmatic nucleus (SCN) display remarkable precision, while either physically or chemically decoupling these cells from each other leads to a dramatic increase in period-to-period variability. Where previous studies have classified cells as either arrhythmic or circadian, our wavelet analysis reveals that individual cells, when removed from network interactions, intermittently express circadian and\\/or longer infradian periods. We reproduce

  16. Mitogen-Activated Protein Kinase Is a Functional Component of the Autonomous Circadian System in the Suprachiasmatic Nucleus

    PubMed Central

    Akashi, Makoto; Hayasaka, Naoto; Yamazaki, Shin; Node, Koichi

    2008-01-01

    The suprachiasmatic nucleus (SCN) is the master circadian pacemaker driving behavioral and physiological rhythms in mammals. Circadian activation of mitogen-activated protein kinase [MAPK; also known as ERK (extracellular signal-regulated kinase)] is observed in vivo in the SCN under constant darkness, although the biological significance of this remains unclear. To elucidate this question, we first examined whether MAPK was autonomously activated in ex vivo SCN slices. Moreover, we investigated the effect of MAPK inhibition on circadian clock gene expression and neuronal firing rhythms using SCN-slice culture systems. We show herein that MAPK is autonomously activated in the SCN, and our data demonstrate that inhibition of the MAPK activity results in dampened rhythms and reduced basal levels in circadian clock gene expression at the SCN single-neuron level. Furthermore, MAPK inhibition attenuates autonomous circadian neuronal firing rhythms in the SCN. Thus, our data suggest that light-independent MAPK activity contributes to the robustness of the SCN autonomous circadian system. PMID:18448638

  17. Topological specificity and hierarchical network of the circadian calcium rhythm in the suprachiasmatic nucleus.

    PubMed

    Enoki, Ryosuke; Kuroda, Shigeru; Ono, Daisuke; Hasan, Mazahir T; Ueda, Tetsuo; Honma, Sato; Honma, Ken-ichi

    2012-12-26

    The circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) is a hierarchical multioscillator system in which neuronal networks play crucial roles in expressing coherent rhythms in physiology and behavior. However, our understanding of the neuronal network is still incomplete. Intracellular calcium mediates the input signals, such as phase-resetting stimuli, to the core molecular loop involving clock genes for circadian rhythm generation and the output signals from the loop to various cellular functions, including changes in neurotransmitter release. Using a unique large-scale calcium imaging method with genetically encoded calcium sensors, we visualized intracellular calcium from the entire surface of SCN slice in culture including the regions where autonomous clock gene expression was undetectable. We found circadian calcium rhythms at a single-cell level in the SCN, which were topologically specific with a larger amplitude and more delayed phase in the ventral region than the dorsal. The robustness of the rhythm was reduced but persisted even after blocking the neuronal firing with tetrodotoxin (TTX). Notably, TTX dissociated the circadian calcium rhythms between the dorsal and ventral SCN. In contrast, a blocker of gap junctions, carbenoxolone, had only a minor effect on the calcium rhythms at both the single-cell and network levels. These results reveal the topological specificity of the circadian calcium rhythm in the SCN and the presence of coupled regional pacemakers in the dorsal and ventral regions. Neuronal firings are not necessary for the persistence of the calcium rhythms but indispensable for the hierarchical organization of rhythmicity in the SCN. PMID:23213253

  18. Resetting of Circadian Time in Peripheral Tissues by Glucocorticoid Signaling

    Microsoft Academic Search

    Aurélio Balsalobre; Steven A. Brown; Lysiane Marcacci; François Tronche; Christoph Kellendonk; Holger M. Reichardt; Günther Schütz; Ueli Schibler

    2000-01-01

    In mammals, circadian oscillators reside not only in the suprachiasmatic nucleus of the brain, which harbors the central pacemaker, but also in most peripheral tissues. Here, we show that the glucocorticoid hormone analog dexamethasone induces circadian gene expression in cultured rat-1 fibroblasts and transiently changes the phase of circadian gene expression in liver, kidney, and heart. However, dexamethasone does not

  19. Temporal precision in circadian systems: a reliable neuronal clock from unreliable components?

    PubMed

    Enright, J T

    1980-09-26

    Mutual coupling among oscillators of an ensemble has been proposed to explain the precision of some circadian rhythms. Reciprocal triggering is one of the most familiar forms of mutual coupling in nervous systems, but it can at best produce only modest improvement in temporal precision. Nevertheless, models with an elementary elaboration of such coupling show that circadian precision could be derived from oscillators that are intrinsically "sloppy"; sufficient conditions are that output of the individual components be summed and that mutual triggering be mediated by a nonlinear phenomenon, such as a threshold. PMID:7433976

  20. [Circadian rhythms in body temperature and sleep].

    PubMed

    Honma, Ken-ichi

    2013-12-01

    A 24 hour variation of core body temperature in humans is primarily regulated by the endogenous circadian pacemaker located in the suprachiasmatic nucleus. And the expression of circadian rhythm is modified by the thermoregulatory mechanism controlling heat production and heat loss, which also show circadian rhythms. On the other hand, circadian rhythms in sleep-wakefulness are expressed by two independent but mutually coupled oscillators, the circadian pacemaker and the oscillator specific to sleep-wakefulness. However, neither the mechanism nor the site of oscillation of the latter is known. The time cues for these two oscillators are different. They are usually but frequently uncoupled under free-running conditions. Body temperature and sleep-wakefulness influence the counterpart in various extents, exerting masking effects on either circadian rhythm. PMID:24437258

  1. IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

    PubMed Central

    Norris, Aaron J.; Carrasquillo, Yarimar; Nerbonne, Jeanne M.; Herzog, Erik D.

    2012-01-01

    Neurons in the suprachiasmatic nucleus (SCN) display coordinated circadian changes in electrical activity that are critical for daily rhythms in physiology, metabolism, and behavior. SCN neurons depolarize spontaneously and fire repetitively during the day and hyperpolarize, drastically reducing firing rates, at night. To explore the hypothesis that rapidly activating and inactivating A-type (IA) voltage-gated K+ (Kv) channels, which are also active at subthreshold membrane potentials, are critical regulators of the excitability of SCN neurons, we examined locomotor activity and SCN firing in mice lacking Kv1.4 (Kv1.4?/?), Kv4.2 (Kv4.2?/?), or Kv4.3 (Kv4.3?/?), the pore-forming (?) subunits of IA channels. Mice lacking either Kv1.4 or Kv4.2 ? subunits have markedly shorter (0.5 h) periods of locomotor activity than wild-type (WT) mice. In vitro extracellular multi-electrode recordings revealed that Kv1.4?/? and Kv4.2?/? SCN neurons display circadian rhythms in repetitive firing, but with shorter periods (0.5 h) than WT cells. In contrast, the periods of wheel-running activity in Kv4.3?/? mice and firing in Kv4.3?/? SCN neurons were indistinguishable from WT animals and neurons. Quantitative real-time PCR revealed that the transcripts encoding all three Kv channel ? subunits, Kv1.4, Kv4.2, and Kv4.3, are expressed constitutively throughout the day and night in the SCN. Together, these results demonstrate that Kv1.4- and Kv4.2-encoded IA channels regulate the intrinsic excitability of SCN neurons during the day and night and determine the period and amplitude of circadian rhythms in SCN neuron firing and locomotor behavior. PMID:22815518

  2. CHEMICAL PACEMAKERS

    PubMed Central

    Hadidian, Zareh; Hoagland, Hudson

    1939-01-01

    1. Iron spicules found in the brains of general paretic patients are formed from endogenous brain iron normally present in another form. This supports our earlier view that the µ value of 16,000 obtained in advanced paretics for alpha brain wave frequencies as a measure of cortical respiration comes about from the slowing of an iron catalyzed link in cortical respiration such as would result from the reduction of available cytochrome and its oxidase, thus making this step a chemical pacemaker. 2. To test the basic theory of chemical pacemakers, a study was made of the succinate-fumarate enzyme system containing succino-dehydrogenase and cytochrome-cytochrome oxidase acting sequentially. 3. The µ value for the unpoisoned system is 11,200 ± 200 calories. 4. According to theory, the addition of a critical amount of cyanide known to be a specific poison of the cytochrome-cytochrome oxidase system (and not of the dehydrogenase) should shift the µ cleanly to 16,000 calories, and it does. 5. According to theory, selenite, a specific poison for the dehydrogenase, should stop all respiration without shifting the µ. This also is found to be the case. 6. The theory also predicts that if the µ is shifted from 11,000 ± to 16,000 ± by cyanide, the subsequent addition of a critical amount of selenite should shift the µ back again to 11,000 ± calories, and this is found to occur. 7. It is concluded that approximately 11,000 calories is the energy of activation of the succino-dehydrogenase-catalyzed step and 16,000 calories is that for the cytochrome-cytochrome oxidase-catalyzed step. These two values are encountered more frequently than any others in physiological systems. It is to be recalled that a shift of µ for alpha brain wave frequencies from 11,000 to 16,000 calories occurs in the course of advancing syphilitic brain infection and is accompanied by a change in form of brain iron. PMID:19873142

  3. Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei.

    PubMed

    Li, Jia-Da; Burton, Katherine J; Zhang, Chengkang; Hu, Shuang-Bao; Zhou, Qun-Yong

    2009-03-01

    The suprachiasmatic nuclei (SCN) serve as the principal circadian pacemakers that coordinate daily cycles of behavior and physiology for mammals. A network of transcriptional and translational feedback loops underlies the operating molecular mechanism for circadian oscillation within the SCN neurons. It remains unclear how timing information is transmitted from SCN neurons to eventually evoke circadian rhythms. Intercellular communication between the SCN and its target neurons is critical for the generation of coherent circadian rhythms. At the molecular level, neuropeptides encoded by clock-controlled genes have been indicated as important output mediators. Arginine vasopressin (AVP) is the product of one such clock-controlled gene. Previous studies have demonstrated a circadian rhythm of AVP levels in the cerebrospinal fluid and the SCN. The physiological effects of AVP are mediated by three types of AVP receptors, designated as V1a, V1b, and V2. In this study, we report that V1a mRNA levels displayed a circadian rhythm in the SCN, peaking during night hours. The circadian rhythmicity of locomotor activities was significantly reduced in V1a-deficient (V1a(-/-)) mice (50-75% reduction in the power of fast Fourier transformation). However, the light masking and light-induced phase shift effects are intact in V1a(-/-) mice. Whereas the expression of clock core genes was unaltered, the circadian amplitude of prokineticin 2 (PK2) mRNA oscillation was attenuated in the SCN of V1a(-/-) mice ( approximately 50% reduction in the peak levels). In vitro experiments demonstrated that AVP, acting through V1a receptor, was able to enhance the transcriptional activity of the PK2 promoter. These studies thus indicate that AVP-V1a signaling plays an important role in the generation of overt circadian rhythms. PMID:19052319

  4. Interactions between bilaterally paired components of the cockroach circadian system

    Microsoft Academic Search

    Terry L. Page

    1978-01-01

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

  5. Pacemaker insertion

    PubMed Central

    Kotsakou, Maria; Kioumis, Ioannis; Lazaridis, George; Pitsiou, Georgia; Lampaki, Sofia; Papaiwannou, Antonis; Karavergou, Anastasia; Tsakiridis, Kosmas; Katsikogiannis, Nikolaos; Karapantzos, Ilias; Karapantzou, Chrysanthi; Baka, Sofia; Mpoukovinas, Ioannis; Karavasilis, Vasilis; Rapti, Aggeliki; Trakada, Georgia; Zissimopoulos, Athanasios; Zarogoulidis, Konstantinos

    2015-01-01

    A pacemaker (PM) (or artificial PM, so as not to be confused with the heart’s natural PM) is a medical device that uses electrical impulses, delivered by electrodes contracting the heart muscles, to regulate the beating of the heart. The primary purpose of this device is to maintain an adequate heart rate, either because the heart’s natural PM is not fast enough, or there is a block in the heart’s electrical conduction system. Modern PMs are externally programmable and allow the cardiologist to select the optimum pacing modes for individual patients. Some combine a PM and defibrillator in a single implantable device. PMs can be temporary or permanent. Temporary PMs are used to treat short-term heart problems, such as a slow heartbeat that’s caused by a heart attack, heart surgery, or an overdose of medicine. Permanent PMs are used to control long-term heart rhythm problems. A PM can relieve some arrhythmia symptoms, such as fatigue and fainting. A PM also can help a person who has abnormal HRs resume a more active lifestyle. In the current mini review we will focus on the insertion of a PM and the possible pneumothorax that can be caused. PMID:25815303

  6. 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)

    Nishino, H.

    1977-01-01

    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.

  7. Synaptophysin is involved in resetting of the mammalian circadian clock

    PubMed Central

    2013-01-01

    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. PMID:24083423

  8. CHEMICAL PACEMAKERS

    PubMed Central

    Hadidian, Zareh; Hoagland, Hudson

    1941-01-01

    1. In a previous paper it was found that 11,200 calories is obtained for the energy of activation in the oxidation of succinate to fumarate in the presence of crude beef heart extract when succino-dehydrogenase was made the limiting factor. 16,000 calories was obtained with this preparation when cytochrome-cytochrome oxidase was made the limiting factor. In the present paper activation energies of the components of this enzyme system are further studied. 2. Oxidation of p-phenylenediamine catalyzed by the extract and known not to involve the dehydrogenase component yields Arrhenius equation plots indicating a pacemaker reaction with a µ of 9,500 calories. 3. An activation energy of 17,500 calories is obtained for the oxidation of succinate to fumarate in the presence of the beef heart extract partially poisoned by pyrophosphate. Evidence is presented that this value corresponds to a link in the respiratory chain other than that of succino-dehydrogenase or cytochrome c-cytochrome oxidase. 4. Addition of a suitable amount of cresyl blue to a beef heart extract reaction mixture, completely inhibited by cyanide, restores the oxidation of succinate to normal in the presence of pure oxygen. In this system, in which the dye is substituted for the oxidase, when the enzyme extract (dehydrogenase) is made the limiting factor, a µ of 18,500 calories is obtained; when cresyl blue is made the limiting factor, the µ value is 22,000 calories. 5. Results of these experiments indicate that energies of activation are associated not with the enzyme as such, but with the particular reaction steps involving them as catalysts. PMID:19873220

  9. Wavelet measurement suggests cause of period instability in mammalian circadian neurons.

    PubMed

    Meeker, Kirsten; Harang, Richard; Webb, Alexis B; Welsh, David K; Doyle, Francis J; Bonnet, Guillaume; Herzog, Erik D; Petzold, Linda R

    2011-08-01

    Cells in the suprachiasmatic nucleus (SCN) display remarkable precision, while either physically or chemically decoupling these cells from each other leads to a dramatic increase in period-to-period variability. Where previous studies have classified cells as either arrhythmic or circadian, our wavelet analysis reveals that individual cells, when removed from network interactions, intermittently express circadian and/or longer infradian periods. We reproduce the characteristic period distribution of uncoupled SCN cells with a stochastic model of the uncoupled SCN cell near a bifurcation in Bmal1 transcription repression. This suggests that the uncoupled cells may be switching between 2 oscillatory mechanisms: the indirect negative feedback of protein complex PER-CRY on the expression of Per and Cry genes, and the negative feedback of CLOCK-BMAL1 on the expression of the Bmal1 gene. The model is particularly sensitive near this bifurcation point, with only a small change in Bmal1 transcription repression needed to switch from the stable precision of coupled SCN cells to the unstable oscillations of decoupled individual cells, making this rate constant, an ideal target for cell signaling in the SCN. PMID:21775294

  10. Wavelet Measurement Suggests Cause of Period Instability in Mammalian Circadian Neurons

    PubMed Central

    Meeker, Kirsten; Harang, Richard; Webb, Alexis B.; Welsh, David K.; Doyle, Francis J.; Bonnet, Guillaume; Herzog, Erik D.; Petzold, Linda R.

    2012-01-01

    Cells in the suprachiasmatic nucleus (SCN) display remarkable precision, while either physically or chemically decoupling these cells from each other leads to a dramatic increase in period-to-period variability. Where previous studies have classified cells as either arrhythmic or circadian, our wavelet analysis reveals that individual cells, when removed from network interactions, intermittently express circadian and/or longer infradian periods. We reproduce the characteristic period distribution of uncoupled SCN cells with a stochastic model of the uncoupled SCN cell near a bifurcation in Bmal1 transcription repression. This suggests that the uncoupled cells may be switching between 2 oscillatory mechanisms: the indirect negative feedback of protein complex PER-CRY on the expression of Per and Cry genes, and the negative feedback of CLOCK-BMAL1 on the expression of the Bmal1 gene. The model is particularly sensitive near this bifurcation point, with only a small change in Bmal1 transcription repression needed to switch from the stable precision of coupled SCN cells to the unstable oscillations of decoupled individual cells, making this rate constant, an ideal target for cell signaling in the SCN. PMID:21775294

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

    PubMed

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

    2011-04-27

    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 released from PRs confers both functions. Both subtypes of larval PRs innervate the main circadian pacemaker neurons of the larva, the neuropeptide PDF (pigment-dispersing factor)-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. PMID:21525293

  12. Phase shifting of the circadian rhythm in the eye of Bulla by inhibition of chloride conductance.

    PubMed

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

    1992-11-01

    Inhibition of Cl- conductance has been previously found to shorten the free-running period of the circadian eye rhythm of the marine snail Bulla gouldiana. In this study, we describe a phase-response curve for 6-h pulses of Cl(-)-free seawater, consisting only of phase advances with the largest in the late subjective night (1.5 h) and smaller phase shifts in the late subjective day. Intracellular recordings revealed that at both circadian times retinal pacemaker neurons hyperpolarized in response to the removal of extracellular chloride. Since previous studies indicate that membrane potential generates both phase advances and delays it seems unlikely that the action of chloride removal is mediated exclusively by the change in membrane potential. PMID:1283451

  13. Cryptochrome-dependent and -independent circadian entrainment circuits in Drosophila.

    PubMed

    Yoshii, Taishi; Hermann-Luibl, Christiane; Kistenpfennig, Christa; Schmid, Benjamin; Tomioka, Kenji; Helfrich-Förster, Charlotte

    2015-04-15

    Entrainment to environmental light/dark (LD) cycles is a central function of circadian clocks. In Drosophila, entrainment is achieved by Cryptochrome (CRY) and input from the visual system. During activation by brief light pulses, CRY triggers the degradation of TIMELESS and subsequent shift in circadian phase. This is less important for LD entrainment, leading to questions regarding light input circuits and mechanisms from the visual system. Recent studies show that different subsets of brain pacemaker clock neurons, the morning (M) and evening (E) oscillators, have distinct functions in light entrainment. However, the role of CRY in M and E oscillators for entrainment to LD cycles is unknown. Here, we address this question by selectively expressing CRY in different subsets of clock neurons in a cry-null (cry(0)) mutant background. We were able to rescue the light entrainment deficits of cry(0) mutants by expressing CRY in E oscillators but not in any other clock neurons. Par domain protein 1 molecular oscillations in the E, but not M, cells of cry(0) mutants still responded to the LD phase delay. This residual light response was stemming from the visual system because it disappeared when all external photoreceptors were ablated genetically. We concluded that the E oscillators are the targets of light input via CRY and the visual system and are required for normal light entrainment. PMID:25878285

  14. CRY1?/? CIRCADIAN RHYTHMICITY DEPENDS ON SCN INTERCELLULAR COUPLING

    PubMed Central

    Evans, Jennifer A.; Pan, Haiyun; Liu, Andrew C.; Welsh, David K.

    2013-01-01

    In mammals, the suprachiasmatic nucleus (SCN) is the central pacemaker organizing circadian rhythms of behavior and physiology. At the cellular level, the mammalian clock consists of autoregulatory feedback loops involving a set of “clock genes”, including the Cryptochrome (Cry) genes, Cry1 and Cry2. Experimental evidence suggests that Cry1 and Cry2 play distinct roles in circadian clock function. In mice, Cry1 is required for sustained circadian rhythms in dissociated SCN neurons or fibroblasts, but not in organotypic SCN slices or at the behavioral level, whereas Cry2 is not required at any of these levels. It has been argued that coupling among SCN cellular oscillators compensates for clock gene defects to preserve oscillatory function. Here we test this hypothesis in Cry1?/? mice by first disrupting intercellular coupling in vivo using constant light (resulting in behavioral arrhythmicity) and then examining circadian clock gene expression in SCN slices at the single cell level. In this manner, we were able to test the role of intercellular coupling without drugs and while preserving tissue organization, avoiding the confounding influences of more invasive manipulations. Cry1?/? mice (as well as control Cry2?/? mice) bearing the PER2::LUC knockin reporter were transferred from a standard light:dark cycle to constant bright light (~650 lux) to induce arrhythmic locomotor patterns. In SCN slices from these animals, we used bioluminescence imaging to monitor PER2::LUC expression in single cells. We show that SCN slices from rhythmic Cry1?/? and Cry2?/? mice had similarly high percentages of functional single-cell oscillators. In contrast, SCN slices from arrhythmic Cry1?/? mice had significantly fewer rhythmic cells than SCN slices from arrhythmic Cry2?/? mice. Thus, constant light in vivo disrupted intercellular SCN coupling to reveal a cell-autonomous circadian defect in Cry1?/? cells that is normally compensated by intercellular coupling in vivo. PMID:23223370

  15. Neural correlates of individual differences in circadian behaviour.

    PubMed

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

    2015-07-01

    Daily rhythms in mammals are controlled by the circadian system, which is a collection of biological clocks regulated by a central pacemaker within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Changes in SCN function have pronounced consequences for behaviour and physiology; however, few studies have examined whether individual differences in circadian behaviour reflect changes in SCN function. Here, PERIOD2::LUCIFERASE mice were exposed to a behavioural assay to characterize individual differences in baseline entrainment, rate of re-entrainment and free-running rhythms. SCN slices were then collected for ex vivo bioluminescence imaging to gain insight into how the properties of the SCN clock influence individual differences in behavioural rhythms. First, individual differences in the timing of locomotor activity rhythms were positively correlated with the timing of SCN rhythms. Second, slower adjustment during simulated jetlag was associated with a larger degree of phase heterogeneity among SCN neurons. Collectively, these findings highlight the role of the SCN network in determining individual differences in circadian behaviour. Furthermore, these results reveal novel ways that the network organization of the SCN influences plasticity at the behavioural level, and lend insight into potential interventions designed to modulate the rate of resynchronization during transmeridian travel and shift work. PMID:26108632

  16. [Relationship between vascular senescence and impaired circadian rhythmicity].

    PubMed

    Hayashi, Yuka; Suda, Masayoshi; Yoshida, Yohko; Minamino, Tohru

    2014-08-01

    Aging is associated with impairment of various circadian rhythms of body, including daily rhythms of blood pressure, core body temperature, and the sleep-waking cycle. In mammals circadian rhythmicity is under control of molecular pacemaker that is composed of products of clock genes. Recent evidence suggests that cellular senescence impairs circadian rhythmicity and contributes to various age-associated diseases. Senescence decreases the ability of cells to transmit circadian signals such as nitric oxide to their clocks. The regulation of clock gene expression may be a novel strategy for treatment of age-associated impairment of circadian rhythmicity. PMID:25167746

  17. Circadian rhythm and its role in malignancy

    PubMed Central

    2010-01-01

    Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer. PMID:20353609

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

    PubMed Central

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

    2008-01-01

    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. PMID:18439407

  19. Heart pacemaker - discharge

    MedlinePLUS

    ... blender, computers and fax machines, hair dryer, stove, CD player, remote controls, and microwave. You should keep ... Swerdlow CD, Hayes DL, Zipes DP. Pacemakers and implantable cardioverter-defibrillators. In: Mann DL, Zipes DP, Libby P, et ...

  20. Pacemaker lead endocarditis

    PubMed Central

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

    2003-01-01

    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 PMID:25696204

  1. Isolating Neural Correlates of the Pacemaker for Food Anticipation

    PubMed Central

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

    2012-01-01

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

  2. Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: insights from a transgenic mouse model.

    PubMed

    Willison, L David; Kudo, Takashi; Loh, Dawn H; Kuljis, Dika; Colwell, Christopher S

    2013-05-01

    Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they manifest early in the disease process. While there are a number of possible mechanisms underlying these sleep disturbances, a primary dysfunction of the circadian system should be considered as a contributing factor. Our laboratory's behavioral phenotyping of a well-validated transgenic mouse model of PD reveals that the electrical activity of neurons within the master pacemaker of the circadian system, the suprachiasmatic nuclei (SCN), is already disrupted at the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remain functional. Our observations suggest that the fundamental circadian deficit in these mice lies in the signaling output from the SCN, which may be caused by known mechanisms in PD etiology: oxidative stress and mitochondrial disruption. Disruption of the circadian system is expected to have pervasive effects throughout the body and may itself lead to neurological and cardiovascular disorders. In fact, there is much overlap in the non-motor symptoms experienced by PD patients and in the consequences of circadian disruption. This raises the possibility that the sleep and circadian dysfunction experienced by PD patients may not merely be a subsidiary of the motor symptoms, but an integral part of the disease. Furthermore, we speculate that circadian dysfunction can even accelerate the pathology underlying PD. If these hypotheses are correct, more aggressive treatment of the circadian misalignment and sleep disruptions in PD patients early in the pathogenesis of the disease may be powerful positive modulators of disease progression and patient quality of life. PMID:23353924

  3. Fast delayed rectifier potassium current: critical for input and output of the circadian system.

    PubMed

    Kudo, Takashi; Loh, Dawn H; Kuljis, Dika; Constance, Cara; Colwell, Christopher S

    2011-02-23

    The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key property of central pacemaker neurons and one essential to the function of the circadian timing system. Previous work has demonstrated that suprachiasmatic nucleus (SCN) neurons express the fast delayed rectifier (FDR) potassium current and raise questions about the function of this current. Here, we report that mice lacking both Kcnc1 and Kcnc2 genes [double knock-out (dKO)] fail to express the Kv3.1 and 3.2 channels in the SCN as well as exhibit a greatly reduced FDR current. SCN neurons from these dKO mice exhibit reduced spontaneous activity during the day as well as reduced NMDA-evoked excitatory responses during the night. Interestingly, the daily rhythm in PER2 expression in the SCN was not altered in the dKO mice, although the photic induction of c-Fos was attenuated. Behaviorally, the dKO mice exhibited extremely disrupted daily rhythms in wheel-running behavior. In a light/dark cycle, some of the dKO mice were arrhythmic, whereas others expressed a diurnal rhythm with low amplitude and significant activity during the day. When placed in constant darkness, the dKO mice exhibited low-amplitude, fragmented rhythms and attenuated light responses. Together, these data are consistent with the hypothesis that the FDR current is critical for the generation of robust circadian rhythms in behavior as well as the synchronization of the circadian system to the photic environment. PMID:21414897

  4. Fast delayed rectifier potassium current: critical for input and output of the circadian system

    PubMed Central

    Kudo, Takashi; Loh, Dawn H.; Kuljis, Dika; Constance, Cara; Colwell, Christopher S.

    2015-01-01

    The ability to generate intrinsic circadian rhythms in electrical activity appears to be a key property of central pacemaker neurons and one essential to the function of the circadian timing system. Previous work has demonstrated that suprachiasmatic nucleus (SCN) neurons express the fast delayed rectifier (FDR) potassium current and raise questions about the function of this current. Here, we report that mice lacking both Kcnc1 and Kcnc2 genes (double knockout, dKO) fail to express the Kv3.1 and 3.2 channels in the SCN as well as exhibit a greatly reduced FDR current. SCN neurons from these dKO mice exhibit reduced spontaneous activity during the day as well as reduced NMDA-evoked excitatory responses during the night. Interestingly, the daily rhythm in PER2 expression in the SCN was not altered in the dKO mice though the photic induction of c-FOS was attenuated. Behaviorally, the dKO mice exhibited extremely disrupted daily rhythms in wheel running behavior. In a light/dark cycle, some of the dKO mice were arrhythmic while others expressed a diurnal rhythm with low amplitude and significant activity during the day. When placed in constant darkness, the dKO mice exhibited low amplitude, fragmented rhythms and attenuated light-responses. Together, this data is consistent with the hypothesis that the FDR current is critical for the generation of robust circadian rhythms in behavior as well as the synchronization of the circadian system to the photic environment. PMID:21414897

  5. Getting through to circadian oscillators: why use constant routines?

    NASA Technical Reports Server (NTRS)

    Duffy, Jeanne F.; Dijk, Derk-Jan

    2002-01-01

    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.

  6. Relationships between the Circadian System and Alzheimer's Disease-Like Symptoms in Drosophila

    PubMed Central

    Dutta, Sudeshna; Holbrook, Scott D.; Kotwica-Rolinska, Joanna; Kretzschmar, Doris; Giebultowicz, Jadwiga M.

    2014-01-01

    Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD), are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-? (A?) peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing A? peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01). No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived A? peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic A? peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of A? peptides causes rhythm degradation downstream from the central clock mechanism. PMID:25171136

  7. Relationships between the circadian system and Alzheimer's disease-like symptoms in Drosophila.

    PubMed

    Long, Dani M; Blake, Matthew R; Dutta, Sudeshna; Holbrook, Scott D; Kotwica-Rolinska, Joanna; Kretzschmar, Doris; Giebultowicz, Jadwiga M

    2014-01-01

    Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD), are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-? (A?) peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing A? peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01). No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived A? peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic A? peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of A? peptides causes rhythm degradation downstream from the central clock mechanism. PMID:25171136

  8. Transcriptional Regulation via Nuclear Receptor Crosstalk Required for the Drosophila Circadian Clock.

    PubMed

    Jaumouillé, Edouard; Machado Almeida, Pedro; Stähli, Patrick; Koch, Rafael; Nagoshi, Emi

    2015-06-01

    Circadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB ? and REV-ERB ?, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks. PMID:26004759

  9. Transcriptional Regulation via Nuclear Receptor Crosstalk Required for the Drosophila Circadian Clock

    PubMed Central

    Jaumouillé, Edouard; Machado Almeida, Pedro; Stähli, Patrick; Koch, Rafael; Nagoshi, Emi

    2015-01-01

    Summary Circadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB ? and REV-ERB ?, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks. PMID:26004759

  10. Influence of Valinomycin on Circadian Leaf Movements of Phaseolus

    PubMed Central

    Bünning, E.; Moser, I.

    1972-01-01

    Phaseolus coccineus was exposed to valinomycin via the transpiration stream for 5-hr periods. The treatment started at various phases of the free-running circadian rhythm in continuous light; it resulted in phase shifts that varied in a manner dependent on the affected phases. The response curves are similar to those for transient withdrawal of water and for light pulses. The results support the hypothesis that membrane processes are important pacemakers in circadian rhythms. PMID:4506792

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

    NASA Technical Reports Server (NTRS)

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

    1995-01-01

    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.

  12. Cannabinoids and hamster circadian activity rhythms.

    PubMed

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

    2008-07-30

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

  13. Reuse of permanent cardiac pacemakers.

    PubMed Central

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

    1985-01-01

    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. PMID:4016637

  14. Integration of human sleep-wake regulation and circadian rhythmicity

    NASA Technical Reports Server (NTRS)

    Dijk, Derk-Jan; Lockley, Steven W.

    2002-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  16. Transforming growth factor-alpha and glial fibrillary acidic protein in the hamster circadian system: daily profile and cellular localization.

    PubMed

    Lindley, Jeremy; Deurveilher, Samüel; Rusak, Benjamin; Semba, Kazue

    2008-03-01

    Transforming growth factor-alpha (TGF-alpha) has been identified as a potential output signal of the principal circadian pacemaker housed in the mammalian suprachiasmatic nucleus (SCN). The goal of the present study was to characterize the temporal pattern and cellular localization of TGF-alpha immunoreactivity (IR), and to examine its localization relative to astrocytic and neuronal markers in the hamster circadian system. In contrast to previous reports of circadian rhythms in TGF-alpha mRNA levels in the hamster SCN, we did not detect any statistically significant changes in the levels of TGF-alpha protein IR in the hamster SCN across a 14:10 light-dark cycle using densitometric analyses. TGF-alpha was found to be colocalized with glial fibrillary acidic protein (GFAP), but not with the general neuronal marker NeuN, or calbindin-D28K which is present in a subgroup of SCN neurons. GFAP IR showed a small but significant daily variation in the SCN, with higher levels early in the light phase compared to the middle of the dark phase. The thalamic intergeniculate leaflet (IGL), another component of the circadian regulatory system, did not show any TGF-alpha IR or any detectable daily variation in GFAP IR. These results suggest that daily variations of TGF-alpha mRNA levels in the hamster SCN are not accompanied by corresponding rhythms of TGF-alpha protein levels, and confirm that TGF-alpha is present primarily in astrocytes within the SCN. PMID:18242590

  17. Effect of substance P on circadian rhythms of firing activity and the 2-deoxyglucose uptake in the rat suprachiasmatic nucleus in vitro.

    PubMed

    Shibata, S; Tsuneyoshi, A; Hamada, T; Tominaga, K; Watanabe, S

    1992-12-01

    The suprachiasmatic nuclei (SCN) have been identified as a pacemaker for many circadian rhythms in mammals. Although substance P (SP) fibers from retina are found to terminate the SCN, the physiological role of this peptide is uncertain. The 2-deoxyglucose (2-DG) uptake and firing activity in the SCN show a robust circadian change. SP causes an increase in 2-DG uptake by SCN during the subjective night but not during subjective day. SP-induced increase in 2-DG uptake is blocked by co-treatment with the SP receptor antagonist, spantide. Treatment with SP produces phase shifts of circadian rhythm in spontaneous neural activity in SCN neurons with a phase-response curve that is similar to the effect of light pulses to animals under constant darkness. SP-induced phase change is also blocked by pretreatment with spantide. SP-induced increase in 2-DG uptake and phase changes in firing activity occur only during subjective night, at circadian times when photic phase shifting of activity occurs. The present results suggest that SP may be an important transmitter for conveying environmental light-dark information from retina to the SCN. PMID:1282077

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

    PubMed Central

    Buhr, Ethan D.; Van Gelder, Russell N.

    2014-01-01

    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

  19. Differential effects of ionizing radiation on the circadian oscillator and other functions in the eye of Aplysia. [X-rays

    SciTech Connect

    Woolum, J.C.; Strumwasser, F.

    1980-09-01

    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 frequency, measured from the optic nerve, whereas irradiation with a 40-krad dose abolishes the rhythm without affecting any of the four other functions of this eye. We estimate a 50% survival of the oscillator function at doses of about 6 krad. The results, including those from selective irradiation of the anterior or posterior poles of the eye, suggest that there are a number of circadian oscillators in the eye-most of them in the posterior portion near the optic nerve. An approximate target size has been obtained from target theory, approx. =10/sup 8/ A/sup 3/, which is somewhat larger than the target size for viral infectivity function, as one example. However, this approximate target size and the fact that recovery or repair can occur in vivo suggest that the oscillator may involve nucleic acid molecules.

  20. The extraretinal eyelet of Drosophila: development, ultrastructure, and putative circadian function.

    PubMed

    Helfrich-Förster, Charlotte; Edwards, Tara; Yasuyama, Kouji; Wisotzki, Barbara; Schneuwly, Stephan; Stanewsky, Ralf; Meinertzhagen, Ian A; Hofbauer, Alois

    2002-11-01

    Circadian rhythms can be entrained by light to follow the daily solar cycle. In Drosophila melanogaster a pair of extraretinal eyelets expressing immunoreactivity to Rhodopsin 6 each contains four photoreceptors located beneath the posterior margin of the compound eye. Their axons project to the region of the pacemaker center in the brain with a trajectory resembling that of Bolwig's organ, the visual organ of the larva. A lacZ reporter line driven by an upstream fragment of the developmental gap gene Krüppel is a specific enhancer element for Bolwig's organ. Expression of immunoreactivity to the product of lacZ in Bolwig's organ persists through pupal metamorphosis and survives in the adult eyelet. We thus demonstrate that eyelet derives from the 12 photoreceptors of Bolwig's organ, which entrain circadian rhythmicity in the larva. Double labeling with anti-pigment-dispersing hormone shows that the terminals of Bolwig's nerve differentiate during metamorphosis in close temporal and spatial relationship to the ventral lateral neurons (LN(v)), which are essential to express circadian rhythmicity in the adult. Bolwig's organ also expresses immunoreactivity to Rhodopsin 6, which thus continues in eyelet. We compared action spectra of entrainment in different fly strains: in flies lacking compound eyes but retaining eyelet (so(1)), lacking both compound eyes and eyelet (so(1);gl(60j)), and retaining eyelet but lacking compound eyes as well as cryptochrome (so(1);cry(b)). Responses to phase shifts suggest that, in the absence of compound eyes, eyelet together with cryptochrome mainly mediates phase delays. Thus a functional role in circadian entrainment first found in Bolwig's organ in the larva is retained in eyelet, the adult remnant of Bolwig's organ, even in the face of metamorphic restructuring. PMID:12417651

  1. Light-induced suppression of endogenous circadian amplitude in humans

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

    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.

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

    PubMed Central

    Hafner, Marc; Koeppl, Heinz; Gonze, Didier

    2012-01-01

    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. PMID:22423219

  3. Trends in Cardiac Pacemaker Batteries

    PubMed Central

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

    2004-01-01

    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. PMID:16943934

  4. Circadian rhythms and addiction: Mechanistic insights and future directions

    PubMed Central

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

    2014-01-01

    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

  5. [Interstitial pacemaker cells].

    PubMed

    Niziaeva, N V; Shchegolev, A I; Mare?, M V; Sukhikh, G T

    2014-01-01

    This article is devoted to interstitial Cajal cells (syn. telocytes, interstitial pacemaker cells, IPC). First those cells were discovered by C.R Cajal in the muscle coat of the gut in 1893. Nowadays they have revealed in all parts of digestive systems (from esophagus to rectum), urinary and biliary tracts, prostate, liver, the walls of arteries and lymphatics, as well Fallopian tube, myometrium, mammary glands. Characteristic ultrastructural features are elongated spindle shape, length from 40 to 100 ?m, the thickness of 0.2-0.5 ?m, the presence of 2-5 processes. Length of them rangingfrom tens to hundreds of micrometers, some of them have secondary and tertiary branching, forming a three-dimensional network. IPC having spontaneous electrical (pacemaker) activity are cause to contraction of smooth muscle cells. Depending on the location of IPC have different morphological and ultrastructural characteristics. Characteristic immunohistochemical markers are CD117, CD34, S100, vimentin. IPC replay to acetylcholine, norepinephrine, estrogen, progesterone, and nitric oxide by influence ofcorresponding receptors. IPC have specific gap junctions with lymphocytes, basophiles, eosinophils, neutrophils, mast cells and dendritic cells. Grave pathology of those cells are forming gastrointestinal stromal tumors. PMID:25563000

  6. Plasticity of the Intrinsic Period of the Human Circadian Timing System

    PubMed Central

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

    2007-01-01

    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. PMID:17684566

  7. Pacemakers and Implantable Defibrillators - Multiple Languages: MedlinePlus

    MedlinePLUS

    ... Institute Pacemaker (Arabic) ??????? Bilingual PDF Health Information Translations Chinese - Simplified (????) Pacemaker ????? - ???? (Chinese - Simplified) Bilingual PDF Health Information Translations Chinese - Traditional (????) Pacemaker ????? - ???? (Chinese - Traditional) ...

  8. The selective tachykinin neurokinin 1 (NK 1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms

    Microsoft Academic Search

    Robert L. Gannon; Mark J. Millan

    2005-01-01

    Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In addition, two other nuclei which form part of the circadian system, the intergeniculate leaflet of the thalamus

  9. Can Smartphones Interfere with Pacemakers?

    MedlinePLUS

    ... As the European researchers explained, pacemakers might "misinterpret" electromagnetic interference (EMI) emanating from nearby smartphones as a ... implanted cardiac device. Participants were exposed to the electromagnetic field of three common smartphones: the Samsung Galaxy ...

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

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

    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.

  11. Gastrin-releasing peptide modulates fast delayed rectifier potassium current in Per1-expressing SCN neurons.

    PubMed

    Gamble, Karen L; Kudo, Takashi; Colwell, Christopher S; McMahon, Douglas G

    2011-04-01

    The mammalian circadian clock in the suprachiasmatic nucleus (SCN) drives and maintains 24-h physiological rhythms, the phases of which are set by the local environmental light-dark cycle. Gastrin-releasing peptide (GRP) communicates photic phase setting signals in the SCN by increasing neurophysiological activity of SCN neurons. Here, the ionic basis for persistent GRP-induced changes in neuronal activity was investigated in SCN slice cultures from Per1::GFP reporter mice during the early night. Recordings from Per1 -fluorescent neurons in SCN slices several hours after GRP treatment revealed a significantly greater action potential frequency, a significant increase in voltage-activated outward current at depolarized potentials, and a significant increase in 4-aminopyridine-sensitive fast delayed rectifier (fDR) potassium currents when compared to vehicle-treated slices. In addition, the persistent increase in spike rate following early-night GRP application was blocked in SCN neurons from mice deficient in Kv3 channel proteins. Because fDR currents are regulated by the clock and are elevated in amplitude during the day, the present results support the model that GRP delays the phase of the clock during the early night by prolonging day-like membrane properties of SCN cells. Furthermore, these findings implicate fDR currents in the ionic basis for GRP-mediated entrainment of the primary mammalian circadian pacemaker. PMID:21454290

  12. Gastrin Releasing Peptide Modulates Fast Delayed Rectifier Potassium Current in Per1-Expressing SCN Neurons

    PubMed Central

    Gamble, Karen L.; Kudo, Takashi; Colwell, Christopher S.; McMahon, Douglas G.

    2011-01-01

    The mammalian circadian clock in the suprachiasmatic nucleus (SCN) drives and maintains 24-h physiological rhythms, the phases of which are set by the local environmental light-dark cycle. Gastrin releasing peptide (GRP) communicates photic phase setting signals in the SCN by increasing neurophysiological activity of SCN neurons. Here, the ionic basis for persistent GRP-induced changes in neuronal activity was investigated in SCN slice cultures from Per1::GFP reporter mice during the early night. Recordings from Per1-fluorescent neurons in SCN slices several hours after GRP treatment revealed a significantly greater action potential frequency, a significant increase in voltage-activated outward current at depolarized potentials, and a significant increase in 4-aminopyridine (4-AP) sensitive fast delayed rectifier (fDR) potassium currents when compared to vehicle-treated slices. In addition, the persistent increase in spike rate following early night GRP application was blocked in SCN neurons from mice deficient in Kv3 channel proteins. Because fDR currents are regulated by the clock and are elevated in amplitude during the day, the present results support the model that GRP delays the phase of the clock during the early night by prolonging day-like membrane properties of SCN cells. Furthermore, these findings implicate fDR currents in the ionic basis for GRP-mediated entrainment of the primary mammalian circadian pacemaker. PMID:21454290

  13. Time-of-day- and light-dependent expression of ubiquitin protein ligase E3 component N-recognin 4 (UBR4) in the suprachiasmatic nucleus circadian clock.

    PubMed

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

    2014-01-01

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

  14. Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria

    PubMed Central

    Johnson, Carl Hirschie; Egli, Martin

    2014-01-01

    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

  15. High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light.

    PubMed

    Lockley, Steven W; Brainard, George C; Czeisler, Charles A

    2003-09-01

    The endogenous circadian oscillator in mammals, situated in the suprachiasmatic nuclei, receives environmental photic input from specialized subsets of photoreceptive retinal ganglion cells. The human circadian pacemaker is exquisitely sensitive to ocular light exposure, even in some people who are otherwise totally blind. The magnitude of the resetting response to white light depends on the timing, intensity, duration, number and pattern of exposures. We report here that the circadian resetting response in humans, as measured by the pineal melatonin rhythm, is also wavelength dependent. Exposure to 6.5 h of monochromatic light at 460 nm induces a two-fold greater circadian phase delay than 6.5 h of 555 nm monochromatic light of equal photon density. Similarly, 460 nm monochromatic light causes twice the amount of melatonin suppression compared to 555 nm monochromatic light, and is dependent on the duration of exposure in addition to wavelength. These studies demonstrate that the peak of sensitivity of the human circadian pacemaker to light is blue-shifted relative to the three-cone visual photopic system, the sensitivity of which peaks at approximately 555 nm. Thus photopic lux, the standard unit of illuminance, is inappropriate when quantifying the photic drive required to reset the human circadian pacemaker. PMID:12970330

  16. Differential contributions of intra-cellular and inter-cellular mechanisms to the spatial and temporal architecture of the suprachiasmatic nucleus circadian circuitry in wild-type, cryptochrome-null and vasoactive intestinal peptide receptor 2-null mutant mice.

    PubMed

    Pauls, S; Foley, N C; Foley, D K; LeSauter, J; Hastings, M H; Maywood, E S; Silver, R

    2014-08-01

    To serve as a robust internal circadian clock, the cell-autonomous molecular and electrophysiological activities of the individual neurons of the mammalian suprachiasmatic nucleus (SCN) are coordinated in time and neuroanatomical space. Although the contributions of the chemical and electrical interconnections between neurons are essential to this circuit-level orchestration, the features upon which they operate to confer robustness to the ensemble signal are not known. To address this, we applied several methods to deconstruct the interactions between the spatial and temporal organisation of circadian oscillations in organotypic slices from mice with circadian abnormalities. We studied the SCN of mice lacking Cryptochrome genes (Cry1 and Cry2), which are essential for cell-autonomous oscillation, and the SCN of mice lacking the vasoactive intestinal peptide receptor 2 (VPAC2-null), which is necessary for circuit-level integration, in order to map biological mechanisms to the revealed oscillatory features. The SCN of wild-type mice showed a strong link between the temporal rhythm of the bioluminescence profiles of PER2::LUC and regularly repeated spatially organised oscillation. The Cry-null SCN had stable spatial organisation but lacked temporal organisation, whereas in VPAC2-null SCN some specimens exhibited temporal organisation in the absence of spatial organisation. The results indicated that spatial and temporal organisation were separable, that they may have different mechanistic origins (cell-autonomous vs. interneuronal signaling) and that both were necessary to maintain robust and organised circadian rhythms throughout the SCN. This study therefore provided evidence that the coherent emergent properties of the neuronal circuitry, revealed in the spatially organised clusters, were essential to the pacemaking function of the SCN. PMID:24891292

  17. Avian Circadian Organization: A Chorus of Clocks

    PubMed Central

    Cassone, Vincent M

    2013-01-01

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

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

    PubMed

    Kolb, P; Kauffmann, P

    1978-11-24

    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

  19. Do we need MR conditional pacemakers?

    Microsoft Academic Search

    Roger Luechinger; Firat Duru

    2010-01-01

    Summary Magnetic resonance imaging (MRI) is a widely accepted tool for the diagnosis of a variety of disease states. However, due to safety concerns the presence of an im- planted cardiac pacemaker is considered to be a con- traindication to MRI in most medical centres. The increasing number of implanted pacemakers and the estimated over 50% probability that a pacemaker

  20. A clockwork Bulla: cellular study of a model circadian system

    Microsoft Academic Search

    Gene D. Block; Michael E. Geusz; Sal Bir S. Khalsa; Stephan Michel

    1995-01-01

    The retina of the cloudy bubble snail, Bulla gouldiana, expresses a circadian rhythm in spontaneous optic nerve impulses. The rhythm is generated by a group of approximately 100 electrically coupled neurons at the base of the retina, each of which is competent to generate a circadian periodicity in complete cellular isolation. While the precise processes responsible for rhythm generation remain

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

    PubMed Central

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

    2013-01-01

    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. PMID:23717599

  2. Crosstalk between the circadian clock circuitry and the immune system.

    PubMed

    Cermakian, Nicolas; Lange, Tanja; Golombek, Diego; Sarkar, Dipak; Nakao, Atsuhito; Shibata, Shigenobu; Mazzoccoli, Gianluigi

    2013-08-01

    Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e.g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e.g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption. PMID:23697902

  3. Linear Demasking Techniques Are Unreliable for Estimating the Circadian Phase of Ambulatory Temperature Data

    Microsoft Academic Search

    Elizabeth B. Klerman; Younsun Lee; Charles A. Czeisler; Richard E. Kronauer

    1999-01-01

    Clinical investigators often use ambulatory temperature monitoring to assess the endogenous phase and amplitude of an individual's circadian pacemaker for diagnostic and research purposes. However, an individual's daily schedule includes changes in levels of activity, in posture, and in sleep-wake state, all of which are known to have masking or evoked effects on core body temperature (CBT) data. To compensate

  4. Fast delayed rectifier potassium current is required for circadian neural activity

    Microsoft Academic Search

    Jason N Itri; Stephan Michel; Mariska J Vansteensel; Johanna H Meijer; Christopher S Colwell

    2005-01-01

    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). The ionic mechanisms that underlie these rhythms are largely unknown. Using the mouse brain slice preparation, we show that the magnitude of fast delayed rectifier (FDR) potassium currents has a diurnal rhythm that

  5. Genetic and molecular analysis of the central and peripheral circadian clockwork of mice

    Microsoft Academic Search

    E. S. Maywood; J. S. O'Neill; A. B. Reddy; J. E. Chesham; H. M. Prosser; C. P. Kyriacou; S. I. H. Godinho; P. M. Nolan; M. H. Hastings

    2007-01-01

    A hierarchy of interacting, tissue-based clocks controls circadian physiology and behavior in mammals. Preeminent are the suprachiasmatic nuclei (SCN): central hypothalamic pacemakers synchronized to solar time via retinal afferents and in turn responsible for internal synchronization of other clocks present in major organ systems. The SCN and peripheral clocks share essentially the same cellular timing mechanism. This consists of autoregulatory

  6. A two-clock model of circadian timing in the immune system of mammals

    Microsoft Academic Search

    J. Berger

    2008-01-01

    It has been confirmed that clock genes, as well as the pineal hormone, have a role in the hypothalamic suprachiasmatic nucleus, the circadian endogenous pacemaker. It seems that the peripheral clock genes in the cells of the immune system subtly control biorhythms; their seeming lack of impact only showing that they work well. Some biorhythms even seem to be independent

  7. Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock

    Microsoft Academic Search

    Satchidananda Panda; Marina P. Antoch; Brooke H. Miller; Andrew I. Su; Andrew B. Schook; Marty Straume; Peter G. Schultz; Steve A. Kay; Joseph S. Takahashi; John B. Hogenesch

    2002-01-01

    In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed ?650 cycling transcripts and showed that the majority of these were specific to either the SCN or

  8. Early development of circadian rhythmicity in the suprachiamatic nuclei and pineal gland of teleost, flounder (Paralichthys olivaeus), embryos.

    PubMed

    Mogi, Makoto; Uji, Susumu; Yokoi, Hayato; Suzuki, Tohru

    2015-08-01

    Circadian rhythms enable organisms to coordinate multiple physiological processes and behaviors with the earth's rotation. In mammals, the suprachiasmatic nuclei (SCN), the sole master circadian pacemaker, has entrainment mechanisms that set the circadian rhythm to a 24-h cycle with photic signals from retina. In contrast, the zebrafish SCN is not a circadian pacemaker, instead the pineal gland (PG) houses the major circadian oscillator. The SCN of flounder larvae, unlike that of zebrafish, however, expresses per2 with a rhythmicity of daytime/ON and nighttime/OFF. Here, we examined whether the rhythm of per2 expression in the flounder SCN represents the molecular clock. We also examined early development of the circadian rhythmicity in the SCN and PG. Our three major findings were as follows. First, rhythmic per2 expression in the SCN was maintained under 24 h dark (DD) conditions, indicating that a molecular clock exists in the flounder SCN. Second, onset of circadian rhythmicity in the SCN preceded that in the PG. Third, both 24 h light (LL) and DD conditions deeply affected the development of circadian rhythmicity in the SCN and PG. This is the first report dealing with the early development of circadian rhythmicity in the SCN in fish. PMID:26010733

  9. Destruction of Serotonergic Neurons in the Median Raphe Nucleus Blocks Circadian Rhythm Phase Shifts to Triazolam but Not to Novel Wheel Access

    Microsoft Academic Search

    Elizabeth L. Meyer-Bernstein; Lawrence P. Morin

    1998-01-01

    Systematic treatment of hamsters with triazolam (TRZ) or novel wheel (NW) access will yield PRCs similar to those for neuropeptide Y. Both TRZ and NW access require an intact intergeniculate leaflet (IGL) to modulate circadian rhythm phase. It is commonly suggested that both stimulus types influence rhythm phase response via a mechanism associated with drug-induced or wheel access-associated locomotion. Furthermore,

  10. Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms.

    PubMed

    Han, Sung; Yu, Frank H; Schwartz, Michael D; Linton, Jonathan D; Bosma, Martha M; Hurley, James B; Catterall, William A; de la Iglesia, Horacio O

    2012-02-01

    Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming ?-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. PMID:22223655

  11. The circadian clock of fruit flies is blind after elimination of all known photoreceptors.

    PubMed

    Helfrich-Förster, C; Winter, C; Hofbauer, A; Hall, J C; Stanewsky, R

    2001-04-01

    Circadian rhythms are entrained by light to follow the daily solar cycle. We show that Drosophila uses at least three light input pathways for this entrainment: (1) cryptochrome, acting in the pacemaker cells themselves, (2) the compound eyes, and (3) extraocular photoreception, possibly involving an internal structure known as the Hofbauer-Buchner eyelet, which is located underneath the compound eye and projects to the pacemaker center in the brain. Although influencing the circadian system in different ways, each input pathway appears capable of entraining circadian rhythms at the molecular and behavioral level. This entrainment is completely abolished in glass(60j) cry(b) double mutants, which lack all known external and internal eye structures in addition to being devoid of cryptochrome. PMID:11343659

  12. Circadian System, Sleep and Endocrinology

    PubMed Central

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

    2011-01-01

    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. PMID:21939733

  13. Circadian regulation of ion channels and their functions

    PubMed Central

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

    2010-01-01

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

  14. Therapeutic implications of the circadian clock on skin function.

    PubMed

    Luber, Adam J; Ensanyat, Shaheen H; Zeichner, Joshua A

    2014-02-01

    The human circadian clock ensures that biochemical and physiological processes occur at the optimal time of day. In addition to a central pacemaker in the body, recent evidence suggests that peripheral mammalian tissues also possess autonomous circadian oscillators, which are regulated by genes linked to distinct tissue-specific functions. The skin is situated in a position naturally exposed to diurnal environmental changes. The skin's chronobiological functioning influences skin aging, cell repair and development of skin cancers, as well as optimal timing of drug delivery to the skin. An understanding of circadian skin-related functions and the impact of their disruption allow clinicians to improve therapeutic decision-making and maximize the effectiveness of prescribed treatments. PMID:24509961

  15. Circadian rhythms. Atomic-scale origins of slowness in the cyanobacterial circadian clock.

    PubMed

    Abe, Jun; Hiyama, Takuya B; Mukaiyama, Atsushi; Son, Seyoung; Mori, Toshifumi; Saito, Shinji; Osako, Masato; Wolanin, Julie; Yamashita, Eiki; Kondo, Takao; Akiyama, Shuji

    2015-07-17

    Circadian clocks generate slow and ordered cellular dynamics but consist of fast-moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear. We identified the adenosine triphosphate (ATP) catalytic region [adenosine triphosphatase (ATPase)] in the amino-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock. Crystal structures of the ATPase revealed that the slowness of this ATPase arises from sequestration of a lytic water molecule in an unfavorable position and coupling of ATP hydrolysis to a peptide isomerization with high activation energy. The slow ATPase is coupled with another ATPase catalyzing autodephosphorylation in the carboxyl-terminal half of KaiC, yielding the circadian response frequency of intermolecular interactions with other clock-related proteins that influences the transcription and translation cycle. PMID:26113637

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

    PubMed

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

    2011-12-01

    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

  17. Circadian disruption and breast cancer: from melatonin to clock genes.

    PubMed

    Stevens, Richard G

    2005-03-01

    The global impact of breast cancer is large and growing. It seems clear that something about modern life is the culprit, yet there is thus far a lack of satisfactory explanations for most of the increases in risk as societies industrialize. Support has developed for a possible role of "circadian disruption," particularly from an altered-lighted environment (such as light at night). Lighting during the night of sufficient intensity can disrupt circadian rhythms, including reduction of circulating melatonin levels and resetting of the circadian pacemaker of the suprachiasmatic nuclei. Reduced melatonin may increase breast cancer risk through several mechanisms, including increased estrogen production and altered estrogen receptor function. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis. Aspects of modern life that can disrupt circadian rhythms during the key developmental periods (eg, in utero and during adolescence) may be particularly harmful. Epidemiologic studies should consider gene and environment interactions such as circadian gene variants and shift work requirements on the job. PMID:15703542

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

    E-print Network

    Kim, Daesoo

    CaV3.1 is a tremor rhythm pacemaker in the inferior olive Young-Gyun Parka,1 , Hye-Yeon Parka,1 , C+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model that the CaV3.1-deficient inferior olive neurons lacked the subthreshold os- cillation of membrane potentials

  19. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...2013-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food...Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and...

  20. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...2014-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food...Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and...

  1. 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 870.3730 Food...Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and...

  2. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...2012-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food...Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and...

  3. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food...Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and...

  4. 21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...2010-04-01 false External transcutaneous cardiac pacemaker (noninvasive). 870.5550...870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a...

  5. 21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 false External transcutaneous cardiac pacemaker (noninvasive). 870.5550...870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a...

  6. Gene Therapy to Create Biological Pacemakers

    Microsoft Academic Search

    Gerard J. J. Boink; Jurgen Seppen; Jacques M. T. Bakker; Hanno L. Tan

    Old age and a variety of cardiovascular disorders may disrupt normal sinus node function. Currently, this is successfully\\u000a treated with electronic pacemakers, which, however, leave room for improvement. During the past decade, different strategies\\u000a to initiate pacemaker function by gene therapy were developed. In the search for a biological pacemaker, various approaches\\u000a were explored, including ?\\u000a 2-adrenergic receptor overexpression, down

  7. Circadian adaptations to meal timing: neuroendocrine mechanisms

    PubMed Central

    Patton, Danica F.; Mistlberger, Ralph E.

    2013-01-01

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

  8. Lithium iodide cardiac pacemakers: initial clinical experience.

    PubMed Central

    Burr, L. H.

    1976-01-01

    A new long-life cardiac pacemaker pulse generator powered by a lithium iodide fuel cell was introduced in Canada in 1973. The compact, hermetically sealed unit is easily implanted and reliable, has excellent patient acceptance and has an anticipated battery life of almost 14 years. Among 105 patients who received a lithium iodide pacemaker, complications occurred in 18. The lithium iodide pacemaker represents a significant advance in pacemaker generator technology and is recommended for long-term cardiac pacing; the manufacturer guarantees the pulse generator for 6 years. Images FIG. 1 PMID:974965

  9. Space Derived Health Aids (Cardiac Pacemaker)

    NASA Technical Reports Server (NTRS)

    1981-01-01

    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.

  10. PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons.

    PubMed

    Ying, Shui-Wang; Tibbs, Gareth R; Picollo, Alessandra; Abbas, Syed Y; Sanford, R Lea; Accardi, Alessio; Hofmann, Franz; Ludwig, Andreas; Goldstein, Peter A

    2011-07-13

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate a pacemaking current, I(h), which regulates neuronal excitability and oscillatory activity in the brain. Although all four HCN isoforms are expressed in the brain, the functional contribution of HCN3 is unknown. Using immunohistochemistry, confocal microscopy, and whole-cell patch-clamp recording techniques, we investigated HCN3 function in thalamic intergeniculate leaflet (IGL) neurons, as HCN3 is reportedly preferentially expressed in these cells. We observed that I(h) recorded from IGL, but not ventral geniculate nucleus, neurons in HCN2(+/+) mice and rats activated slowly and were cAMP insensitive, which are hallmarks of HCN3 channels. We also observed strong immunolabeling for HCN3, with no labeling for HCN1 and HCN4, and only very weak labeling for HCN2. Deletion of HCN2 did not alter I(h) characteristics in mouse IGL neurons. These data together indicate that the HCN3 channel isoform generated I(h) in IGL neurons. Intracellular phosphatidylinositol-4,5-bisphosphate (PIP(2)) shifted I(h) activation to more depolarized potentials and accelerated activation kinetics. Upregulation of HCN3 function by PIP(2) augmented low-threshold burst firing and spontaneous oscillations; conversely, depletion of PIP(2) or pharmacologic block of I(h) resulted in a profound inhibition of excitability. The results indicate that functional expression of HCN3 channels in IGL neurons is crucial for intrinsic excitability and rhythmic burst firing, and PIP(2) serves as a powerful modulator of I(h)-dependent properties via an effect on HCN3 channel gating. Since the IGL is a major input to the suprachiasmatic nucleus, regulation of pacemaking function by PIP(2) in the IGL may influence sleep and circadian rhythms. PMID:21753018

  11. The influence of carbachol on glutamate-induced activity of the intergeniculate leaflet neurons--in vitro studies.

    PubMed

    Pekala, Dobromila; Blasiak, Anna; Lewandowski, Marian H

    2007-12-01

    The intergeniculate leaflet (IGL) is a very important component of the mammalian circadian timing system. One of the best known, but still barely understood functions of the IGL, is the integration of photic (retina-derived) and non-photic information, conveyed to the suprachiasmatic nucleus (SCN)--the site of the circadian pacemaker. Glutamate, the main neurotransmitter released from the axonal endings of the retinal ganglion cells to the SCN and most probably to the IGL, is thought to be responsible for mediating the effects of light on the circadian clock. The influence of carbachol, a non-specific cholinergic agonist, on locomotor activity, c-fos expression in the SCN, and the activity of this structure has been previously studied. However, no information is available concerning the influence of acetylcholine on the activity of the IGL neurons. Therefore, the purpose of the present study was to analyze the influence of carbachol (equivalent of non-photic stimulus) on the glutamate-induced activity of the IGL neurons. Experiments were performed on thalamic rat brain slices, using extracellular, single unit recordings. After reaching a stable response to focally applied glutamate, carbachol was added to the recording medium. In the presence of the cholinergic agonist, glutamate-induced activity was decreased in 32% and increased in 13% of investigated cases. Carbachol failed to evoke any change in glutamate-induced activity in 55% of the recording cells. Our results are in agreement with previous, mainly behavioral studies, where the influence of non-photic stimulus on photic-induced changes in circadian locomotor activity was determined. PMID:17997396

  12. SLEEPAND CIRCADIAN NEUROBIOLOGY (SCN)

    E-print Network

    Kay, Mark A.

    STANFORD SLEEPAND CIRCADIAN NEUROBIOLOGY (SCN) LABORATORY STANFORD SLEEP DISORDERS CLINIC SLEEPAND CIRCADIAN NEUROBIOLOGY LABORATORY (SCN LAB) The SCN lab is an integrated, multidisciplinary research facility dedicated to: (1) understanding sleep-wake control and biological rhythms at all levels

  13. Pigment-Dispersing Factor Signaling and Circadian Rhythms in Insect Locomotor Activity.

    PubMed

    Shafer, Orie T; Yao, Zepeng

    2014-07-01

    Though expressed in relatively few neurons in insect nervous systems, pigment-dispersing factor (PDF) plays many roles in the control of behavior and physiology. PDF's role in circadian timekeeping is its best-understood function and the focus of this review. Here we recount the isolation and characterization of insect PDFs, review the evidence that PDF acts as a circadian clock output factor, and discuss emerging models of how PDF functions within circadian clock neuron network of Drosophila, the species in which this peptide's circadian roles are best understood. PMID:25386391

  14. Circadian clocks in symbiotic corals: the duet between Symbiodinium algae and their coral host.

    PubMed

    Sorek, Michal; Díaz-Almeyda, Erika M; Medina, Mónica; Levy, Oren

    2014-04-01

    To date, the association and synchronization between two organismal circadian clocks ticking in parallel as part of a meta-organism (termed a symbiotic association), have rarely been investigated. Reef-building corals exhibit complex rhythmic responses to diurnal, lunar, and annual changes. Understanding circadian, circatidal, and annual regulation in reef-building corals is complicated by the presence of photosynthetic endosymbionts, which have a profound physiochemical influence on the intracellular environment. How corals tune their animal-based clock machinery to respond to external cues while simultaneously responding to internal physiological changes imposed by the symbiont, is not clear. There is insufficient molecular or physiological evidence of the existence of a circadian pacemaker that controls the metabolism, photosynthesis, synchronized mass spawning, and calcification processes in symbiotic corals. In this review, we present current knowledge regarding the animal pacemaker and the symbiotic-algal pacemaker. We examine the evidence from behavioral, physiological, molecular, and evolutionary perspectives. We explain why symbiotic corals are an interesting model with which to study the complexities and evolution of the metazoan circadian clock. We also provide evidence of why the chronobiology of corals is fundamental and extremely important for explaining the biology, physiology, and metabolism of coral reefs. A deeper understanding of these complex issues can help explain coral mass spawning, one of the earth's greatest and most mysterious behavioral phenomena. PMID:24508015

  15. Models of Neuronal Bursting Behavior: Implications for In-Vivo Versus In-Vitro Respiratory Rhythmogenesis

    Microsoft Academic Search

    Ilya A. Rybak; Walter M. John; Julian F. R. Paton

    \\u000a Neonatal in-vitro preparations can generate respiratory-like oscillations based on the intrinsic bursting or pacemaker properties in some neurons\\u000a within the medullary preBötzinger complex (PBC)1-3. This discovery provided a basis for a hybrid pacemaker-network theory that suggests that pacemaker PBC neurons form a kernel of the central pattern generator and hence provide a necessary contribution to the genesis of the respiratory

  16. Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

    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.

  17. Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics

    NASA Technical Reports Server (NTRS)

    Dijk, D. J.; Duffy, J. F.

    1999-01-01

    The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.

  18. Circadian behaviour in neuroglobin deficient mice.

    PubMed

    Hundahl, Christian A; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID:22496809

  19. Peripheral circadian clocks--a conserved phenotype?

    PubMed

    Weigl, Yuval; Harbour, Valerie L; Robinson, Barry; Dufresne, Line; Amir, Shimon

    2013-05-01

    The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock genes. Yet, additional posttranscriptional and translational events can contribute to the robustness and periodicity of the clock output. PMID:23425359

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

    PubMed Central

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

    2013-01-01

    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. PMID:24076244

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

    NASA Technical Reports Server (NTRS)

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

    1995-01-01

    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.

  2. The Circadian Timing System: A Recent Addition in the Physiological Mechanisms Underlying Pathological and Aging Processes

    PubMed Central

    Arellanes-Licea, Elvira; Caldelas, Ivette; De Ita-Pérez, Dalia; Díaz-Muñoz, Mauricio

    2014-01-01

    Experimental findings and clinical observations have strengthened the association between physio-pathologic aspects of several diseases, as well as aging process, with the occurrence and control of circadian rhythms. The circadian system is composed by a principal pacemaker in the suprachiasmatic nucleus (SNC) which is in coordination with a number of peripheral circadian oscillators. Many pathological entities such as metabolic syndrome, cancer and cardiovascular events are strongly connected with a disruptive condition of the circadian cycle. Inadequate circadian physiology can be elicited by genetic defects (mutations in clock genes or circadian control genes) or physiological deficiencies (desynchronization between SCN and peripheral oscillators). In this review, we focus on the most recent experimental findings regarding molecular defects in the molecular circadian clock and the altered coordination in the circadian system that are related with clinical conditions such as metabolic diseases, cancer predisposition and physiological deficiencies associated to jet-lag and shiftwork schedules. Implications in the aging process will be also reviewed. PMID:25489492

  3. Physiologically based modelling of circadian control on cell proliferation.

    PubMed

    Clairambault, Jean

    2006-01-01

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

  4. Pacemakers charging using body energy.

    PubMed

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

    2010-01-01

    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

  5. Pacemakers charging using body energy

    PubMed Central

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

    2010-01-01

    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

  6. Synaptic Depression Mediates Bistability in Neuronal Networks with Recurrent Inhibitory Connectivity

    E-print Network

    Nadim, Farzan

    Synaptic Depression Mediates Bistability in Neuronal Networks with Recurrent Inhibitory, New Jersey Institute of Technology and Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102 When depressing synapses are embedded in a circuit com- posed of a pacemaker neuron

  7. Effects of gravity on the circadian period in rats

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

    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.

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

    PubMed

    Nesbit, Katherine T; Christie, Andrew E

    2014-12-01

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

  9. Weakly Circadian Cells Improve Resynchrony

    PubMed Central

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

    2012-01-01

    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. PMID:23209395

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

    PubMed Central

    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

    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. PMID:24531181

  11. How Will a Pacemaker Affect My Lifestyle?

    MedlinePLUS

    ... check for changes in your heart's electrical activity. Battery Replacement Pacemaker batteries last between 5 and 15 years (average 6 ... doctor will replace the generator along with the battery before the battery starts to run down. Replacing ...

  12. Targeted mutation of the calbindin D28K gene disrupts circadian rhythmicity and entrainment

    E-print Network

    Silver, Rae

    . Kriegsfeld,1 Dan Feng Mei,2 Lily Yan,3 Paul Witkovsky,5 Joseph LeSauter,2 Toshiyuki Hamada4 and Rae Silver2 marks a subregion critical for circadian rhythmicity. In mouse SCN, a dense cluster of CalB neuronsB subregion is critical for the maintenance of circadian function at the behavioral level (LeSauter & Silver

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

  14. Circadian modulation in the intestinal absorption of p-glycoprotein substrates in monkeys.

    PubMed

    Iwasaki, Masaru; Koyanagi, Satoru; Suzuki, Norio; Katamune, Chiharu; Matsunaga, Naoya; Watanabe, Nobuaki; Takahashi, Masayuki; Izumi, Takashi; Ohdo, Shigehiro

    2015-07-01

    Recent studies in laboratory rodents have revealed that circadian oscillation in the physiologic functions affecting drug disposition underlies the dosing time-dependent change in pharmacokinetics. However, it is difficult to predict the circadian change in the drug pharmacokinetics in a diurnal human by using the data collected from nocturnal rodents. In this study, we used cynomolgus monkeys, diurnal active animals, to evaluate the relevance of intestinal expression of P-glycoprotein (P-gp) to the dosing time dependency of the pharmacokinetics of its substrates. The rhythmic phases of circadian gene expression in the suprachiasmatic nuclei (the mammalian circadian pacemaker) of cynomolgus monkeys were similar to those reported in nocturnal rodents. On the other hand, the expression of circadian clock genes in the intestinal epithelial cells of monkeys oscillated at opposite phases in rodents. The intestinal expression of P-gp in the small intestine of monkeys was also oscillated in a circadian time-dependent manner. Furthermore, the intestinal absorption of P-gp substrates (quinidine and etoposide) was substantially suppressed by administering the drugs at the times of day when P-gp levels were abundant. By contrast, there was no significant dosing time-dependent difference in the absorption of the non-P-gp substrate (acetaminophen). The oscillation in the intestinal expression of P-gp appears to affect the pharmacokinetics of its substrates. Identification of circadian factors affecting the drug disposition in laboratory monkeys may improve the predictive accuracy of pharmacokinetics in humans. PMID:25901027

  15. Biological Clocks & Circadian Rhythms

    ERIC Educational Resources Information Center

    Robertson, Laura; Jones, M. Gail

    2009-01-01

    The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian

  16. Pacemaker leads: performance and progress.

    PubMed

    de Voogt, W G

    1999-03-11

    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

  17. Circadian Rhythm Abnormalities

    PubMed Central

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

    2013-01-01

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

  18. World's Tiniest Pacemaker Seems Safe, Effective in Trial

    MedlinePLUS

    ... nlm.nih.gov/medlineplus/news/fullstory_152575.html World's Tiniest Pacemaker Seems Safe, Effective in Trial Device ... 2015 FRIDAY, May 15, 2015 (HealthDay News) -- The world's smallest pacemaker is safe and effective in patients ...

  19. Neuropeptide Y does not reset the circadian clock in NPY Y2-/- mice.

    PubMed

    Soscia, Stephanie J; Harrington, Mary E

    2005-01-20

    Mammalian circadian rhythms are modulated by neuropeptide Y (NPY), a peptide contained in the projection from the intergeniculate leaflet to the suprachiasmatic nuclei of the circadian pacemaker. NPY resets the circadian clock during the subjective day, mediating non-photic inputs. Previous studies using receptor-selective agonists have indicated that this action of NPY is mediated by the Y2 receptor in hamsters. The present study determined if NPY applied to the suprachiasmatic nuclei in the mid-subjective day can phase-advance the rhythm of spontaneous firing rate of Y2-/- mice. We observed that NPY did reset the rhythm of control mice but did not significantly shift the phase of this rhythm in the Y2-/- mice. These results provide strong evidence for the role of the Y2 receptor mediating neuropeptide Y subjective day phase-advance shifts in mice. PMID:15619538

  20. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light

    NASA Technical Reports Server (NTRS)

    Boivin, D. B.; Czeisler, C. A.

    1998-01-01

    The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p < or = 0.003). After light-induced phase advances, the circadian rhythms of plasma melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.

  1. The selective tachykinin neurokinin 1 (NK1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms.

    PubMed

    Gannon, Robert L; Millan, Mark J

    2005-12-19

    Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In addition, two other nuclei which form part of the circadian system, the intergeniculate leaflet of the thalamus and the raphe nuclei, also contain fibers and/or cell bodies immunoreactive for substance P. In light of these observations, we evaluated the influence of the selective tachykinin NK1 receptor antagonist, GR 205,171, upon circadian activity rhythms in the hamster. Systemic injection of GR 205,171 dose-dependently (2.5-40.0 mg/kg, i.p.) inhibited light-induced phase advances in hamster circadian wheel running activity rhythms by approximately 50%. In contrast, GR 226,206, the less active enantiomer of GR 205,171, failed to affect light-induced phase advances. In addition, we examined the potential ability of GR 205,171 to induce non-photic phase shifts in hamster wheel running rhythms when injected at mid-day to late night circadian times. However, GR 205,171 (40 mg/kg) did not elicit non-photic phase shifts at these times indicating that tachykinin NK1 receptor antagonists are only effective when a light stimulus is applied to the pacemaker. Although GR 205,171 may, in theory, activate several sites within the circadian system, we suggest that GR 205,171 acts in the raphe nuclei to increase inhibitory serotonergic input to pacemaker cells in the suprachiasmatic nuclei, thereby suppressing photic modulation of the pacemaker. These findings have important implications for the use of tachykinin NK1 receptor antagonists in the treatment of depression and other central nervous system disorders. PMID:16307740

  2. Modeling circadian and sleep-homeostatic effects on short-term interval timing.

    PubMed

    Späti, Jakub; Aritake, Sayaka; Meyer, Andrea H; Kitamura, Shingo; Hida, Akiko; Higuchi, Shigekazu; Moriguchi, Yoshiya; Mishima, Kazuo

    2015-01-01

    Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior. PMID:25741253

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

    PubMed Central

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

    2006-01-01

    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. PMID:16990400

  4. Circadian organization of the mammalian retina: from gene regulation to physiology and diseases.

    PubMed

    McMahon, Douglas G; Iuvone, P Michael; Tosini, Gianluca

    2014-03-01

    The retinal circadian system represents a unique structure. It contains a complete circadian system and thus the retina represents an ideal model to study fundamental questions of how neural circadian systems are organized and what signaling pathways are used to maintain synchrony of the different structures in the system. In addition, several studies have shown that multiple sites within the retina are capable of generating circadian oscillations. The strength of circadian clock gene expression and the emphasis of rhythmic expression are divergent across vertebrate retinas, with photoreceptors as the primary locus of rhythm generation in amphibians, while in mammals clock activity is most robust in the inner nuclear layer. Melatonin and dopamine serve as signaling molecules to entrain circadian rhythms in the retina and also in other ocular structures. Recent studies have also suggested GABA as an important component of the system that regulates retinal circadian rhythms. These transmitter-driven influences on clock molecules apparently reinforce the autonomous transcription-translation cycling of clock genes. The molecular organization of the retinal clock is similar to what has been reported for the SCN although inter-neural communication among retinal neurons that form the circadian network is apparently weaker than those present in the SCN, and it is more sensitive to genetic disruption than the central brain clock. The melatonin-dopamine system is the signaling pathway that allows the retinal circadian clock to reconfigure retinal circuits to enhance light-adapted cone-mediated visual function during the day and dark-adapted rod-mediated visual signaling at night. Additionally, the retinal circadian clock also controls circadian rhythms in disk shedding and phagocytosis, and possibly intraocular pressure. Emerging experimental data also indicate that circadian clock is also implicated in the pathogenesis of eye disease and compelling experimental data indicate that dysfunction of the retinal circadian system negatively impacts the retina and possibly the cornea and the lens. PMID:24333669

  5. Circadian genomics of the chick pineal gland in vitro

    PubMed Central

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

    2008-01-01

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

  6. Delayed pacemaker erosion due to electrode seal defects.

    PubMed

    Cohn, J D; Santhanam, R; Rosenbloom, M A; Thorson, R F

    1979-11-01

    Over a 7-year period, follow-up data were available on 163 patients who underwent 209 pacemaker-related operations for initial insertion or revision of previously implanted units. During the follow-up period, 16 pacemaker generator units were remoaved from 16 pacemaker generator units were removed from 12 patients solely because of the development of local skin erosion. This represents a 7.7% incidence of pacemaker generator erosion. Tree units were removed within a 3-month interval following pacemaker implantation and were associated with positive bacterial cultures, theraby indicating an infectious cause. Findings at removal of the remaining 13 pacemaker generators included extensive fibrosis with chronic inflammation, fibroblastic proliferation, and granulation tissue, which was most prominent at the site of insertion of the pacemaker lead into the pacemaker generator unit. Granulation tissue frequently led from this area to the area of skin attenuation and erythema. Inspection of the pacemaker generator units and electrodes demonstrated fluid ingress and tissue ingrowth toward the electrode due to inadequate seal mechanisms. Inadequate seal design of the pacemaker generator and electrode junction leads to tissue ingrowth with fibroblastic proliferatiog chronic inflammation, and eventual pacemaker erosion. PMID:496497

  7. MRI-conditional pacemakers: current perspectives

    PubMed Central

    Ferreira, António M; Costa, Francisco; Tralhão, António; Marques, Hugo; Cardim, Nuno; Adragão, Pedro

    2014-01-01

    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. PMID:24851058

  8. Morning and evening oscillators cooperate to reset circadian behavior in response to light input.

    PubMed

    Lamba, Pallavi; Bilodeau-Wentworth, Diana; Emery, Patrick; Zhang, Yong

    2014-05-01

    Light is a crucial input for circadian clocks. In Drosophila, short light exposure can robustly shift the phase of circadian behavior. The model for this resetting posits that circadian photoreception is cell autonomous: CRYPTOCHROME senses light, binds to TIMELESS (TIM), and promotes its degradation, which is mediated by JETLAG (JET). However, it was recently proposed that interactions between circadian neurons are also required for phase resetting. We identify two groups of neurons critical for circadian photoreception: the morning (M) and the evening (E) oscillators. These neurons work synergistically to reset rhythmic behavior. JET promotes acute TIM degradation cell autonomously in M and E oscillators but also nonautonomously in E oscillators when expressed in M oscillators. Thus, upon light exposure, the M oscillators communicate with the E oscillators. Because the M oscillators drive circadian behavior, they must also receive inputs from the E oscillators. Hence, although photic TIM degradation is largely cell autonomous, neural cooperation between M and E oscillators is critical for circadian behavioral photoresponses. PMID:24746814

  9. Measuring pacemaker dose: a clinical perspective.

    PubMed

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

    2012-01-01

    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

  10. Measuring pacemaker dose: A clinical perspective

    SciTech Connect

    Studenski, Matthew T., E-mail: matthew.studenski@jeffersonhospital.org [Department of Radiation Oncology at the Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Xiao Ying; Harrison, Amy S. [Department of Radiation Oncology at the Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States)

    2012-07-01

    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.

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

  12. The suprachiasmatic nucleus and the circadian timing system.

    PubMed

    Moore, Robert Y

    2013-01-01

    The circadian timing system (CTS) in mammals may be defined as a network of interconnected diencephalic structures that regulate the timing of physiological processes and behavioral state. The central feature of the CTS is the suprachiasmatic nucleus (SCN) of the hypothalamus, a self-sustaining circadian oscillator entrained by visual afferents, input from other brain and peripheral oscillators. The SCN was first noted as a distinct component of the hypothalamus during the late nineteenth century and recognized soon after as a uniform feature of the mammalian and lower vertebrate brain. But, as was true for so many brain components identified in that era, its function was unknown and remained so for nearly a century. In the latter half of the twentieth century, numerous tools for studying the brain were developed including neuroanatomical tracing methods, electrophysiological methods including long-term recording in vivo and in vitro, precise methods for producing localized lesions in the brain, and molecular neurobiology. Application of these methods provided a body of data strongly supporting the view that the SCN is a circadian pacemaker in the mammalian brain. This chapter presents an analysis of the functional organization of the SCN as a component of a neural network, the CTS. This network functions as a coordinator of hypothalamic regulatory systems imposing a temporal organization of physiological processes and behavioral state to promote environmental adaptation. PMID:23899592

  13. Influence of gravity on the circadian timing system

    NASA Astrophysics Data System (ADS)

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

    1994-08-01

    The circadian timing system (CTS) is responsible for daily temporal coordination of physiological and behavioral functions both internally and with the external environment. Experiments in altered gravitational environments have revealed changes in circadian rhythms of species ranging from fungi to primates. The altered gravitational environments examined included both the microgravity environment of spaceflight and hyperdynamic environments produced by centrifugation. Acute exposure to altered gravitational environments changed homeostatic parameters such as body temperature. These changes were time of day dependent. Exposure to gravitational alterations of relatively short duration produced changes in both the homeostatic level and the amplitude of circadian rhythms. Chronic exposure to a non-earth level of gravity resulted in changes in the period of the expressed rhythms as well as in the phase relationships between the rhythms and between the rhythms and the external environment. In addition, alterations in gravity appeared to act as a time cue for the CTS. Altered gravity also affected the sensitivity of the pacemaker to other aspects of the environment (i.e., light) and to shifts of time cues. Taken together, these studies lead to the conclusion that the CTS is indeed sensitive to gravity and its alterations. This finding has implications for both basic biology and space medicine.

  14. Influence of gravity on the circadian timing system

    NASA Technical Reports Server (NTRS)

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

    1994-01-01

    The circadian timing system (CTS) is responsible for daily temporal coordination of physiological and behavioral functions both internally and with the external environment. Experiments in altered gravitational environments have revealed changes in circadian rhythms of species ranging from fungi to primates. The altered gravitational environments examined included both the microgravity environment of spaceflight and hyperdynamic environments produced by centrifugation. Acute exposure to altered gravitational environments changed homeostatic parameters such as body temperature. These changes were time of day dependent. Exposure to gravitational alterations of relatively short duration produced changes in both the homeostatic level and the amplitude of circadian rhythms. Chronic exposure to a non-earth level of gravity resulted in changes in the period of the expressed rhythms as well as in the phase relationships between the rhythms and between the rhythms and the external environment. In addition, alterations in gravity appeared to act as a time cue for the CTS. Altered gravity also affected the sensitivity of the pacemaker to other aspects of the environment (i.e., light) and to shifts of time cues. Taken together, these studies lead to the conclusion that the CTS is indeed sensitive to gravity and its alterations. This finding has implications for both basic biology and space medicine.

  15. microRNA modulation of circadian clock period and entrainment

    PubMed Central

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

    2007-01-01

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

  16. Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms

    PubMed Central

    St. Hilaire, Melissa A.; Lockley, Steven W.

    2015-01-01

    Objective/Background Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep–wake disorder. Patients/Methods Three totally blind males (63.0?±?7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48?h every 1–2 weeks. Participants completed daily sleep–wake logs, and rated their alertness and mood using nine-point scales every ~2–4?h while awake on urine sampling days. Caffeine capsules (150?mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period ? and compared to placebo (n?=?2) or no treatment (n?=?1) in a single-masked manner. Results Non-24-h aMT6s rhythms were confirmed in all three participants (? range?=?24.32–24.57?h). Daily administration of 150?mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases (p?circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep–Wake Disorder in the blind appropriately. PMID:25891543

  17. Circadian regulation of slow waves in human sleep: Topographical aspects.

    PubMed

    Lazar, Alpar S; Lazar, Zsolt I; Dijk, Derk-Jan

    2015-08-01

    Slow waves (SWs, 0.5-4Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

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

    PubMed Central

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

    2014-01-01

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

  19. Socially synchronized circadian oscillators

    PubMed Central

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

    2013-01-01

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

  20. Effects of Gravity on Insect Circadian Rhythmicity

    NASA Technical Reports Server (NTRS)

    Hoban-Higgins, Tana M.

    2000-01-01

    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.

  1. Optic enucleation eliminates circadian rhythm shifts induced by stimulating the intergeniculate leaflet in Syrian hamsters.

    PubMed

    Kaur, Satvinder; Rusak, Benjamin

    2007-11-01

    The intergeniculate leaflet (IGL) is a region of the lateral geniculate complex that is part of the circadian system. It receives direct innervation by specialized retinal ganglion cells involved in circadian rhythm entrainment and is also reciprocally connected to the suprachiasmatic nucleus (SCN), which is the principal circadian pacemaker. Electrical stimulation in the IGL results in shifts of circadian rhythms with a pattern of phase dependence that resembles that elicited by periods of darkness. IGL stimulation also increases levels of c-Fos in the dorsolateral part of the caudal SCN. A previous study showed that optic enucleation prevents increases in c-Fos in the SCN, suggesting the hypothesis that this increase is related to antidromic activation of retinal ganglion cells which bifurcate and project to both SCN and IGL. We tested whether phase shifts induced by IGL stimulation are also dependent on intact retinal innervation. Electrical stimulation of the IGL for 60 min at circadian time (CT)9 (with CT12 defined as activity onset) induced phase advances in nine hamsters with electrodes in the IGL, while other placements did not evoke shifts. After optic enucleation, six of these hamsters received an identical second stimulation; none showed substantial phase shifts. These results are consistent with the hypothesis that phase shifts induced by IGL stimulation depend on antidromic activation of retinal ganglion cells. PMID:17931778

  2. Circadian Rhythms of PER2::LUC in Individual Primary Mouse Hepatocytes and Cultures

    PubMed Central

    Molyneux, Penny C.; Yu, Jimmy K.; Li, Alexander S.; Leise, Tanya L.; Harrington, Mary E.

    2014-01-01

    Background Hepatocytes, the parenchymal cells of the liver, express core clock genes, such as Period2 and Cryptochrome2, which are involved in the transcriptional/translational feedback loop of the circadian clock. Whether or not the liver is capable of sustaining rhythms independent of a central pacemaker is controversial. Whether and how circadian information may be shared among cells in the liver in order to sustain oscillations is currently unknown. Results In this study we isolated primary hepatocytes from transgenic Per2Luc mice and used bioluminescence as a read-out of the state of the circadian clock. Hepatocytes cultured in a collagen gel sandwich configuration exhibited persistent circadian rhythms for several weeks. The amplitude of the rhythms damped, but medium changes consistently reset the phase and amplitude of the cultures. Cry2?/? Per2Luc cells oscillated robustly and expressed a longer period. Co-culturing with wildtype cells did not significantly shorten the period, indicating that coupling among hepatocytes is insufficient to synchronize cells with significantly differing periods. However, spatial patterns revealed by cellular imaging of wildtype cultures provided evidence of weak local coupling among the hepatocytes. Conclusions Our results with primary hepatocyte cultures demonstrate that cultured hepatocytes are weakly coupled. While this coupling is not sufficient to sustain global synchrony, it does increase local synchrony, which may stabilize the circadian rhythms of peripheral oscillators, such as the liver, against noise in the entraining signals. PMID:24498336

  3. Circadian clock regulation of the cell cycle in the zebrafish intestine.

    PubMed

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

    2013-01-01

    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. PMID:24013905

  4. Circadian Clock Regulation of the Cell Cycle in the Zebrafish Intestine

    PubMed Central

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

    2013-01-01

    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. PMID:24013905

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

    NSDL National Science Digital Library

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

    2012-10-02

    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.

  6. Neural regulation of the hepatic circadian rhythm.

    PubMed

    Shibata, Shigenobu

    2004-09-01

    A microarray analysis experiment has revealed that there are many genes, including so-called clock genes, expressing a circadian rhythm in the liver. The clock genes mentioned above are expressed not only in the suprachiasmatic nucleus (SCN) of the hypothalamus, where the master clock exists, but also in other brain regions and various peripheral tissues. In the liver, clock genes are abundantly expressed and show a clear circadian rhythm. Thus, clock genes seem to play a critical role in the molecular clockworks of both the SCN and the liver. Although oscillation of clock genes in the liver is controlled under the circadian clock mechanism in the SCN, we do not know the resetting signals on liver clock function. Over the past few years, use of the pseudorabies virus, a transsynaptic tract tracer, has allowed us to map neural connections between the SCN and peripheral tissues in several physiological systems. Communication between the SCN and peripheral tissues occurs through autonomic nervous systems involving the sympathetic and parasympathetic neurons. This review mainly describes both anatomical and physiological experiments to reveal the sympathetic control over liver clock function. Although further study is necessary to produce the precise mechanism underlying neural control of liver clock systems, evolution of this mechanism will help our understanding of liver clock functions such as drug metabolism and energy metabolism. PMID:15382011

  7. 77 FR 39924 - Effective Date of Requirement for Premarket Approval for Cardiovascular Permanent Pacemaker...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ...for Premarket Approval for Cardiovascular Permanent Pacemaker Electrode...protocol (PDP) for the cardiovascular permanent pacemaker electrode...established a comprehensive system for the regulation of medical...completion of a PDP for the cardiovascular permanent pacemaker...

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

    PubMed

    Garg, Naveen; Moorthy, Nagaraja

    2012-12-01

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

  9. Melatonin Signaling Controls Circadian Swimming Behavior in Marine Zooplankton

    PubMed Central

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

    2014-01-01

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

  10. Melatonin signaling controls circadian swimming behavior in marine zooplankton.

    PubMed

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

    2014-09-25

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

  11. Development of the circadian clockwork in the kidney.

    PubMed

    Mészáros, Krisztina; Pruess, Linda; Szabó, Attila J; Gondan, Matthias; Ritz, Eberhard; Schaefer, Franz

    2014-11-01

    The circadian molecular clock is an internal time-keeping system composed of centrally synchronized tissue-level pacemakers. Here, we explored the ontogeny of the clock machinery in the developing kidney. Pregnant rats were housed at 12-12?h light-dark cycles. Offsprings were killed at 4-h intervals on embryonic day 20 and at postnatal weeks 1, 4, and 12. Canonical clock gene (Clock, Bmal1, Rev-erb?, Cry1, Cry2, Per1, Per2) and kidney-specific clock-controlled gene (?ENaC, SGK1, NHE3, AVPR2) expression was profiled by RT-PCR. To investigate the role of nutritional cues, the feeding pattern was modified postpartum. Clock, Rev-erb?, Per2, ?ENaC, SGK1, NHE3, and AVPR2 showed circadian expression at the end of intrauterine development. By 1 week, all genes oscillated with a distinct acrophase shift toward the time of peak feeding activity. Daily 4-hour withdrawal of mothers induced a 12-hour phase shift of Clock and Bmal1 expression, while disrupting oscillations of the other genes. After weaning, oscillation phases shifted back toward the adult pattern, which was fully expressed at 12 weeks. Thus, functional circadian molecular clockwork evolves in the late fetal and early postnatal kidney. During the nursing period, oscillations are entrained by nutritional cues. The coupling of the circadian expression of tubular regulators of fluid and electrolyte excretion to the feeding-entrained clockwork may be important to maintain homeostasis during this critical period. PMID:24897033

  12. Motor Pattern Production in Reciprocally Inhibitory Neurons Exhibiting Postinhibitory Rebound

    Microsoft Academic Search

    Donald H. Perkel; Brian Mulloney

    1974-01-01

    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

  13. Modulation of pacemaker activity by IPSP and brief length perturbations in the crayfish stretch receptor.

    PubMed

    Buño, W; Fuentes, J; Barrio, L

    1987-03-01

    We have studied the influences of brief stretches and releases and of inhibitory postsynaptic potentials (IPSPs) on pacemaker activity of the crayfish stretch receptor (RM1). Stimuli shift or reset the ongoing rhythm. Resettings were different if evaluated in interspike intervals containing perturbations, or in succeeding ones, and are referred to as early and late, respectively. Early resetting revealed that stretches and releases or IPSPs advance and delay, respectively, the next spike. With small stretches and releases or IPSPs, effects depend on the timing of the perturbation relative to the previous spike or phase, but above a characteristic mechanical perturbation amplitude the next spike fires at a fixed latency, invariant with the phase. Of particular interest was the finding that during late resetting the first successive intervals following stretches and releases or IPSPs were longer and shorter, respectively, than the period. This led, in approximately 50% of the cases, to a gradual recovery of the original pacemaker beat in the sense that spikes fire timed as if the early rhythm shift had not occurred. In conclusion, the recent firing history is essential in determining the RM1's response. The receptor's sensitivity is a complex nonlinear and periodic function of the pacemaker activity, and the response is due to interactions between pacemaker- and perturbation-induced transmembrane ionic currents. Although several alternative mechanisms may underly beat recovery, the results suggest that at least two coupled oscillators, one perturbable and the other not, provide a better explanation than a single oscillator. The physiological significance of resettings is unknown, but the early rhythm shift may synchronize RM1s in several segments when the animal's tail is moved, and conversely recovery would reduce synchrony, with obvious influences on shared postsynaptic neurons. PMID:3031234

  14. SLEEP&CIRCADIAN NEUROBIOLOGY

    E-print Network

    Bushman, Frederic

    . In Behavioral Sleep Medicine, Drs. Perlis and Gehrman investigate the mechanisms of insomnia and effects at the University of Pennsylvania in sleep/circadian research and in the clinical practice in sleep medicine the Peter C. Farrell Prize in Sleep Medicine from Harvard Medical School Division of Sleep Medicine

  15. The progression of circadian phase during light exposure in animals and humans.

    PubMed

    Beersma, Domien G M; Comas, Marian; Hut, Roelof A; Gordijn, Marijke C M; Rueger, Melanie; Daan, Serge

    2009-04-01

    Studies in humans and mice revealed that circadian phase shifting effects of light are larger at the beginning of a light exposure interval than during subsequent exposure. Little is known about the dynamics of this response reduction phenomenon. Here the authors propose a method to obtain information on the progression of phase during light exposure. Phase response curves to intervals of light exposure over a wide range in duration are available for flesh flies, mice, and humans. By comparing the phase shifts induced by pulses of various durations but starting at the same circadian phase, the progression of phase during a long interval (hours) of light exposure is reconstructed for each of these 3 species. For flies, the phase progression curves show that light pulses-if long enough- eventually make the pacemaker stabilize around InT18 (near subjective dusk), as is typical for strong resetting. The progression of phase toward the final value never shows advances larger than 7 h, while delays can be as large as 18 h. By applying the phase progression curve method presented in this study, differences between advances and delays in type-0 phase response curves can be distinguished clearly. In flesh flies (Sarcophaga) this bifurcation between delays and advance occurs when light exposure starts at InT0 (subjective midnight). The present study confirms earlier findings in mice showing that the beginning of the light pulse generates stronger phase shifts than subsequent hours of light. Response reduction is complete within 1 h of exposure. It is argued that the variation is not so much due to light adaptation processes, but rather to response saturation. In contrast to light adaptation, response saturation is fundamental to proper functioning of the circadian pacemaker during natural entrainment. For understanding entrainment of the pacemaker to natural light, phase progression curves in which naturalistic light profiles are applied could be an important tool. PMID:19346452

  16. Circadian clocks and neurodegenerative diseases: time to aggregate?

    PubMed

    Hastings, Michael H; Goedert, Michel

    2013-10-01

    The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features - altered daily rhythms and molecular aggregation - are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases. PMID:23797088

  17. N-NITROSOMELATONIN ENHANCES PHOTIC SYNCHRONIZATION OF MAMMALIAN CIRCADIAN RHYTHMS

    PubMed Central

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

    2014-01-01

    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 two-fold 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 cFOS and PER1. 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-hour delay). Here we demonstrate the chronobiotic properties of N-nitrosomelatonin, emphasizing the importance of nitric oxide-mediated transduction for circadian phase advances. PMID:24261470

  18. Decoupling circadian clock protein turnover from circadian period determination

    PubMed Central

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

    2015-01-01

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

  19. The ROP vesicle release factor is required in adult Drosophila glia for normal circadian behavior

    PubMed Central

    Ng, Fanny S.; Jackson, F. Rob

    2015-01-01

    We previously showed that endocytosis and/or vesicle recycling mechanisms are essential in adult Drosophila glial cells for the neuronal control of circadian locomotor activity. In this study, our goal was to identify specific glial vesicle trafficking, recycling, or release factors that are required for rhythmic behavior. From a glia-specific, RNAi-based genetic screen, we identified eight glial factors that are required for normally robust circadian rhythms in either a light-dark cycle or in constant dark conditions. In particular, we show that conditional knockdown of the ROP vesicle release factor in adult glial cells results in arrhythmic behavior. Immunostaining for ROP reveals reduced protein in glial cell processes and an accumulation of the Par Domain Protein 1? (PDP1?) clock output protein in the small lateral clock neurons. These results suggest that glia modulate rhythmic circadian behavior by secretion of factors that act on clock neurons to regulate a clock output factor.

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

    Microsoft Academic Search

    Günter Görge; Michael Kirstein; Raimund Erbel

    2001-01-01

    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

  1. Circadian and sleep-dependent regulation of hormone release in humans

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

    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.

  2. A new multiprogrammable isotopic powered cardiac pacemaker

    SciTech Connect

    Smyth, N.P.; Purdy, D.L.; Sager, D.; Keshishian, J.M.

    1982-09-01

    A new multiprogrammable, isotopic-powered cardiac pacemaker was implanted in six patients as a custom device. Five were initial implants and one was a replacement. The patients were studied for up to two years. In five of the six cases it was found advantageous to change one of the programmable parameters. Multiprogrammability is obviously as important in an isotopic pulse generator as in a lithium unit, if not more so, because of the unit's greater longevity. Further studies are continuing in an FDA approved clinical trial.

  3. Phase resetting in duper hamsters: specificity to photic zeitgebers and circadian phase.

    PubMed

    Manoogian, Emily N C; Leise, Tanya L; Bittman, Eric L

    2015-04-01

    The duper mutation in Syrian hamsters shortens the free-running period of locomotor activity (?DD) to about 23 h and results in a type 0 phase-response curve (PRC) to 15-min light pulses. To determine whether exaggerated phase shifts are specific to photic cues and/or restricted to subjective night, we subjected hamsters to novel wheel confinements and dark pulses during subjective day. Small phase shifts elicited by the nonphotic cue were comparable in mutant and wild-type (WT) hamsters, but dark pulses triggered larger shifts in dupers. To assess further the effects of the duper mutation on light-dark transitions, we transferred hamsters between constant light (LL) and constant dark (DD) or between DD and LL at various circadian phases. Duper hamsters displayed significantly larger phase shifts than WT hamsters when transferred from LL to DD during subjective day and from DD to LL during subjective night. The variability of phase shifts in response to all light/dark transitions was significantly greater in duper hamsters at all time points. In addition, most duper hamsters, but none of the WTs, displayed transient ultradian wheel-running patterns for 5 to 12 days when transferred from light to dark at CT 18. The ?(2) periodogram and autocorrelation analyses indicate that these ultradian patterns differ from the disruption of rhythmicity by SCN lesions or exposure to constant bright light. We conclude that the duper mutation specifically amplifies phase shifts to photic cues and may destabilize coupling of circadian organization upon photic challenge due to weakened coupling among components of the circadian pacemaker. Mathematical modeling of the circadian pacemaker supports this hypothesis. PMID:25633984

  4. Phase Resetting in Duper Hamsters: Specificity to Photic Zeitgebers and Circadian Phase

    PubMed Central

    Manoogian, Emily N. C.; Leise, Tanya L.; Bittman, Eric L.

    2015-01-01

    The duper mutation in Syrian hamsters shortens the free-running period of locomotor activity (?DD) to about 23 h and results in a type 0 phase-response curve (PRC) to 15-min light pulses. To determine whether exaggerated phase shifts are specific to photic cues and/or restricted to subjective night, we subjected hamsters to novel wheel confinements and dark pulses during subjective day. Small phase shifts elicited by the nonphotic cue were comparable in mutant and wild-type (WT) hamsters, but dark pulses triggered larger shifts in dupers. To assess further the effects of the duper mutation on light-dark transitions, we transferred hamsters between constant light (LL) and constant dark (DD) or between DD and LL at various circadian phases. Duper hamsters displayed significantly larger phase shifts than WT hamsters when transferred from LL to DD during subjective day and from DD to LL during subjective night. The variability of phase shifts in response to all light/dark transitions was significantly greater in duper hamsters at all time points. In addition, most duper hamsters, but none of the WTs, displayed transient ultradian wheel-running patterns for 5 to 12 days when transferred from light to dark at CT 18. The ?2 periodogram and autocorrelation analyses indicate that these ultradian patterns differ from the disruption of rhythmicity by SCN lesions or exposure to constant bright light. We conclude that the duper mutation specifically amplifies phase shifts to photic cues and may destabilize coupling of circadian organization upon photic challenge due to weakened coupling among components of the circadian pacemaker. Mathematical modeling of the circadian pacemaker supports this hypothesis. PMID:25633984

  5. Postoperative circadian disturbances.

    PubMed

    Gögenur, Ismail

    2010-12-01

    An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention has also been directed towards the circadian variation in endogenous rhythms in relation to surgery. The attention has been directed to the question whether the circadian variation in endogenous rhythms can affect postoperative recovery, morbidity and mortality. Based on the lack of studies where these endogenous rhythms have been investigated in relation to surgery we performed a series of studies exploring different endogenous rhythms and factors affecting these rhythms. We also wanted to examine whether the disturbances in the postoperative circadian rhythms could be correlated to postoperative recovery parameters, and if pharmacological administration of chronobiotics could improve postoperative recovery. Circadian rhythm disturbances were found in all the examined endogenous rhythms. A delay was found in the endogenous rhythm of plasma melatonin and excretion of the metabolite of melatonin (AMT6s) in urine the first night after both minor and major surgery. This delay after major surgery was correlated to the duration of surgery. The amplitude in the melatonin rhythm was unchanged the first night but increased in the second night after major surgery. The amplitude in AMT6s was reduced the first night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively. There was also a shift in the autonomic nervous balance after major surgery with a significantly increased number of myocardial ischaemic episodes during the nighttime period. The circadian activity rhythm was also disturbed after both minor and major surgery. The daytime AMT6s excretion in urine after major surgery was increased on the fourth day after surgery and the total excretion of AMT6s in urine was correlated to sleep efficiency and wake time after sleep onset, but was not correlated to the occurrence of postoperative cognitive dysfunction. We could only prove an effect of melatonin substitution in patients with lower than median pain levels for a three days period after laparoscopic cholecystectomy. In the series of studies included in this thesis we have systematically shown that circadian disturbances are found in the secretion of hormones, the sleep-wake cycle, core body temperature rhythm, autonomic nervous system tone, myocardial ischaemia and activity rhythm after surgery. Correlation exists between circadian rhythm parameters and measures of postoperative sleep quality and recovery. However, oral melatonin treatment in the first three nights after surgery, cannot yet be generally recommended for improvement of sleep quality or other recovery parameters based on the available results. It may be indicated in subgroups or if other perioperative treatment algorithms were used, but this has to be investigated in future trials. PMID:21122464

  6. Sleep and circadian rhythms

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.

    1991-01-01

    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.

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

    PubMed Central

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

    2013-01-01

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

  8. Do pacemakers drive the central pattern generator for locomotion in mammals?

    PubMed

    Brocard, Frédéric; Tazerart, Sabrina; Vinay, Laurent

    2010-04-01

    Locomotor disorders profoundly impact quality of life of patients with spinal cord injury. Understanding the neuronal networks responsible for locomotion remains a major challenge for neuroscientists and a fundamental prerequisite to overcome motor deficits. Although neuronal circuitry governing swimming activities in lower vertebrates has been studied in great details, determinants of walking activities in mammals remain elusive. The manuscript reviews some of the principles relevant to the functional organization of the mammalian locomotor network and mainly focuses on mechanisms involved in rhythmogenesis. Based on recent publications supplemented with new experimental data, the authors will specifically discuss a new working hypothesis in which pacemakers, cells characterized by inherent oscillatory properties, might be functionally integrated in the locomotor network in mammals. PMID:20400712

  9. Circadian rate variation in rate-adaptive pacing systems.

    PubMed

    Lee, M T; Baker, R

    1990-12-01

    By mimicking the natural rate slowdown during sleep, a pacing system can enhance patient comfort while improving device longevity. A new family of rate-adaptive pacemakers accomplishes this circadian rate variation by modeling the patient's sleep-wake cycle using a time-of-day clock inside the device. Furthermore, to account for minor variations in the patient's sleep-wake cycle, sensor data can be used to automatically adapt the starting and stopping points of this change in rate. Using the model, the device begins to gradually reduce the pacing rate beginning one-half hour before the selected bed time. Similarly, the rate begins to increase one-half hour before the selected waking time. Sensor data indicating the presence or absence of patient activity are used to adapt the selected bed and wake times, enabling the system to maintain an appropriate schedule despite changes in the patient's actual schedule. The model approximates natural human adaptation times for time zone or work shift changes. This circadian rate adaptation does not preclude the system's rate response to patient activity; even during sleep time the response to moderate or heavy exercise is essentially unchanged. PMID:1704544

  10. Circadian entrainment and its role in depression: a mechanistic review.

    PubMed

    Lall, G S; Atkinson, L A; Corlett, S A; Broadbridge, P J; Bonsall, D R

    2012-10-01

    The natural rotation of the earth generates an environmental day-night cycle that repeats every 24 h. This daily transition from dawn to dusk provides one of the most important time cues to which the majority of organisms synchronise their activity. Under these conditions, natural light, a photic stimulus, provides the principal entraining cue. In mammals, an endogenous circadian pacemaker located within the suprachiasmatic nucleus (SCN) of the hypothalamus acts as a coordinating centre to align physiological activity with the environmental light-dark cycle. However, the SCN also receives regulatory input from a number of behavioural, non-photic, cues such as physical activity, social interactions and feeding routines. The unique ability of the SCN to integrate both photic and non-photic cues allows it to generate a rhythm that is tailored to the individual and entrained to the environment. Here, we review the key neurotransmitter systems involved in both photic and non-photic transmission to the SCN and their interactions that assist in generating an entrained output rhythm. We also consider the impact on health of a desynchronised circadian system with a focus on depressive affective disorders and current therapies aimed at manipulating the relationship between photic and non-photic SCN regulators. PMID:22798027

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

    PubMed

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

    2012-01-01

    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

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

    PubMed Central

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

    2013-01-01

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

  13. Dopaminergic Regulation of Circadian Food Anticipatory Activity Rhythms in the Rat

    PubMed Central

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

    2013-01-01

    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. PMID:24312417

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

    NASA Technical Reports Server (NTRS)

    Fuller, Charles A.

    2000-01-01

    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.

  15. Daily variation in the electrophysiological activity of mouse medial habenula neurones.

    PubMed

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

    2014-02-15

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

  16. Disrupted reproduction, estrous cycle, and circadian rhythms in female mice deficient in vasoactive intestinal peptide.

    PubMed

    Loh, D H; Kuljis, D A; Azuma, L; Wu, Y; Truong, D; Wang, H B; Colwell, C S

    2014-10-01

    The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN neurons. On a molecular level, the VIP-deficient SCN tissue exhibits lower amplitude oscillations with altered phase relationships between the SCN and peripheral oscillators as measured by PER2-driven bioluminescence. The simplest explanation of our data is that the loss of VIP results in a weakened SCN oscillator, which reduces the synchronization of the female circadian system. These results clarify one of the mechanisms by which disruption of the circadian system reduces female reproductive success. PMID:25252712

  17. Circadian Disorganization Alters Intestinal Microbiota

    PubMed Central

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

    2014-01-01

    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

  18. Proton Beam Therapy Interference With Implanted Cardiac Pacemakers

    SciTech Connect

    Oshiro, Yoshiko [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan)], E-mail: ooyoshiko@pmrc.tsukuba.ac.jp; Sugahara, Shinji [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan); Noma, Mio; Sato, Masato; Sakakibara, Yuzuru [Department of Cardiovascular Surgery, University of Tsukuba, Ibaraki (Japan); Sakae, Takeji [Proton Medical Research Center, University of Tsukuba, Ibaraki (Japan); Hayashi, Yasutaka [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan); Nakayama, Hidetsugu; Tsuboi, Koji; Fukumitsu, Nobuyoshi [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan); Proton Medical Research Center, University of Tsukuba, Ibaraki (Japan); Kanemoto, Ayae [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan); Hashimoto, Takayuki [Division of Radiation Oncology, Shizuoka Cancer Center Hospital, Shizuoka (Japan); Tokuuye, Koichi [Department of Radiation Oncology, University of Tsukuba, Ibaraki (Japan); Proton Medical Research Center, University of Tsukuba, Ibaraki (Japan)

    2008-11-01

    Purpose: To investigate the effect of proton beam therapy (PBT) on implanted cardiac pacemaker function. Methods and Materials: After a phantom study confirmed the safety of PBT in patients with cardiac pacemakers, we treated 8 patients with implanted pacemakers using PBT to a total tumor dose of 33-77 gray equivalents (GyE) in dose fractions of 2.2-6.6 GyE. The combined total number of PBT sessions was 127. Although all pulse generators remained outside the treatment field, 4 patients had pacing leads in the radiation field. All patients were monitored by means of electrocardiogram during treatment, and pacemakers were routinely examined before and after PBT. Results: The phantom study showed no effect of neutron scatter on pacemaker generators. In the study, changes in heart rate occurred three times (2.4%) in 2 patients. However, these patients remained completely asymptomatic throughout the PBT course. Conclusions: PBT can result in pacemaker malfunctions that manifest as changes in pulse rate and pulse patterns. Therefore, patients with cardiac pacemakers should be monitored by means of electrocardiogram during PBT.

  19. Regulation of the vgf gene in the golden hamster suprachiasmatic nucleus by light and by the circadian clock.

    PubMed

    Wisor, J P; Takahashi, J S

    1997-02-10

    By using in situ hybridization in the golden hamster brain, we have found that vgf mRNA levels are induced as a response to light stimulation in the suprachiasmatic nuclei (SCN), the site of the mammalian circadian pacemaker. The induction exhibits delayed kinetics relative to known light-induced immediate early genes: induction of vgf mRNA occurs over a period of 3 to 9 hours after light exposure. Photic induction of vgf expression does not occur in the paraventricular nucleus (PVN) of the hypothalamus, though this nucleus expresses vgf at the mRNA and protein levels. Photic induction of vgf in the SCN occurs only at circadian times when light also causes a phase shift of the circadian system. The irradiance threshold of vgf induction in the SCN closely matches that of the behavioral phase shifting response. In addition, basal expression of vgf in the SCN, but not in the PVN, exhibits a circadian rhythm in constant darkness. The photic induction and circadian rhythm of vgf expression are anatomically separated in the caudal and rostral portions of the SCN, respectively. These results represent the first example of a delayed response to light relative to light-induced immediate early genes at the mRNA level in the SCN. PMID:9120062

  20. The tick-tock of language: is language processing sensitive to circadian rhythmicity and elevated sleep pressure?

    PubMed

    Rosenberg, Jessica; Pusch, Kathrin; Dietrich, Rainer; Cajochen, Christian

    2009-07-01

    The master circadian pacemaker emits signals that trigger organ-specific oscillators and, therefore, constitutes a basic biological process that enables organisms to anticipate daily environmental changes by adjusting behavior, physiology, and gene regulation. Although circadian rhythms are well characterized on a physiological level, little is known about circadian modulations of higher cognitive functions. Thus, we investigated circadian repercussions on language performance at the level of minimal syntactic processing by means of German noun phrases in ten young healthy men under the unmasking conditions of a 40 h constant-routine protocol. Language performance for both congruent and incongruent noun phrases displayed a clear diurnal rhythm with a peak performance decrement during the biological night. The nadirs, however, differed such that worst syntactic processing of incongruent noun phrases occurred 3 h earlier (07:00 h) than that of congruent noun phrases (10:00 h). Our results indicate that language performance displays an internally generated circadian rhythmicity with optimal time for parsing language between 3 to 6 h after the habitual wake time, which usually corresponds to 10:00-13:00 h. These results may have important ramifications for establishing optimal times for shiftwork changes or testing linguistically impaired people. PMID:19637054

  1. Preliminary experience with the use of a programmable pacemaker.

    PubMed

    Morse, D; Fernandez, J; Samuel, A; Lemole, G; Parsonnet, V

    1975-05-01

    One hundred sixty-four patients, in whom new externally programmable pacemakers had been inserted, were studied over a two year period, beginning July, 1972. Following implantation, the rate and current output of this pacemaker could be changed at any time by a non-invasive technique involving electromagnetic pulse trains emitted by an external "programmer". In 89 percent of the patients it was possible to reduce battery output by half, implying greater longevity of the pacer in these cases. In 15 percent of the patients, manipulative control of the pacemaker rate was employed and found beneficial. PMID:1126191

  2. Neonatal monosodium glutamate treatment counteracts circadian arrhythmicity induced by phase shifts of the light-dark cycle in female and male Siberian hamsters

    PubMed Central

    Prendergast, Brian J.; Onishi, Kenneth G.; Zucker, Irving

    2013-01-01

    Studies of rats and voles suggest that distinct pathways emanating from the anterior hypothalamic-retrochiasmatic area and the mediobasal hypothalamic arcuate nucleus independently generate ultradian rhythms (URs) in hormone secretion and behavior. We evaluated the hypothesis that destruction of arcuate nucleus (ARC) neurons, in concert with dampening of suprachiasmatic nucleus (SCN) circadian rhythmicity, would compromise the generation of ultradian rhythms (URs) of locomotor activity. Siberian hamsters of both sexes treated neonatally with monosodium glutamate (MSG) that destroys ARC neurons were subjected in adulthood to a circadian disrupting phase-shift protocol (DPS) that produces SCN arrhythmia. MSG treatments induced hypogonadism and obesity, and markedly reduced the size of the optic chiasm and primary optic tracts. MSG-treated hamsters exhibited normal entrainment to the light-dark cycle, but MSG treatment counteracted the circadian arrhythmicity induced by the DPS protocol: only 6% of MSG-treated hamsters exhibited circadian arrhythmia, whereas 50% of control hamsters were circadian disrupted. In MSG-treated hamsters that retained circadian rhythmicity after DPS treatment, quantitative parameters of URs appeared normal, but in the 2 MSG-treated hamsters that became circadian arrhythmic after DPS, both dark-phase and light-phase URs were abolished. Although preliminary, these data are consistent with reports in voles suggesting that the combined disruption of SCN and ARC function impairs the expression of behavioral URs. The data also suggest that light thresholds for entrainment of circadian rhythms may be lower than those required to disrupt circadian organization. PMID:23701725

  3. Urinary tract pacemaker cells: current knowledge and insights from nonrenal pacemaker cells provide a basis for future discovery.

    PubMed

    Feeney, Meghan M; Rosenblum, Norman D

    2014-04-01

    Coordinated ureteric peristalsis propels urine from the kidney to the bladder. Cells in the renal pelvis and ureter spontaneously generate and propagate electrical activity to control this process. Recently, c-kit tyrosine kinase and hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) were identified in the upper urinary tract. Both of these proteins are required for coordinated proximal to distal contractions in the ureter. Alterations in pacemaker cell expression are present in multiple congenital kidney diseases, suggesting a functional contribution by these cells to pathologic states. In contrast to gut and heart pacemaker cells, the developmental biology of ureteric pacemaker cells, including cell lineage and signaling mechanisms, is undefined. Here, we review pacemaker cell identify and function in the urinary pelvis and ureter and the control of pacemaker function by Hedgehog-GLI signaling. Next, we highlight current knowledge of gut and heart pacemaker cells that is likely to provide insight into developmental mechanisms that could control urinary pacemaker cells. PMID:24129851

  4. Intergeniculate leaflet: contributions to photic and non-photic responsiveness of the hamster circadian system.

    PubMed

    Muscat, L; Morin, L P

    2006-06-19

    The circadian visual system is able to integrate light energy over time, enabling phase response and Fos induction in the suprachiasmatic nucleus to increase in proportion to the total energy of the photic stimulus. In the present studies, the contribution of the intergeniculate leaflet to light energy integration by the hamster circadian rhythm system was evaluated. Fos protein is induced in intergeniculate leaflet neurons at much lower irradiance levels than seen in suprachiasmatic nucleus neurons. Bilateral N-methyl-d-aspartate lesions of the intergeniculate leaflet decreased phase response of the circadian locomotor rhythm to high irradiance and, in animals exposed to long duration light stimuli, reduced Fos induction in the suprachiasmatic nucleus. Normal photon integration, as indicated by attenuated rhythm phase shifts and Fos induction in suprachiasmatic nucleus cells in response to the energy in light stimuli, does not occur in the absence of the intergeniculate leaflet and is likely to be a property of the circadian rhythm system, rather than solely of the suprachiasmatic nucleus. Anatomical analysis showed that virtually no intergeniculate leaflet neurons projecting to the suprachiasmatic nucleus contain Fos induced by either light or locomotion in a novel wheel. However, cells projecting to the pretectum were found to contain novel-wheel induced Fos. The intergeniculate leaflet is implicated in the normal assessment of light by the circadian rhythm system, but the circuitry by which either photic or non-photic information gains access to the suprachiasmatic nucleus may be more complex than previously thought. PMID:16549274

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

    NASA Astrophysics Data System (ADS)

    Kumar, Vinod; Gwinner, Eberhard

    2005-09-01

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

  6. Circadian phase shifting: Relationships between photic and nonphotic phase-response curves.

    PubMed

    Rosenwasser, A M; Dwyer, S M

    2001-05-01

    A variety of photic and nonphotic stimuli can phase-shift the mammalian circadian pacemaker. It has been suggested that the phase-response curves (PRCs) characterizing these diverse stimuli may comprise two major PRC families, one typified by the photic PRC describing the response to brief light pulses, and the other typified by the nonphotic PRC describing the response to stimuli evoking behavioral arousal and/or locomotor activity. Additionally, the mammalian circadian pacemaker can be phase-shifted by dark pulses presented on a constant-light (LL) background. While dark pulse-induced phase shifting was interpreted originally as a mirror-image photic effect, other observations suggest that the dark pulse PRC may instead belong to the family of nonphotic, activity-dependent PRCs. In a recent study, we reexamined the phase-shifting effects of dark pulses in the Syrian hamster, and concluded that the dark pulse PRC reflects both nonphotic and photic mirror-image mechanisms. In the current report, we reanalyze previously published hamster PRC data using polynomial curve-fitting procedures. The results of these analyses reveal that (a) the photic and nonphotic PRCs have identical shape but opposite phasing, and (b) the dark pulse PRC can be modeled by simple summation of nonphotic and photic mirror-image PRCs. This model predicts accurately the shape of the dark pulse PRC, particularly the extension of the phase-advance region into the subjective night. PMID:11399309

  7. Materials aspects of implantable cardiac pacemaker leads.

    PubMed

    Bruck, S D; Mueller, E P

    1988-01-01

    The reliability of the leads of the entire pacemaker system is vital as the risks of failure include: (1) loss of pacing due to the deterioration of the polymeric insulator in the physiological environment; (2) thromboembolism due to inadequate blood compatibility of the insulator; (3) tissue reactions at the electrode/tissue interface; (4) general foreign body rejection phenomena; (5) perforation of the leads; and (6) excessive stress applied by sutures causing abrasion and stress cracking. Although silicone has been used widely, some years ago Pellethane (a segmented polyetherurethane-urea) has been introduced as an alternate lead insulator, chiefly because it can be extruded using additives into smooth and thin tubes. The additives (antioxidants), extrusion aids, and low molecular weight polymer chains (oligomers) together represent up to approximately 8% by weight of leachables, depending on the extraction medium. The in vivo degradation of Pellethane is biologic in nature and is most likely associated with the absorption and premeation of body fluids from the surrounding physiologic environment leading to stress cracking via the formation of microvoids. Thermally and biologically unstable biuret and allophonate groups in this polyurethane, exposure of the polymer to high extrusion temperatures, and stresses created within the polymer also play key roles in the degradation process. In the case of electrodes, some corrosion can occur even with noble metals and ions formed with the involvement of penetrating body fluids which may combine with the urethane and/or urea groups of the polyurethane, leading to its further degradation in vivo. The totality of the situation indicates a need for the development of a standard guideline for the uniform and consistent pre-clinical testing and evaluation of new materials and fabrication processes of implantable pacemaker leads. Such guidelines should take into consideration, among others, the physiological environment, species-differences between test animals and humans, and observe reliable statistical interpretations based on sufficient data. PMID:3285160

  8. Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network

    PubMed Central

    Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun

    2014-01-01

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

  9. Translational Profiling of Clock Cells Reveals Circadianly Synchronized Protein Synthesis

    PubMed Central

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

    2013-01-01

    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. PMID:24348200

  10. Modeling Feedback Loops of the Mammalian Circadian Oscillator

    PubMed Central

    Becker-Weimann, Sabine; Wolf, Jana; Herzel, Hanspeter; Kramer, Achim

    2004-01-01

    The suprachiasmatic nucleus governs daily variations of physiology and behavior in mammals. Within single neurons, interlocked transcriptional/translational feedback loops generate circadian rhythms on the molecular level. We present a mathematical model that reflects the essential features of the mammalian circadian oscillator to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-h period and are robust toward parameter variations even when the positive feedback is replaced by a constantly expressed activator. This demonstrates the crucial role of the negative feedback for rhythm generation. Moreover, it explains the rhythmic phenotype of Rev-erb??/? mutant mice, where a positive feedback is missing. The interplay of negative and positive feedback reveals a complex dynamics. In particular, the model explains the unexpected rescue of circadian oscillations in Per2Brdm1/Cry2?/? double-mutant mice (Per2Brdm1 single-mutant mice are arrhythmic). Here, a decrease of positive feedback strength associated with mutating the Per2 gene is compensated by the Cry2?/? mutation that simultaneously decreases the negative feedback strength. Finally, this model leads us to a testable prediction of a molecular and behavioral phenotype: circadian oscillations should be rescued when arrhythmic Per2Brdm1 mutant mice are crossed with Rev- erb? ?/? mutant mice. PMID:15347590

  11. Genes for iron metabolism influence circadian rhythms in Drosophila melanogaster.

    PubMed

    Mandilaras, Konstantinos; Missirlis, Fanis

    2012-08-01

    Haem has been previously implicated in the function of the circadian clock, but whether iron homeostasis is integrated with circadian rhythms is unknown. Here we describe an RNA interference (RNAi) screen using clock neurons of Drosophila melanogaster. RNAi is targeted to iron metabolism genes, including those involved in haem biosynthesis and degradation. The results indicate that Ferritin 2 Light Chain Homologue (Fer2LCH) is required for the circadian activity of flies kept in constant darkness. Oscillations of the core components in the molecular clock, PER and TIM, were also disrupted following Fer2LCH silencing. Other genes with a putative function in circadian biology include Transferrin-3, CG1358 (which has homology to the FLVCR haem export protein) and five genes implicated in iron-sulfur cluster biosynthesis: the Drosophila homologues of IscS (CG12264), IscU (CG9836), IscA1 (CG8198), Iba57 (CG8043) and Nubp2 (CG4858). Therefore, Drosophila genes involved in iron metabolism are required for a functional biological clock. PMID:22885802

  12. Properties of the pacemaker current (If) in latent pacemaker cells isolated from cat right atrium.

    PubMed Central

    Zhou, Z; Lipsius, S L

    1992-01-01

    1. Single latent pacemaker cells were isolated from the Eustachian ridge of cat right atrium using Langendorff perfusion and enzyme dispersion techniques. Whole-cell patch-clamp techniques were used to study the hyperpolarization-activated inward current (I(f)). 2. All cells studied beat rhythmically. Pacemaker activity was recorded in the voltage range -68 +/- 1 to -54 +/- 2 mV and its cycle length was 901 +/- 67 ms (72 +/- 5 beats min-1) at 34-36 degrees C. Cells were elongated with tapered ends, and appeared bent or crinkled without obvious striations. Mean cell diameter and length were 7.4 +/- 0.5 microns and 93.1 +/- 5.9 microns, respectively (n = 15). Input resistance and total membrane capacitance were 2.2 +/- 0.2 G omega and 27.8 +/- 3.1 pF, respectively. 3. Hyperpolarizing clamp steps more negative than -50 mV elicited a time-dependent increasing inward current that was maximally activated at -120 mV. Activation of I(f) was well within the pacemaker voltage range. Half-maximal activation voltage and slope factor were calculated, using a Boltzmann function, to be -80.5 mV and 8.4, respectively. 4. The fully activated current-voltage (I-V) relationship was approximately linear at voltages more negative than -30 mV and showed outward rectification at more positive voltages. The reversal potential of I(f) was -26 mV and the fully activated conductance was 1.75 +/- 0.14 nS (n = 21). Caesium (2 mM) blocked I(f) at voltages more negative than the reversal potential. Reducing extracellular Na+ or K+ shifted the reversal potential more negative, and increasing extracellular K+ exerted the opposite effect. Reducing extracellular Na+ decreased I(f) amplitude and the slope of the fully activated I-V relationship, and elevated extracellular K+ increased I(f) amplitude and the slope of the fully activated I-V relationship. 5. Some pacemaker cells exhibited a short delay in the onset of I(f) activation whereas other pacemaker cells exhibited little, if any, delay in activation. I(f) currents exhibiting no delay in activation were best fitted by a single exponential function with a mean time constant of 3.20 +/- 1.03 s at -70 mV (n = 4). 6. A nystatin-permeabilized patch recording method was used to record spontaneous pacemaker action potentials and I(f) from the same pacemaker cell. Caesium (2 mM) inhibited I(f) by more than 90% (at -70 mV), and decreased the slope of diastolic depolarization, resulting in a 48 +/- 5% decrease in spontaneous rate.(ABSTRACT TRUNCATED AT 400 WORDS) Images Fig. 1 PMID:1281505

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

    SciTech Connect

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

    1986-12-01

    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.

  14. Circadian gene variants in cancer

    PubMed Central

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

    2014-01-01

    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

  15. Sexual dimorphism in the complexity of cardiac pacemaker activity

    NSDL National Science Digital Library

    Terry B. Kuo (Tzu Chi Buddhist General Hospital Department of Neurology)

    2007-10-03

    Journal article titled "Sexual Dimorphism in the Complexity of Cardiac Pacemaker Activity" from The American Journal of PhysiologyÂ?Heart and Circulatory Physiology, by Terry B. J. Kuo, and Cheryl C. H. Yang.

  16. Implanted cardiac pacemaker pulses as recorded from the body surface.

    PubMed

    Luo, Shen; Johnston, Paul; Macfarlane, Peter W

    2012-01-01

    This study investigates the characteristics of contemporary pacemaker pulses as recorded from the body surface. Twelve-lead paced ECGs from 140 patients (68 ± 12 years, 71% males) were collected at 32,000 samples per second. Pacer pulses were manually annotated based on the high-sampling rate data stream. The results show that durations of the various pulses are stable, while amplitudes exhibit large variations. Also, more than 50% of pulses have either durations <0.5 ms or amplitudes <2 mV, which are the AAMI/IEC thresholds for detection and marking of pacemaker pulses on an ECG report. Therefore the current standards for pacemaker pulse detection are not fit for purpose and require to be updated. Further, this study suggests that a high-sampling rate database should be used as a standard test for pacemaker annotation and detection from body surface ECGs. PMID:23034404

  17. A patient with dizziness, tachycardia and a DDDR pacemaker

    PubMed Central

    Balt, J.C.; Dekker, P.; de Voogt, W.G.

    2006-01-01

    An 84-year-old female patient presented to the coronary care unit with dizziness. A DDD-R minute ventilation sensor pacemaker had been implanted eight years previously. The ECG showed an atrial and ventricular paced rhythm of 140 beats/min. After disconnecting the patient from the cardiac monitor the pacemaker rate dropped gradually to 90 beats/min. The cardiac rhythm monitoring system applies low-amplitude electrical pulses in order to measure respiration rate by transthoracic impedance (TTI) measurement. The minute ventilation pacemaker sensor is driven by the same TTI measurement for rate response. Inappropriate interference between these two systems caused a sensor-driven high pacemaker rate. The dizziness was not related to the sensor-driven high rate. ImagesFigure 1Figure 2 PMID:25696553

  18. Magnetic Resonance Imaging Conditional Pacemakers: Rationale, Development and Future Directions

    PubMed Central

    Cronin, Edmond M; Wilkoff, Bruce L

    2012-01-01

    Pacemakers and other cardiac implantable electronic devices (CIEDs) have long been considered an absolute contraindication to magnetic resonance imaging (MRI), a crucial and growing imaging modality. In the last 20 years, protocols have been developed to allow MR scanning of CIED patients with a low complication rate. However, this practice has remained limited to a relatively small number of centers, and many pacemaker patients continue to be denied access to clinically indicated imaging. The introduction of MRI conditional pacemakers has provided a widely applicable and satisfactory solution to this problem. Here, the interactions of pacemakers with the MR environment, the results of MR scanning in patients with conventional CIEDs, the development and clinical experience with MRI conditional devices, and future directions are reviewed. PMID:23071382

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

    PubMed

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

    2014-01-01

    From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH. PMID:24454829

  20. Treatment strategy for infections in patients with permanent pacemakers

    Microsoft Academic Search

    Atsushi Morishita; Tadayuki Shimakura; Masaki Nonoyama; Taiichi Takasaki

    2001-01-01

    Infection after pacemaker implantation can be the most lethal potential complication, although such infections occur infrequently.\\u000a In this report, we review our experience with patients who were infected after pacemaker implantation and assess their treatment.\\u000a The infection rate was 1.3% (9 patients) after 712 operations performed in 588 patients. Four men and five women were infected;\\u000a their mean age was

  1. Biological Clocks and Circadian Rhythms

    NSDL National Science Digital Library

    Laura Robertson

    2009-02-01

    The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian 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.

  2. CIRCADIAN RHYTHMS: Integrating Circadian Timekeeping with Cellular Physiology

    NSDL National Science Digital Library

    Marie C. Harrisingh (Yale School of Medicine; Department of Cellular and Molecular Physiology)

    2008-05-16

    Access to the article is free, however registration and sign-in are required: Models of circadian timekeeping mechanisms in plants, flies, and mammals are expanding to include intracellular small-molecule signals.

  3. Colour As a Signal for Entraining the Mammalian Circadian Clock

    PubMed Central

    Walmsley, Lauren; Hanna, Lydia; Mouland, Josh; Martial, Franck; West, Alexander; Smedley, Andrew R.; Bechtold, David A.; Webb, Ann R.; Lucas, Robert J.; Brown, Timothy M.

    2015-01-01

    Twilight is characterised by changes in both quantity (“irradiance”) and quality (“colour”) of light. Animals use the variation in irradiance to adjust their internal circadian clocks, aligning their behaviour and physiology with the solar cycle. However, it is currently unknown whether changes in colour also contribute to this entrainment process. Using environmental measurements, we show here that mammalian blue–yellow colour discrimination provides a more reliable method of tracking twilight progression than simply measuring irradiance. We next use electrophysiological recordings to demonstrate that neurons in the mouse suprachiasmatic circadian clock display the cone-dependent spectral opponency required to make use of this information. Thus, our data show that some clock neurons are highly sensitive to changes in spectral composition occurring over twilight and that this input dictates their response to changes in irradiance. Finally, using mice housed under photoperiods with simulated dawn/dusk transitions, we confirm that spectral changes occurring during twilight are required for appropriate circadian alignment under natural conditions. Together, these data reveal a new sensory mechanism for telling time of day that would be available to any mammalian species capable of chromatic vision. PMID:25884537

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

    PubMed

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

    2014-10-01

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

  5. Morphological characterization of respiratory neurons in the pre-Bötzinger complex.

    PubMed

    Zavala-Tecuapetla, Cecilia; Tapia, Dagoberto; Rivera-Angulo, Ana Julia; Galarraga, Elvira; Peña-Ortega, Fernando

    2014-01-01

    Although the pre-Bötzinger complex (preBötC) was defined as the inspiratory rhythm generator long ago, the functional-anatomical characterization of its neuronal components is still being achieved. Recent advances have identified the expression of molecular markers in the preBötC neurons that, however, are not exclusive to specific respiratory neuron subtypes and have not always been related to specific cell morphologies. Here, we evaluated the morphology and the axonal projections of electrophysiologically defined respiratory neurons in the preBötC using whole-cell recordings and intracellular biocytin labeling. We found that respiratory pacemaker neurons are larger than expiratory neurons and that inspiratory neurons are smaller than pacemaker and expiratory neurons. Other morphological features such as somata shapes or dendritic branching patterns were not found to be significantly different among the preBötC neurons sampled. We also found that both pacemaker and inspiratory nonpacemaker neurons, but not expiratory neurons, show extensive axonal projections to the contralateral preBötC and show signs of electrical coupling. Overall, our data suggest that there are morphological differences between subtypes of preBötC respiratory neurons. It will be important to take such differences in consideration since morphological differences would influence synaptic responses and action potential propagation. PMID:24746042

  6. Impact of Pacemaker Lead Characteristics on Pacemaker Related Infection and Heart Perforation: A Nationwide Population-Based Cohort Study

    PubMed Central

    Lin, Yu-Sheng; Chen, Tien-Hsing; Hung, Sheng-Ping; Chen, Dong Yi; Mao, Chun-Tai; Tsai, Ming-Lung; Chang, Shih-Tai; Wang, Chun-Chieh; Wen, Ming-Shien; Chen, Mien-Cheng

    2015-01-01

    Background Several risk factors for pacemaker (PM) related complications have been reported. However, no study has investigated the impact of lead characteristics on pacemaker-related complications. Methods and Results Patients who received a new pacemaker implant from January 1997 to December 2011 were selected from the Taiwan National Health Insurance Database. This population was grouped according to the pacemaker lead characteristics in terms of fixation and insulation. The impact of the characteristics of leads on early heart perforation was analyzed by multivariable logistic regression analysis, while the impact of the lead characteristics on early and late infection and late heart perforation over a three-year period were analyzed using Cox regression. This study included 36,104 patients with a mean age of 73.4±12.5 years. In terms of both early and late heart perforations, there were no significant differences between groups across the different types of fixation and insulations. In the multivariable Cox regression analysis, the pacemaker-related infection rate was significantly lower in the active fixation only group compared to either the both fixation (OR, 0.23; 95% CI, 0.07–0.80; P = 0.020) or the passive fixation group (OR, 0.26; 95% CI, 0.08–0.83; P = 0.023). Conclusions There was no difference in heart perforation between active and passive fixation leads. Active fixation leads were associated with reduced risk of pacemaker-related infection. PMID:26075602

  7. CHAPTER SEVEN Circadian Rhythms, Sleep

    E-print Network

    Pennsylvania, University of

    ­wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing process that neurobiologically modulates both the homeostatic drive for sleep and waking alertnessCHAPTER SEVEN Circadian Rhythms, Sleep Deprivation, and Human Performance Namni Goel*, Mathias

  8. [Circadian rhythms and systems biology].

    PubMed

    Goldbeter, Albert; Gérard, Claude; Leloup, Jean-Christophe

    2010-01-01

    Cellular rhythms represent a field of choice for studies in system biology. The examples of circadian rhythms and of the cell cycle show how the experimental and modeling approaches contribute to clarify the conditions in which periodic behavior spontaneously arises in regulatory networks at the cellular level. Circadian rhythms originate from intertwined positive and negative feedback loops controlling the expression of several clock genes. Models can be used to address the dynamical bases of physiological disorders related to dysfunctions of the mammalian circadian clock. The cell cycle is driven by a network of cyclin-dependent kinases (Cdks). Modeled in the form of four modules coupled through multiple regulatory interactions, the Cdk network operates in an oscillatory manner in the presence of sufficient amounts of growth factor. For circadian rhythms and the cell cycle, as for other recently observed cellular rhythms, periodic behavior represents an emergent property of biological systems related to their regulatory structure. PMID:20132775

  9. Circadian insights into dopamine mechanisms.

    PubMed

    Mendoza, J; Challet, E

    2014-10-01

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

  10. Circadian Timing in Cancer Treatments

    E-print Network

    Clairambault, Jean

    repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous clock, drug delivery, chronotherapeutics, gender, mathematical models, clinical trial methodology clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA

  11. Circadian Dysrhythmias in the Intensive Care Unit.

    PubMed

    Billings, Martha E; Watson, Nathaniel F

    2015-07-01

    Circadian rhythms underlie nearly all physiologic functions and organ systems. Circadian abnormalities have attendant implications for critical illness survival. The intensive care unit (ICU) environment, with its lack of diurnal variation in sound, light, and social cues, may precipitate circadian dysrhythmias. Additional features of critical care, including mechanical ventilation and sedation, likely perpetuate circadian misalignment. Critical illness itself, from sepsis to severe brain injury, can compromise circadian health. Use of daylight, time-restricted feedings, and administration of melatonin can possibly restore circadian rhythm. However, further study is necessary to assess the effectiveness of these interventions and their impact on ICU outcomes. PMID:26118911

  12. JNK regulates the photic response of the mammalian circadian clock.

    PubMed

    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

    2012-05-01

    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. PMID:22441692

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

    PubMed Central

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

    2010-01-01

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

  14. The circadian visual system, 2005.

    PubMed

    Morin, L P; Allen, C N

    2006-06-01

    The primary mammalian circadian clock resides in the suprachiasmatic nucleus (SCN), a recipient of dense retinohypothalamic innervation. In its most basic form, the circadian rhythm system is part of the greater visual system. A secondary component of the circadian visual system is the retinorecipient intergeniculate leaflet (IGL) which has connections to many parts of the brain, including efferents converging on targets of the SCN. The IGL also provides a major input to the SCN, with a third major SCN afferent projection arriving from the median raphe nucleus. The last decade has seen a blossoming of research into the anatomy and function of the visual, geniculohypothalamic and midbrain serotonergic systems modulating circadian rhythmicity in a variety of species. There has also been a substantial and simultaneous elaboration of knowledge about the intrinsic structure of the SCN. Many of the developments have been driven by molecular biological investigation of the circadian clock and the molecular tools are enabling novel understanding of regional function within the SCN. The present discussion is an extension of the material covered by the 1994 review, "The Circadian Visual System." PMID:16337005

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

    PubMed Central

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

    2014-01-01

    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. PMID:24831114

  16. Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock.

    PubMed

    Hunt, A E; Al-Ghoul, W M; Gillette, M U; Dubocovich, M L

    2001-01-01

    The aim of this study was to identify the melatonin receptor type(s) (MT(1) or MT(2)) mediating circadian clock resetting by melatonin in the mammalian suprachiasmatic nucleus (SCN). Quantitative receptor autoradiography with 2-[(125)I]iodomelatonin and in situ hybridization histochemistry, with either (33)P- or digoxigenin-labeled antisense MT(1) and MT(2) melatonin receptor mRNA oligonucleotide probes, revealed specific expression of both melatonin receptor types in the SCN of inbred Long-Evans rats. The melatonin receptor type mediating phase advances of the circadian rhythm of neuronal firing rate in the SCN slice was assessed using competitive melatonin receptor antagonists, the MT(1)/MT(2) nonselective luzindole and the MT(2)-selective 4-phenyl-2-propionamidotetraline (4P-PDOT). Luzindole and 4P-PDOT (1 nM-1 microM) did not affect circadian phase on their own; however, they blocked both the phase advances (approximately 4 h) in the neuronal firing rate induced by melatonin (3 pM) at temporally distinct times of day [i.e., subjective dusk, circadian time (CT) 10; and dawn, CT 23], as well as the associated increases in protein kinase C activity. We conclude that melatonin mediates phase advances of the SCN circadian clock at both dusk and dawn via activation of MT(2) melatonin receptor signaling. PMID:11121382

  17. An ecdysone-responsive nuclear receptor regulates circadian rhythms in Drosophila

    PubMed Central

    Kumar, Shailesh; Chen, Dechun; Jang, Christopher; Nall, Alexandra; Zheng, Xiangzhong; Sehgal, Amita

    2014-01-01

    Summary Little is known about molecular links between circadian clocks and steroid hormone signaling although both are important for normal physiology. Here we report a circadian function for a nuclear receptor, Ecdysone Induced Protein 75 (Eip75/E75), which we identify through a gain-of-function screen for circadian genes in Drosophila melanogaster. Overexpression or knockdown of E75 in clock neurons disrupts rest:activity rhythms and dampens molecular oscillations. E75 represses expression of the gene encoding the transcriptional activator, CLOCK (CLK), and may also affect circadian output. PER inhibits the activity of E75 on the Clk promoter, thereby providing a mechanism for a previously proposed de-repressor effect of PER on Clk transcription. The ecdysone receptor is also expressed in central clock cells and manipulations of its expression produce effects similar to those of E75 on circadian rhythms. We find that E75 protects rhythms under stressful conditions, suggesting a function for steroid signaling in the maintenance of circadian rhythms in Drosophila. PMID:25511299

  18. Radioisotope thermoelectric generators for implanted pacemakers

    SciTech Connect

    Pustovalov, A.A.; Bovin, A.V.; Fedorets, V.I.; Shapovalov, V.P.

    1986-08-01

    This paper discusses the development and application of long-life lithium batteries and the problems associated with miniature radioisotope thermoelectric generators (RITEG) with service lives of 10 years or longer. On eof the main problems encountered when devising a radioisotope heat source (RHS) for an RITEG is to obtain biomedical /sup 238/PuO/sub 2/ with a specific neutron yield of 3.10/sup 3/-4.10/sup 3/ (g /SUP ./ sec)/sup -1/, equivalent to metallic Pu 238, and with a content of gamma impurities sufficient to ensure a permissible exposure a permissible exposure does rate (EDR) of a mixture of neutron and gamma radiation. After carrying out the isotope exchange and purifying the initial sample of its gamma impurity elements, the authors obtain biomedical Pu 238 satisfying the indicated requirements king suitable for use in the power packs of medical devices. Taking the indicated specifications into account, the Ritm-1o and gamma radioisotope heat sources were designed, built, tested in models and under natural conditions, and then into production as radioisotope thermoelectric generators designed to power the electronic circuits of implanted pacemakers. The Ritm-MT and Gemma radioisotope thermoelectric generators described are basic units, which can be used as self-contained power supplies for electronic equipment with power requirements in the micromilliwatt range.

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

    PubMed

    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

    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

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

    PubMed Central

    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

    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

  1. Effects of restricted feeding schedules on circadian organization in squirrel monkeys

    NASA Technical Reports Server (NTRS)

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

    1989-01-01

    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.

  2. Phase shifting the hamster circadian clock by 15-minute dark pulses.

    PubMed

    Rosenwasser, Alan M; Dwyer, Suzanne M

    2002-06-01

    The mammalian circadian pacemaker can be phase shifted by exposure to a period of darkness interrupting otherwise continuous light. Circadian phase shifting by dark pulses was interpreted originally as reflecting a photic mirror-image mechanism, but more recent observations suggest that dark pulse-induced phase shifting may be mediated by a nonphotic, behavioral state-dependent mechanism. The authors recently presented evidence indicating that the dark-pulse phase response curve (PRC) is in fact a complex function, reflecting both photic mirror image and nonphotic mechanisms at different phases of the circadian cycle. Previous studies of dark pulse-induced phase shifting have universally employed relatively long (2 to 6 h) pulses, which complicates PRC analysis due to the extended segment of the underlying PRC spanned by such a long pulse. The present study was therefore designed to examine the phase-shifting effects of brief 15-min dark pulses presented at both mid-subjective day and subjective dusk, and to explore the possible activity dependence of these effects by using physical restraint to prevent evoked locomotor activity. The results indicate that 15-min dark pulses are effective phase-shifting stimuli at both midday and dusk. Furthermore, as with longer dark pulses, phase shifting by 15-min dark pulses is completely blocked by physical restraint during subjective day but combines in a simple additive manner with the independent phase-shifting effect of restraint at subjective dusk. PMID:12054195

  3. Integration and saturation within the circadian photic entrainment pathway of hamsters.

    PubMed

    Nelson, D E; Takahashi, J S

    1999-11-01

    The sensitivity of the visual pathway that subserves circadian entrainment was measured in hamsters after prior stimulation and using trains of multiple pulses. Immediately after subsaturating stimulation in the late subjective night, there was a significant decrease in responsiveness that persisted for at least 1 h. The reduced responsiveness was not due to light adaptation (shifting of the stimulus-response curve) but rather to response saturation, which appeared to reduce the sensitivity to subsequent stimulation and limit the maximum response of the pacemaker. The system, therefore, integrates the total number of photons delivered in two light stimuli separated in time by up to 1 h. The responsiveness was also measured using stimulus trains containing 10-1,000 individual pulses of equal irradiance and equal total photons. Results suggest that this pathway is responsive to the total photons delivered in all of the stimuli and is not responsive to light onsets or offsets associated with individual stimuli. These data outline several fundamental characteristics of phase shifting for the circadian photic entrainment pathway in hamsters. Knowledge of these characteristics is important for designing and interpreting results of future studies to dissect the cellular and molecular nature of the mammalian circadian clock and for understanding how visual information affects the cellular clock during entrainment. PMID:10564207

  4. The role of retinal photoreceptors in the regulation of circadian rhythms

    PubMed Central

    Paul, Ketema N.; Saafir, Talib B.; Tosini, Gianluca

    2010-01-01

    The circadian clock is an evolutionarily, highly conserved feature of most organisms. This internal timing mechanism coordinates biochemical, physiological and behavioral processes to maintain synchrony with the environmental cycles of light, temperature and nutrients. Several studies have shown that light is the most potent cue used by most organisms (humans included) to synchronize daily activities. In mammals, light perception occurs only in the retina; three different types of photoreceptors are present within this tissue: cones, rods and the newly discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). Researchers believe that the classical photoreceptors (e.g., the rods and the cones) are responsible for the image-forming vision, whereas the ipRGCs play a key role in the non-image forming vision. This non-image-forming photoreceptive system communicates not only with the master circadian pacemaker located in the suprachiasmatic nuclei of the hypothalamus, but also with many other brain areas that are known to be involved in the regulation of several functions; thus, this non-image forming system may also affect several aspects of mammalian health independently from the circadian system. PMID:19777353

  5. 76 FR 44872 - Effective Date of Requirement for Premarket Approval for an Implantable Pacemaker Pulse Generator

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-27

    ...8. Other Complications Other risks of pacemaker implantation include...myopotential sensing, and additional surgery for replacement. Risks are also associated with pacemaker...the Federal Food, Drug, and Cosmetic Act and under authority...

  6. Preliminary Test of a New Haemodynamic Pacemaker: Evaluation of Sensor Safety

    Microsoft Academic Search

    N. Galizio; J. Gonzalez; H. Fraguas; J. Barra; S. Graf; E. Forteza; R. Chirife; F. Gregorio

    In the present animal model study, the pacemaker Sophós 100 proved fully reliable in a 1 month follow-up period. TVI sensor operation did not interfere with conventional pacemaker functions, opening the way to its implantation in human beings.

  7. Benefits of the advances in cardiac pacemaker technology.

    PubMed

    Shakespeare, C F; Camm, A J

    1992-08-01

    Pacemaker technology has expanded rapidly in the last thirty years. Each phase of development has been marked by both improvements in clinical benefit and disadvantageous interactions of physiology and technology. Each phase of development has led to smaller, more reliable devices with greater programmability. Advances in generator technology and battery design have increased longevity of devices. The first devices used asynchronous pacing which had a significant effect in reducing the mortality of surgically induced complete heart block. Ventricular demand pacemakers overcame the problems of asynchronous competitive pacing, but exposed the pacemaker syndrome. Atrioventricular sequential pacing restored atrioventricular synchrony, resulting in hemodynamic improvement, but created the phenomenon of pacemaker-mediated tachycardia. Alternative dual chamber modes and algorithms have largely resolved this. Adaptive-rate devices have been of benefit to patients with chronotropic incompetence, and are now incorporating an increasing variety of biosensors. Almost all the problems of pacing have been overcome, but the increasing complexity of pacemaker technology is now a major limitation to its proper use. PMID:1499189

  8. Circadian rhythm of photosynthesis in

    Microsoft Academic Search

    H Schubert; S Gerbersdorf; E Titlyanov; T Titlyanova; M Granbom; C Pape; K Lüning

    2004-01-01

    Various processes in the output pathway of the circadian clock are thought to act as important clock targets resulting in the circadian rhythms of photosynthesis observed in various algae. Examples of such processes are synchronization of the cell cycle, pigmentation, and light or dark reaction of photosynthesis. The newly detected, robust photosynthetic circadian rhythm in the red macroalga Kappaphycus alvarezii

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

    PubMed

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

    2012-12-01

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

  10. Radioisotope-powered cardiac pacemaker program. Clinical studies of the nuclear pacemaker model NU-5. Final report

    SciTech Connect

    Not Available

    1980-06-01

    Beginning in February, 1970, the Nuclear Materials and Equipment Corporation (NUMEC) undertook a program to design, develop and manufacture a radioisotope powered cardiac pacemaker system. The scope of technical work was specified to be: establish system, component, and process cost reduction goals using the prototype Radioisotope Powered Cardiac Pacemaker (RCP) design and develop production techniques to achieve these cost reduction objectives; fabricate radioisotope powered fueled prototype cardiac pacemakers (RCP's) on a pilot production basis; conduct liaison with a Government-designated fueling facility for purposes of defining fueling requirements, fabrication and encapsulation procedures, safety design criteria and quality control and inspection requirements; develop and implement Quality Assurance and Reliability Programs; conduct performance, acceptance, lifetime and reliability tests of fueled RCP's in the laboratory; conduct liaison with the National Institutes of Health and with Government specified medical research institutions selected for the purpose of undertaking clinical evaluation of the RCP in humans; monitor and evaluate, on a continuing basis, all test data; and perform necessary safety analyses and tests. Pacemaker designs were developed and quality assurance and manufacturing procedures established. Prototype pacemakers were fabricated. A total of 126 radioisotope powered units were implanted and have been followed clinically for approximately seven years. Four (4) of these units have failed. Eighty-three (83) units remain implanted and satisfactorily operational. An overall failure rate of less than the target 0.15% per month has been achieved.

  11. Concerns about sources of electromagnetic interference in patients with pacemakers.

    PubMed

    Sakakibara, Y; Mitsui, T

    1999-11-01

    Electromagnetic noise is rapidly increasing in our environment so electromagnetic interference (EMI) with pacemakers (PM) may become a more important problem despite technological improvements in PM. The aim of this study was to evaluate the kinds of EMI which affect the quality of life of PM patients. The participants (1,942 Japanese Association for Pacemaker Patients: Pacemaker-Tomonokai) were asked to respond to a questionnaire about their major EMI troubles, and 1,567 patients (80.7%) responded by mail. The main concerns were from mobile telephones (MT) (39%), magnetic resonance imaging (MRI) (17%), electronic kitchen appliances, automobile engines and high voltage power lines. If possible, PM implantation sites should be carefully selected not only according to the physician's convenience but also considering information on each patient's habits and physical limitations. PMID:10737557

  12. Advanced light-entrained activity onsets and restored free-running suprachiasmatic nucleus circadian rhythms in per2/dec mutant mice.

    PubMed

    Bode, Brid; Taneja, Reshma; Rossner, Moritz J; Oster, Henrik

    2011-11-01

    Many behavioral and physiological processes display diurnal (24-h) rhythms controlled by an internal timekeeping system?the circadian clock. In mammals, a circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronizes peripheral oscillators found in most other tissues with the external light-dark (LD) cycle. At the molecular level, circadian clocks are regulated by transcriptional translational feedback loops (TTLs) involving a set of clock genes. The mammalian core TTL includes the transcriptional modulators PER?(1?3) and CRY?(1/2) that inhibit their own expression by interaction with CLOCK/NPAS2 and BMAL1 (ARNTL). The basic helix-loop-helix transcription factors DEC1 (BHLHE40) and DEC2 (BHLHE41) can interact with this core TTL, forming an accessory feedback mechanism. The authors measured circadian locomotor behavior and clock gene expression in the SCN of Per2/Dec double- and triple-mutant mice to analyze the functional interaction of PER2 and DEC feedback on circadian pacemaker function in the SCN. The data suggest a synergistic interaction of Per2 and Dec1/2 in activity entrainment to a standard LD cycle, correlating with a cumulative deficiency in negative-masking capacities in Per2/Dec double- and triple-mutant mice and suggesting an involvement of Per2-Dec1/2 interactivity in activity-onset regulation and masking under LD, but not under constant conditions. In contrast, under constant darkness (DD) conditions, a deletion of either Dec1 or Dec2 partially rescued the Per2 mutant short-period/arrhythmicity phenotype, accompanied by a restoration of time-of-day effects on clock gene expression in the SCN. Together, these results show an interaction of Per2 and Dec1/2 feedback processes in the SCN with differential modes of interactivity under entrained and free-run conditions. (Author correspondence: henrik.oster@mpibpc.mpg.de ). PMID:22080784

  13. [Development and research of temporary demand pacemaker with electrocardiosignal display].

    PubMed

    Fan, Shounian; Jiang, Chenxi; Cai, Yunchang; Pan, Yangzhong; Yang, Tianhe; Wu, Qiang; Zheng, Yaxi; Liu, Xiaoqiao; Li, Shiying

    2004-08-01

    A temporary demand pacemaker with electrocardiosignal display is introduced in this paper. Double way low-noise electrocardiosignal preamplifier, amplitude limiter, high and low pass filter, 50 Hz notch filter, TTL level generator and stimulating pulse formation circuit are components of the hardware electrocircuit. The demand pacing and the electrocardiosignal display are separately controlled by the software in which the double microcontrollers communications technique is used. In this study, liquid crystal display is firstly used in body surface electrocardiosignal display or intracardial electrophysiologic signal display when the temporary demand pacemaker is installed and put into use. The machine has proven clinically useful and can be of wide appliation. PMID:15357453

  14. Circadian clock, cancer, and chemotherapy.

    PubMed

    Sancar, Aziz; Lindsey-Boltz, Laura A; Gaddameedhi, Shobhan; Selby, Christopher P; Ye, Rui; Chiou, Yi-Ying; Kemp, Michael G; Hu, Jinchuan; Lee, Jin Hyup; Ozturk, Nuri

    2015-01-20

    The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock-DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID:25302769

  15. Impact of the Circadian Clock on the Aging Process

    PubMed Central

    Fonseca Costa, Sara S.; Ripperger, Jürgen A.

    2015-01-01

    The increase of life expectancy and the decline of biological functions with advancing age are impending obstacles for our society. In general, age-related changes can be separated into two processes. Primary aging is based on programs governing gradual changes which are generally not harmful. On the other hand, secondary aging or senescence is more aleatory in nature and it is at this stage that the progressive impairment of metabolic, physiological, and neurological functions increases the risk of death. Exploiting genetic animal models, we obtain more and more information on the underlying regulatory networks. The aim of this review is to identify potential links between the output of the circadian oscillator and secondary aging. The reasons to suspect such links rely on the fact that the mouse models without functional circadian clocks sometimes exhibit reduced life expectancy. This may be due to their inability to properly control and synchronize energy expenditure, affecting, for example, the integrity of neurons in the brain. Hence, it is tempting to speculate that re-synchronization of metabolic and physiological functions by the circadian clock may slow down the aging process. PMID:25798127

  16. Class IIa histone deacetylases are conserved regulators of circadian function.

    PubMed

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

    2014-12-01

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

  17. Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*

    PubMed Central

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

    2014-01-01

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

  18. Metabolism and the circadian clock converge.

    PubMed

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2013-01-01

    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

  19. The brain's master circadian clock: implications and opportunities for therapy of sleep disorders.

    PubMed

    Zee, Phyllis C; Manthena, Prasanth

    2007-02-01

    The suprachiasmatic nuclei (SCN) residing in the anterior hypothalamus maintains a near-24-h rhythm of electrical activity, even in the absence of environmental cues. This circadian rhythm is generated by intrinsic molecular mechanisms in the neurons of the SCN; however, the circadian clock is modulated by a wide variety of influences, including glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from the retinohypothalamic tract, melatonin from the pineal gland, and neuropeptide Y from the intergeniculate leaflet. By virtue of these and other inputs, the SCN responds to environmental cues such as light, social and physical activities. In turn, the SCN controls or influences a wide variety of physiologic and behavioral functions, including attention, endocrine cycles, body temperature, melatonin secretion, and the sleep-wake cycle. Regulation of the sleep-wake cycle by the SCN has important implications for development of therapies for sleep disorders, including those involving desynchronization of circadian rhythms and insomnia. PMID:16973392

  20. The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb.

    PubMed

    Granados-Fuentes, Daniel; Prolo, Laura M; Abraham, Ute; Herzog, Erik D

    2004-01-21

    The suprachiasmatic nucleus (SCN) of the hypothalamus has been termed the master circadian pacemaker of mammals. Recent discoveries of damped circadian oscillators in other tissues have led to the hypothesis that the SCN synchronizes and sustains daily rhythms in these tissues. We studied the effects of constant lighting (LL) and of SCN lesions on behavioral rhythmicity and Period 1 (Per1) gene activity in the SCN and olfactory bulb (OB). We found that LL had similar effects on cyclic locomotor and feeding behaviors and Per1 expression in the SCN but had no effect on rhythmic Period 1 expression in the OB. LL lengthened the period of locomotor and SCN rhythms by approximately 1.6 hr. After 2 weeks in LL, nearly 35% of rats lost behavioral rhythmicity. Of these, 90% showed no rhythm in Per1-driven expression in their SCN. Returning the animals to constant darkness rapidly restored their daily cycles of running wheel activity and gene expression in the SCN. In contrast, the OB remained rhythmic with no significant change in period, even when cultured from animals that had been behaviorally arrhythmic for 1 month. Similarly, we found that lesions of the SCN abolished circadian rhythms in behavior but not in the OB. Together, these results suggest that LL causes the SCN to lose circadian rhythmicity and its ability to coordinate daily locomotor and feeding rhythms. The SCN, however, is not required to sustain all rhythms because the OB continues to oscillate in vivo when the SCN is arrhythmic or ablated. PMID:14736846

  1. Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

    1. Both the timing of behavioural events (activity, sleep and social interactions) and the environmental light-dark cycle have been reported to contribute to entrainment of human circadian rhythms to the 24 h day. Yet, the relative contribution of those putative behavioural synchronizers to that of light exposure remains unclear. 2. To investigate this, we inverted the schedule of rest, sedentary activity and social contact of thirty-two young men either with or without exposure to bright light. 3. On this inverted schedule, the endogenous component of the core temperature rhythm of subjects who were exposed to bright light showed a significant phase shift, demonstrating that they were adapting to the new schedule. In contrast, the core temperature rhythm of subjects who were not exposed to bright light moved on average 0.2 h later per day and after 10 days had not significantly adapted to the new schedule. 4. The direction of phase shift in the groups exposed to bright light was dependent on the time of bright light exposure, while control subjects drifted to a later hour regardless of the timing of their schedule of sleep timing, social contact and meals. 5. These results support the concept that the light-dark cycle is the most important synchronizer of the human circadian system. They suggest that inversion of the sleep-wake, rest-activity and social contact cycles provides relatively minimal drive for resetting the human circadian pacemaker. 6. These data indicate that interventions designed to phase shift human circadian rhythms for adjustment to time zone changes or altered work schedules should focus on properly timed light exposure.

  2. Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.

    PubMed

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-09-01

    The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum, as revealed by immunohistochemistry. These findings give reason to further pursue the physiological significance of circadian oscillators in the mouse neocortex and cerebellum. PMID:24842045

  3. Atypical pattern of lung involvement in pacemaker endocarditis.

    PubMed

    Ampatzidou, Fotini C; Sileli, Maria N; Koutsogiannidis, Charilaos-Panagiotis C; Ananiadou, Olga G; Madesis, Athanasios A; Michaelidis, Vassilis G; Drossos, George E

    2014-08-01

    Pacemaker endocarditis has a high rate of morbidity and mortality and is associated with substantial health-care cost. To maximize the effectiveness of treatment, diagnosis of pacemaker endocarditis should be made as early as possible. Medical treatment alone is not successful, and the removal of the entire artificial pacing system is often required. We present a case of a female patient with a permanent transvenous pacemaker, recurring episodes of fever and chills, general malaise, and a computed tomography image of a solitary tumor-like lesion indicating pneumonia. The symptoms subsided with empirical antibiotics but without improvement in the radiologic images. A wedge resection of the lesion by thoracotomy was performed, revealing a necrotic lung lesion compatible with pulmonary infarct. Transesophageal echocardiography showed a mass that was adherent to the pacemaker lead. The therapeutic approach consisted of surgical removal of the complete pacing system along with long-term antibiotic therapy and implantation of a new device with an epicardial lead. Serial follow-up echocardiograms for a 1-y period did not show any recurrence, and the subsequent course was uneventful. PMID:24194574

  4. A model of respiration rhythmogenesis bridging network and pacemaker theories

    Microsoft Academic Search

    Efstratios K. Kosmidis; Jean-françois Vibert

    2001-01-01

    Respiration generation occurs at the brainstem. It is still unclear if it relies on pacemaker units or on network properties. Using a computational model we show that the two theories are not mutually exclusive. Based on experimental data we propose a network architecture that takes advantage of noise to ignite and maintain the respiratory rhythm. We show that a population

  5. Pacemaker Related Infective Endocarditis from Staphylococcus Lugdunensis: A Case Report

    PubMed Central

    Ward, Michael; Boehm, Kevin M.

    2013-01-01

    Staphylococcus lugdunensis is a common skin flora not typically associated with infection. There are, however, several cases reported in the literature of Staphylococcus lugdunensis as a causative bacterium of various infections. This paper reports an additional case of pacemaker associated endocarditis with Staphylococcus lugdunensis as the causative bacterium. PMID:24829817

  6. Pacemaker lead infection: echocardiographic features, management, and outcome

    PubMed Central

    Victor, F; De Place, C; Camus, C; Le Breton, H; Leclercq, C; Pavin, D; Mabo, P; Daubert, C

    1999-01-01

    Objective—To compare transthoracic and transoesophageal echocardiography (TTE, TOE) in patients with permanent pacemaker lead infection and to evaluate the safety of medical extraction in cases of large vegetations.?Methods—TTE and TOE were performed in 23 patients with definite pacemaker lead infection. Seventeen patients without previous infection served as a TOE reference for non-infected leads.?Results—TTE was positive in seven cases (30%) whereas with TOE three different types of vegetations attached to the leads were visualised in 21 of the 23 cases (91%). Of the 20 patients with vegetations and lead culture, 17 (85%) had bacteriologically active infection. Left sided valvar endocarditis was diagnosed in two patients. In the control group, strands were visualised by TOE in five patients, and vegetations in none. Medical extraction of vegetations ? 10 mm was performed in 12 patients and was successful in nine (75%) without clinical pulmonary embolism. After 31.2 (19.1) months of follow up (mean (SD)), all patients except one were cured of infection; three died from other causes.?Conclusions—Combined with bacteriological data, vegetations seen on TOE strongly suggest pacemaker lead infection. Normal TTE examinations do not exclude this diagnosis because of its poor sensitivity. Medical extraction of even large vegetations appeared to be safe.?? Keywords: pacemaker lead infection;  transoesophageal echocardiography PMID:10220550

  7. A semi-automatic device for pacemaker function analysis.

    PubMed

    Behar, S; Fischler, H; Feldman, S; Neufeld, H N

    1980-01-01

    An external semi-automatic Pacemaker Function Analyzer (PFA) has been designed for routine examination (screening) of ambulatory-paced patients in general medical practice. The evaluation of the pacemaker (PM) function is based on recognition, decoding, and measurement of the occurrence of QRS complexes and pacing artifacts, and on logic processing of the decoded data. In this way, the state of the batteries and the integrity of the electronic circuitry and the electrodes can be determined. Other PFA applications concern supervision of hospitalized patients by interfacing the analyzer with the monitoring system of a Coronary Care Unit (CCU), transtelephone checking, and adaptation for use in specialized pacemaker clinics. The performance of the PFA was checked on 92 ambulatory patients. The PFA system recognized all but 0.29% of the QRS complexes and 0.21% of the pacing artifacts. Thirty-two of these patients were tested simultaneously by the PFA and the pacemaker clinic physician, both arriving at the same results. Twelve hospitalized patients were monitored in the CCU, after permanent PM implantation, for an average of 4 hours per patient. Although the PFA indicated 5% false-negative alarms for the hospitalized patients, it should be stressed that every true PM failure was promptly detected. It is anticipated that routine use of the PFA for management of paced patients will reduce the expenses incurred by frequent visits, as well as simplify the follow-up and surveillance of ambulatory and hospitalized patients, thereby facilitating the work of the medical staff. PMID:6160494

  8. Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet.

    PubMed

    Webb, Ian C; Patton, Danica F; Hamson, Dwayne K; Mistlberger, Ralph E

    2008-02-01

    In Syrian hamsters, some procedures for stimulating behavioural arousal (e.g. running in a novel wheel and sleep deprivation by gentle handling with minimal activity) markedly phase-advance circadian rhythms when applied during the middle of the daily rest period, while other arousal procedures do not (e.g. physical restraint, caffeine and modafinil). The neural basis for this differential effect of arousal procedures on clock resetting is unknown. We used c-fos expression as a marker for neuronal activation to determine whether these arousal procedures differentially activate two nonphotic inputs to the circadian system, the thalamic intergeniculate leaflet (IGL; a proposed nonphotic gateway to the circadian clock) and the hypothalamic hypocretin system (which depolarizes arousal-related cell groups throughout the brain and innervates both the IGL and the peri-suprachiasmatic nucleus region). c-FOS in hypocretin-1-immunoreactive neurons, in hypothalamic nonhypocretin neurons and in the IGL was significantly increased by novel wheel running, gentle handling and physical restraint, but only weakly by systemic injections of modafinil (300 mg/kg) or caffeine (75 mg/kg), at doses that are strongly alerting. Spatial analysis revealed few regional differences in the percentage of cells double-labelled for hypocretin-1 and c-FOS following each treatment. These results suggest that activation of hypocretin neurons (as in the restraint condition) is not sufficient to induce phase shifts, and that gating of arousal effects on circadian clock phase may be downstream from the hypocretin system and from IGL neurons activated by these procedures. PMID:18279358

  9. Evidence for a role of orcokinin-related peptides in the circadian clock controlling locomotor activity of the cockroach Leucophaea maderae.

    PubMed

    Hofer, Sabine; Homberg, Uwe

    2006-07-01

    The accessory medulla (AMe), a small neuropil in the optic lobe, houses the master circadian clock in the brain of the cockroach Leucophaea maderae and controls circadian rhythms in locomotor activity. Recently, members of the orcokinin family of crustacean neuropeptides were identified in a cockroach and a locust and were shown by immunocytochemistry to be prominently present in the AMe. In the cockroach L. maderae, about 30 neurons in five of six established cell groups of the AMe showed orcokinin immunostaining. By means of tracer injections into one AMe and immunostaining with anti-orcokinin antiserum, we show here that one orcokinin-immunoreactive ventral neuron and three ventromedian neurons directly connect both AMae. To determine a possible circadian function of orcokinin in the cockroach, we injected 150 fmol Asn(13)-orcokinin into the vicinity of the AMe at different circadian times. These experiments resulted in stable phase-dependent phase shifts of circadian locomotor activity of the cockroach. The shape of the resulting phase-response curve closely matched the phase-shifting effects of light pulses, and its amplitude was dependent on the amount of the injected peptide. Together with the anatomical data, the results suggest that orcokinin-related peptides play an important role in light entrainment pathways to the circadian clock via the contralateral compound eye. This study, furthermore, provides the first evidence for a physiological role of an orcokinin-related peptide in insects. PMID:16809470

  10. Circadian phase-dependent effect of nitric oxide on L-type voltage-gated calcium channels in avian cone photoreceptors

    PubMed Central

    Ko, Michael L.; Shi, Liheng; Huang, Cathy Chia-Yu; Grushin, Kirill; Park, So-Young; Ko, Gladys Y.-P.

    2014-01-01

    Nitric oxide (NO) plays an important role in phase-shifting of circadian neuronal activities in the suprachiasmatic nucleus and circadian behavior activity rhythms. In the retina, NO production is increased in a light-dependent manner. While endogenous circadian oscillators in retinal photoreceptors regulate their physiological states, it is not clear whether NO also participates in the circadian regulation of photoreceptors. In the present study, we demonstrate that NO is involved in the circadian phase-dependent regulation of L-type voltage-gated calcium channels (L-VGCCs). In chick cone photoreceptors, the L-VGCC?1 subunit expression and the maximal L-VGCC currents are higher at night, and both Ras-MAPK (mitogen-activated protein kinase)-Erk (extracellular-signal-regulated kinase) and Ras-phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) are part of the circadian output pathways regulating L-VGCCs. The NO-cGMP-protein kinase G (PKG) pathway decreases L-VGCC?1 subunit expression and L-VGCC currents at night, but not during the day, and exogenous NO donor or cGMP decreases the phosphorylation of Erk and Akt at night. The protein expression of neural NO synthase (nNOS) is also under circadian control, with both nNOS and NO production being higher during the day. Taken together, NO/cGMP/PKG signaling is involved as part of the circadian output pathway to regulate L-VGCCs in cone photoreceptors. PMID:23895452

  11. Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish

    PubMed Central

    Elbaz, Idan; Foulkes, Nicholas S.; Gothilf, Yoav; Appelbaum, Lior

    2012-01-01

    The circadian clock and homeostatic processes are fundamental mechanisms that regulate sleep. Surprisingly, despite decades of research, we still do not know why we sleep. Intriguing hypotheses suggest that sleep regulates synaptic plasticity and consequently has a beneficial role in learning and memory. However, direct evidence is still limited and the molecular regulatory mechanisms remain unclear. The zebrafish provides a powerful vertebrate model system that enables simple genetic manipulation, imaging of neuronal circuits and synapses in living animals, and the monitoring of behavioral performance during day and night. Thus, the zebrafish has become an attractive model to study circadian and homeostatic processes that regulate sleep. Zebrafish clock- and sleep-related genes have been cloned, neuronal circuits that exhibit circadian rhythms of activity and synaptic plasticity have been studied, and rhythmic behavioral outputs have been characterized. Integration of this data could lead to a better understanding of sleep regulation. Here, we review the progress of circadian clock and sleep studies in zebrafish with special emphasis on the genetic and neuroendocrine mechanisms that regulate rhythms of melatonin secretion, structural synaptic plasticity, locomotor activity and sleep. PMID:23378829

  12. Chronic artificial blue-enriched white light is an effective countermeasure to delayed circadian phase and neurobehavioral decrements.

    PubMed

    Najjar, Raymond P; Wolf, Luzian; Taillard, Jacques; Schlangen, Luc J M; Salam, Alex; Cajochen, Christian; Gronfier, Claude

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  14. Restricted feeding entrains circadian wheel-running activity rhythms of the kowari.

    PubMed

    Kennedy, G A; Coleman, G J; Armstrong, S M

    1991-10-01

    The effect of daily restricted feeding (RF) on the circadian wheel-running rhythms of the kowari, Dasyuroides byrnei, was examined in two experiments. Kowaris were presented with a preferred food (determined in a pilot study) during a daily 2-h meal in the light period of a 14:10 light-dark (LD) cycle (expts 1 and 2), during constant dark (DD) immediately after termination of the LD cycle (expt 1), and during DD when kowaris were free running (expt 1). Results showed that 1) RF elicited anticipatory activity similar in duration and phasing to that observed in the rat; 2) cycles of meal-associated activity free ran for up to 6 days after the termination of RF; 3) activity persists at a phase near that of the former mealtime during periods of food deprivation; and 4) activity indicative of beating between two pacemakers occurred when feeding was restricted to the L period of LD cycles. Together these observations suggest that the activity rhythms of the kowari may be controlled by separate, but possibly coupled, light-entrainable and food-entrainable pacemakers, as are those of the rat. PMID:1928428

  15. Role of Circadian Rhythms in Potassium Homeostasis

    PubMed Central

    Gumz, Michelle L.; Rabinowitz, Lawrence

    2013-01-01

    It has been known for decades that urinary potassium excretion varies with a circadian pattern. In this review, we consider the historical evidence for this phenomenon and present an overview of recent developments in the field. Extensive evidence from the latter part of the last century clearly demonstrates that circadian potassium excretion does not depend on endogenous aldosterone. Of note is the recent discovery that the expression of several renal potassium transporters varies with a circadian pattern that appears to be consistent with substantial clinical data regarding daily fluctuations in urinary potassium levels. We propose the circadian clock mechanism as a key regulator of renal potassium transporters, and consequently renal potassium excretion. Further investigation into the mechanism of regulation of renal potassium transport by the circadian clock is warranted in order to increase our understanding of the clinical relevance of circadian rhythms to potassium homeostasis. PMID:23953800

  16. CIRCADIAN RHYTHM REPROGRAMMING DURING LUNG INFLAMMATION

    PubMed Central

    Haspel, Jeffrey A.; Chettimada, Sukrutha; Shaik, Rahamthulla S.; Chu, Jen-Hwa; Raby, Benjamin A.; Cernadas, Manuela; Carey, Vincent; Process, Vanessa; Hunninghake, G. Matthew; Ifedigbo, Emeka; Lederer, James A.; Englert, Joshua; Pelton, Ashley; Coronata, Anna; Fredenburgh, Laura E.; Choi, Augustine M. K.

    2014-01-01

    Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here, we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian program exhibits unique features, including a divergent group of rhythmic genes and metabolites compared to the basal state and a distinct periodicity and phase distribution. At the cellular level endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex reorganization of cellular and molecular circadian rhythms that are relevant to early events in lung injury. PMID:25208554

  17. Mechanism of the circadian clock in physiology

    PubMed Central

    Richards, Jacob

    2013-01-01

    It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiological process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of “clock-independent effects” of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed. PMID:23576606

  18. Endogenous circadian rhythm in human motor activity uncoupled from circadian influences

    E-print Network

    Stanley, H. Eugene

    -mediated changes in motor activity or whether activ- ity and heart rate dynamics are decoupled across the circadian influences key physiologic functions, such as body temperature and heart rate, and is nor- mally synchronizedEndogenous circadian rhythm in human motor activity uncoupled from circadian influences on cardiac

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

    PubMed

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

    2013-07-01

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

  20. Circadian Clock, Cell Cycle and Cancer

    Microsoft Academic Search

    Zhaoyang Zhao; Cheng Chi Lee

    \\u000a The circadian clock is a fundamental biological process that is pervasive in living organisms. Over the past decade, much\\u000a has been learned about the molecular mechanism of the mammalian circadian clock. Studies have also led to the revelation of\\u000a various connections between the circadian clock function and other basic biological processes, including the cell cycle and\\u000a the DNA damage response.

  1. Circadian Rhythms: A Circadian Loop asSIRTs Itself

    NSDL National Science Digital Library

    Herman Wijnen (University of Virginia; Department of Biology)

    2009-05-01

    Access to the article is free, however registration and sign-in are required: Daily time keeping in many organisms depends on internal circadian clocks that temporally organize biological functions relative to each other as well as the environment. These clocks generate rhythms in physiology and behavior by using circuits of gene expression that are organized in negative-feedback loops. Two studies in this issue, by Nakahata et al. and Ramsey et al., propose the addition of a new negative-feedback loop to this circuitry that involves the metabolite nicotinamide adenine dinucleotide (NAD+) and the protein SIRTUIN1 (SIRT1). The new loop suggests connections between the circadian clock and SIRT1-dependent functions associated with cell survival, development, inflammation, and metabolism.

  2. N-acetyltransferase (nat) Is a Critical Conjunct of Photoperiodism between the Circadian System and Endocrine Axis in Antheraea pernyi

    PubMed Central

    Bembenek, Jadwiga; Hiragaki, Susumu; Suzuki, Takeshi; Takeda, Makio

    2014-01-01

    Since its discovery in 1923, the biology of photoperiodism remains a mystery in many ways. We sought the link connecting the circadian system to an endocrine switch, using Antheraea pernyi. PER-, CLK- and CYC-ir were co-expressed in two pairs of dorsolateral neurons of the protocerebrum, suggesting that these are the circadian neurons that also express melatonin-, NAT- and HIOMT-ir. The results suggest that a melatonin pathway is present in the circadian neurons. Melatonin receptor (MT2 or MEL-1B-R)-ir in PTTH-ir neurons juxtaposing clock neurons suggests that melatonin gates PTTH release. RIA showed a melatonin rhythm with a peak four hours after lights off in adult brain both under LD16?8 (LD) and LD12?12 (SD), and both the peak and the baseline levels were higher under LD than SD, suggesting a photoperiodic influence. When pupae in diapause were exposed to 10 cycles of LD, or stored at 4°C for 4 months under constant darkness, an increase of NAT activity was observed when PTTH released ecdysone. DNA sequence upstream of nat contained E-boxes to which CYC/CLK could bind, and nat transcription was turned off by clk or cyc dsRNA. dsRNANAT caused dysfunction of photoperiodism. dsRNAPER upregulated nat transcription as anticipated, based on findings in the Drosophila melanogaster circadian system. Transcription of nat, cyc and clk peaked at ZT12. RIA showed that dsRNANAT decreased melatonin while dsRNAPER increased melatonin. Thus nat, a clock controlled gene, is the critical link between the circadian clock and endocrine switch. MT-binding may release PTTH, resulting in termination of diapause. This study thus examined all of the basic functional units from the clock: a photoperiodic counter as an accumulator of mRNANAT, to endocrine switch for photoperiodism in A. pernyi showing this system is self-complete without additional device especially for photoperiodism. PMID:24667367

  3. Sleep and circadian dysfunction in neurodegenerative disorders: insights from a mouse model of Huntington’s disease

    PubMed Central

    Kuljis, Dika; Schroeder, Analyne M.; Kudo, Takashi; Loh, Dawn H.; Willison, David L.; Colwell, Christopher S.

    2013-01-01

    Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington’s disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD patients and the consequences of circadian disruption. This raises the possibility that the disordered sleep and circadian function experienced by HD patients may be an integral part of the disease. Furthermore, we speculate that circadian dysfunction may accelerate the pathology underlying HD. If these hypotheses are correct, we should focus on treating circadian misalignment and sleep disruptions early in disease progression. PMID:23687390

  4. The Central Circadian Timing System

    PubMed Central

    Saper, Clifford B.

    2013-01-01

    It has been known since the 1970’s that the suprachiasmatic nucleus (SCN) is the brain’s main biological clock, and since the 1990’s that it uses a genetic clock based on transcriptional-translational loops to tell time. However, the recent demonstration that many other cells in the brain and the body also make use of the same genetic clock raises the question of how the SCN synchronizes all of the other clocks to arrive at a coherent circadian profile of physiology and behavior. In this review, we re-examine the evidence that the SCN clock is necessary for bringing order to the body’s biological rhythms, and the circuitry of the circadian timing system by which it accomplishes this goal. Finally, we review the evidence that under conditions of restricted food availability, other clocks may be able to take over from the SCN to determine rhythms of behavior and physiology. PMID:23706187

  5. Circadian rhythmometry of mammalian radiosensitivity

    NASA Technical Reports Server (NTRS)

    Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

    1974-01-01

    In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

  6. A Spatially-Ordered Pacemaker Observed in Squid Giant Axons

    NASA Astrophysics Data System (ADS)

    Matsumoto, Gen; Aihara, Kazuyuki; Utsunomiya, Toshio

    1982-03-01

    It was both theoretically and experimentally demonstrated that a spatially-ordered pacemaker generating action potentials at a constant rhythm was formed at a restricted region on the squid giant axon in the state of self-sustained oscillation of the action potentials. The dynamics of the Hodgkin-Huxley equations with one-dimensional diffusion were analysed to study the spatially-ordered pacemaker under the following conditions; (1) the rate constants of sodium activation and inactivation, and potassium activation changed with the effective calcium concentration in the external medium, according to Frankenhaeuser and Hodgkin (J. Physiol. 137 (1957) 218), and (2) the membrane potentials at both ends of the axon were fixed to be zero. These experiments and calculation show that the repetitive firing state is spatially well organized and integrated, and that it could be called as the dissipative structure of Glansdorff and Prigogine macroscopically

  7. Effects of time delay and random rewiring on the stochastic resonance in excitable small-world neuronal networks.

    PubMed

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

    2013-05-01

    The effects of time delay and rewiring probability on stochastic resonance and spatiotemporal order in small-world neuronal networks are studied in this paper. Numerical results show that, irrespective of the pacemaker introduced to one single neuron or all neurons of the network, the phenomenon of stochastic resonance occurs. The time delay in the coupling process can either enhance or destroy stochastic resonance on small-world neuronal networks. In particular, appropriately tuned delays can induce multiple stochastic resonances, which appear intermittently at integer multiples of the oscillation period of the pacemaker. More importantly, it is found that the small-world topology can significantly affect the stochastic resonance on excitable neuronal networks. For small time delays, increasing the rewiring probability can largely enhance the efficiency of pacemaker-driven stochastic resonance. We argue that the time delay and the rewiring probability both play a key role in determining the ability of the small-world neuronal network to improve the noise-induced outreach of the localized subthreshold pacemaker. PMID:23767608

  8. Endovascular extraction techniques for pacemaker and ICD lead extraction

    PubMed Central

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

    2001-01-01

    In the last few years, comprehensive endovascular techniques have been developed to extract chronically implanted pacemaker and defibrillator leads. It is important that referring physician have knowledge of the advantages and limitations of the different techniques. In this paper we discuss the techniques and results of the currently used endovascular extraction techniques. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7 PMID:25696690

  9. Circadian Entrainment, Sleep-Wake Regulation and Neurobehavioral Performance During Extended Duration Space Flight

    NASA Technical Reports Server (NTRS)

    Czeisler, Charles A.

    1999-01-01

    Long-duration manned space flight requires crew members to maintain a high level of cognitive performance and vigilance while operating and monitoring sophisticated instrumentation. However, the reduction in the strength of environmental synchronizers in the space environment leads to misalignment of circadian phase among crew members, coupled with restricted time available to sleep, results in sleep deprivation and consequent deterioration of neurobehavioral function. Crew members are provided, and presently use, long-acting benzodiazepine hypnotics on board the current, relatively brief space shuttle missions to counteract such sleep disruption, a situation that is only likely to worsen during extended duration missions. Given the known carry-over effects of such compounds on daytime performance, together with the reduction in emergency readiness associated with their use at night, NASA has recognized the need to develop effective but safe countermeasures to allow crew members to obtain an adequate amount of sleep. Over the past eight years, we have successfully implemented a new technology for shuttle crew members involving bright light exposure during the pre-launch period to facilitate adaptation of the circadian timing system to the inversions of the sleep-wake schedule often required during dual shift missions. However for long duration space station missions it will be necessary to develop effective and attainable countermeasures that can be used chronically to optimize circadian entrainment. Our current research effort is to study the effects of light-dark cycles with reduced zeitgeber strength, such as are anticipated during long-duration space flight, on the entrainment of the endogenous circadian timing system and to study the effects of a countermeasure that consists of scheduled brief exposures to bright light on the human circadian timing system. The proposed studies are designed to address the following Specific Aims: (1) test the hypothesis that synchronization of the human circadian pacemaker will be disturbed in men and women by the reduction in LD cycle strength. (2) test the hypothesis that this disturbed circadian synchronization will result in the secretion of the sleep-promoting hormone melatonin during the waking day, disturbed sleep, reduced growth hormone secretion, and impaired performance and daytime alertness; (3) as a countermeasure, test the hypothesis that brief daily exposures to bright light (10,000 lux) will reestablish normal entrained circadian phase, resulting in improved sleep consolidation, normalized sleep structure and endogenous growth hormone secretion and enhanced daytime performance. To date, we have carried out twelve experiments to address Hypotheses I and 2 and data analyses are in progress. The results of the current research may have important implications for the treatment of circadian rhythm sleep disorders, such as delayed sleep phase syndrome and shift-work dyssomnia, which are anticipated to have a high incidence and prevalence during extended duration space flight such as planned for the International Space Station and manned missions to Mars.

  10. Circadian rhythms investigated on the cellular and molecular levels.

    PubMed

    Gebicke-Haerter, P J; Pildaín, L V; Matthäus, F; Schmitt, A; Falkai, P

    2013-05-01

    Investigations on circadian rhythms have markedly advanced our understanding of health and disease with the advent of high-throughput technologies like microarrays and epigenetic profiling. They elucidated the multi-level behaviour of interactive oscillations from molecules to neuronal networks and eventually to processes of learning and memory in an impressive manner. The small-world topology of synchronized firing through neuron-neuron and neuron-glia gap junctions is discussed as a mathematical approach to these intensively studied issues. It has become evident that, apart from some disorders caused by gene mutations, the majority of disorders originating from disturbances of rhythms arise from environmental influences and epigenetic changes. In this context, it was mandatory to think of and devise experiments on temporary scales, which exponentially increased the volumes of data obtained from time-series and rapidly became prohibitive of manual inspection. Therefore, more and more sophisticated mathematical algorithms have been developed to identify rhythmic expression of genes and to find coexpression by their clustering. It is expected that disturbed rhythmic behaviour in mental disorders is reflected in altered oscillatory behaviour of gene expression. PMID:23599242

  11. Disturbances in the murine hepatic circadian clock in alcohol-induced hepatic steatosis

    PubMed Central

    Zhou, Peng; Ross, Ruth A.; Pywell, Cameron M.; Liangpunsakul, Suthat; Duffield, Giles E.

    2014-01-01

    To investigate the role of the circadian clock in the development of alcohol-induced fatty liver disease we examined livers of mice chronically alcohol-fed over 4-weeks that resulted in steatosis. Here we show time-of-day specific changes in expression of clock genes and clock-controlled genes, including those associated with lipid and bile acid regulation. Such changes were not observed following a 1-week alcohol treatment with no hepatic lipid accumulation. Real-time bioluminescence reporting of PERIOD2 protein expression suggests that these changes occur independently of the suprachiasmatic nucleus pacemaker. Further, we find profound time-of-day specific changes to the rhythmic synthesis/accumulation of triglycerides, cholesterol and bile acid, and the NAD/NADH ratio, processes that are under clock control. These results highlight not only that the circadian timekeeping system is disturbed in the alcohol-induced hepatic steatosis state, but also that the effects of alcohol upon the clock itself may actually contribute to the development of hepatic steatosis. PMID:24430730

  12. Haemophilus parainfluenzae bacteremia associated with a pacemaker wire localized by gallium scan

    SciTech Connect

    Rosenbaum, G.S.; Calubiran, O.; Cunha, B.A. (Winthrop-Univ. Hospital, Mineola, NY (USA))

    1990-05-01

    A young woman with a history of sick sinus syndrome and placement of a permanent pacemaker 6 months before admission had fever and Haemophilus parainfluenzae bacteremia. A gallium scan localized the infection to the site of the pacemaker wire. Echocardiograms were negative for any vegetations. The patient responded to cefotaxime and trimethoprim-sulfamethoxazole therapy. We believe that this is the first case of H. parainfluenzae bacteremia associated with a pacemaker wire and localized by gallium scan.

  13. The value of redundancy in chronic bipolar pacemaker electrode systems.

    PubMed

    Holmes, D R; Gersh, B J; Shub, C; Maloney, J D; Merideth, J

    1980-07-01

    Bipolar pacing systems, because of the presence of two intracardiac electrodes, provide lead redundancy. This allows conversion of bipolar to unipolar pacing or the reversal of lead polarity. During a 3-year period, this redundancy was utilized in 34 (13.7%) of 248 patients with chronic bipolar lead systems during follow-up pacemaker surgery. Of the 34 patients, elective pulse generator change was the most frequent indication for surgery (23 patients) and in this group redundancy was used most often to select the lead configuration with the highest R-wave amplitude and lowest stimulation threshold, or to solve the problem of weld defects of the connector pins or frayed insulation. The remaining 11 patients underwent surgery for pacemaker system malfunction and in this group redundancy was used to avoid the need for lead repositioning or placement of a new catheter system. Lead redundancy in those patients in whom bipolar pacing has been selected provides flexibility at the time of additional pacemaker surgery, and its use may obviate the need for a change in catheter system when stimulation thresholds are excessive, wire fraction is irreparable, or bipolar sensing signals are inadequate. PMID:6160536

  14. Radiation therapy planning of a breast cancer patient with in situ pacemaker--challenges and lessons.

    PubMed

    Munshi, Anusheel; Wadasadawala, Tabassum; Sharma, Pramod Kumar; Sharma, Dayananda; Budrukkar, Ashwini; Jalali, Rakesh; Dinshaw, Ketayun A

    2008-01-01

    A postmenopausal lady with an in situ pacemaker developed a lump in the left breast and was diagnosed to have breast cancer. The patient underwent breast conservative surgery and was planned for post operative radiotherapy. The location of the tumor relative to the pacemaker provided a unique challenge in planning radiotherapy and the patient had an uneventful post radiotherapy course. A literature review revealed that modern generation pacemakers are very sensitive to radiation compared to their older counterparts. The present article makes suggestions towards reducing dose in radiotherapy planning in pacemaker patients. PMID:17943474

  15. Reuse Of Pacemakers In Ghana And Nigeria: Medical, Legal, Cultural And Ethical Perspectives.

    PubMed

    Ochasi, Aloysius; Clark, Peter

    2014-04-11

    According to the World Health Organization (WHO) cardiovascular disease (CVD) is the leading cause of death globally. Over 80% of CVD deaths take place in low- and middle-income countries (LMICs). It is estimated that 1 million to 2 million people worldwide die each year due to lack of access to an implantable cardiac defibrillator (ICD) or a pacemaker. Despite the medical, legal, cultural and ethical controversies surrounding the pacemaker reutilization, studies done so far on the reuse of postmortem pacemakers show it to be safe and effective with an infection rate of 1.97% and device malfunction rate of 0.68%. Pacemaker reutilization can be effectively and safely done and does not pose significant additional risk to the recipient. Heart patients with reused pacemakers have an improved quality of life compared to those without pacemakers. The thesis of this paper is that pacemaker reutilization is a life-saving initiative in LMICs of Nigeria and Ghana. It is cost effective; consistent with the principles of beneficence, nonmaleficence, and justice with a commitment to stewardship of resources and the Common Good. Used pacemakers with adequate battery life can be properly sterilized for use by patients in LMICs who cannot afford the cost of a new pacemaker. PMID:24720369

  16. Powering pacemakers from heartbeat vibrations using linear and nonlinear energy harvesters

    NASA Astrophysics Data System (ADS)

    Amin Karami, M.; Inman, Daniel J.

    2012-01-01

    Linear and nonlinear piezoelectric devices are introduced to continuously recharge the batteries of the pacemakers by converting the vibrations from the heartbeats to electrical energy. The power requirement of a pacemaker is very low. However, after few years, patients require another surgical operation just to replace their pacemaker battery. Linear low frequency and nonlinear mono-stable and bi-stable energy harvesters are designed according to the especial signature of heart vibrations. The proposed energy harvesters are robust to variation of heart rate and can meet the power requirement of pacemakers.

  17. Inhibition of hippocampal neurogenesis by sleep deprivation is independent of circadian disruption and melatonin suppression.

    PubMed

    Mueller, A D; Mear, R J; Mistlberger, R E

    2011-10-13

    Procedures that restrict or fragment sleep can inhibit neurogenesis in the hippocampus of adult rodents, although the underlying mechanism is unknown. We showed that rapid-eye-movement (REM) sleep deprivation (RSD) by the platform-over-water method inhibits hippocampal cell proliferation in adrenalectomized rats with low-dose corticosterone clamp. This procedure also greatly disrupts daily behavioral rhythms. Given recent evidence for circadian clock regulation of cell proliferation, we asked whether disruption of circadian rhythms might play a role in the anti-neurogenic effects of sleep loss. Male Sprague-Dawley rats were subjected to a 4-day RSD procedure or were exposed to constant bright light (LL) for 4 days or 10 weeks, a non-invasive procedure for eliminating circadian rhythms of behavior and physiology in this species. Proliferating cells in the granule cell layer of the dentate gyrus were identified by immunolabeling for the thymidine analogue 5-bromo-2-deoxyuridine. Consistent with our previous results, the RSD procedure suppressed cell proliferation by ?50%. By contrast, although LL attenuated or eliminated daily rhythms of activity and sleep-wake without affecting daily amounts of REM sleep, cell proliferation was not affected. Melatonin, a nocturnally secreted neurohormone that is inhibited by light, has been shown to promote survival of new neurons. We found that 3-weeks of LL eliminated daily rhythms and decreased plasma melatonin by 88% but did not significantly affect either total cell survival or survival of new neurons (doublecortin+). Finally, we measured cell proliferation rates at the beginning and near the end of the daily light period in rats entrained to a 12:12 light/lark (LD) cycle, but did not detect a daily rhythm. These results indicate that the antineurogenic effect of RSD is not secondary to disruption of circadian rhythms, and provide no evidence that hippocampal cell proliferation and survival are regulated by the circadian system or by nocturnal secretion of pineal melatonin. PMID:21771640

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

    PubMed

    Fifel, Karim; Cooper, Howard M

    2014-11-01

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

  19. Dysfunctions in Circadian Behavior and Physiology in Mouse Models of Huntington's Disease

    PubMed Central

    Kudo, Takashi; Schroeder, Analyne; Loh, Dawn H.; Kuljis, Dika; Jordan, Maria C.; Roos, Kenneth P.; Colwell, Christopher S.

    2015-01-01

    Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease. PMID:21184755

  20. Gonadal- and sex-chromosome-dependent sex differences in the circadian system.

    PubMed

    Kuljis, Dika A; Loh, Dawn H; Truong, Danny; Vosko, Andrew M; Ong, Margaret L; McClusky, Rebecca; Arnold, Arthur P; Colwell, Christopher S

    2013-04-01

    Compelling reasons to study the role of sex in the circadian system include the higher rates of sleep disorders in women than in men and evidence that sex steroids modulate circadian control of locomotor activity. To address the issue of sex differences in the circadian system, we examined daily and circadian rhythms in wheel-running activity, electrical activity within the suprachiasmatic nucleus, and PER2::LUC-driven bioluminescence of gonadally-intact adult male and female C57BL/6J mice. We observed greater precision of activity onset in 12-hour light, 12-hour dark cycle for male mice, longer activity duration in 24 hours of constant darkness for female mice, and phase-delayed PER2::LUC bioluminescence rhythm in female pituitary and liver. Next, in order to investigate whether sex differences in behavior are sex chromosome or gonadal sex dependent, we used the 4 core genotypes (FCG) mouse model, in which sex chromosome complement is independent of gonadal phenotype. Gonadal males had more androgen receptor expression in the suprachiasmatic nucleus and behaviorally reduced photic phase shift response compared with gonadal female FCG mice. Removal of circulating gonadal hormones in adults, to test activational vs organizational effects of sex revealed that XX animals have longer activity duration than XY animals regardless of gonadal phenotype. Additionally, we observed that the activational effects of gonadal hormones were more important for regulating activity levels in gonadal male mice than in gonadal female FCG mice. Taken together, sex differences in the circadian rhythms of activity, neuronal physiology, and gene expression were subtle but provide important clues for understanding the pathophysiology of the circadian system. PMID:23439698

  1. Circadian Tick-Talking Across the Neuroendocrine System and Suprachiasmatic Nuclei Circuits: The Enigmatic Communication Between the Molecular and Electrical Membrane Clocks.

    PubMed

    Belle, M D C

    2015-07-01

    As with many processes in nature, appropriate timing in biological systems is of paramount importance. In the neuroendocrine system, the efficacy of hormonal influence on major bodily functions, such as reproduction, metabolism and growth, relies on timely communication within and across many of the brain's homeostatic systems. The activity of these circuits is tightly orchestrated with the animal's internal physiological demands and external solar cycle by a master circadian clock. In mammals, this master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), where the ensemble activity of thousands of clock neurones generates and communicates circadian time cues to the rest of the brain and body. Many regions of the brain, including areas with neuroendocrine function, also contain local daily clocks that can provide feedback signals to the SCN. Although much is known about the molecular processes underpinning endogenous circadian rhythm generation in SCN neurones and, to a lesser extent, extra-SCN cells, the electrical membrane clock that acts in partnership with the molecular clockwork to communicate circadian timing across the brain is poorly understood. The present review focuses on some circadian aspects of reproductive neuroendocrinology and processes involved in circadian rhythm communication in the SCN, aiming to identify key gaps in our knowledge of cross-talk between our daily master clock and neuroendocrine function. The intention is to highlight our surprisingly limited understanding of their interaction in the hope that this will stimulate future work in these areas. PMID:25845396

  2. "Subclinical" pacemaker syndrome: a randomised study of symptom free patients with ventricular demand (VVI) pacemakers upgraded to dual chamber devices.

    PubMed Central

    Sulke, N; Dritsas, A; Bostock, J; Wells, A; Morris, R; Sowton, E

    1992-01-01

    OBJECTIVE--To determine whether symptom free patients with single chamber pacemakers benefit from dual chamber pacing. DESIGN--A randomised double blind crossover comparison of ventricular demand (VVI), dual chamber demand (DDI), and dual chamber universal (DDD) modes after upgrading from a VVI device. SETTING--Cardiology outpatient department. PATIENTS--Sixteen patients aged 41-84 years who were symptom free during VVI mode pacing for three or more years. INTERVENTION--Pacemaker upgrade during routine generator change. MAIN OUTCOME MEASURES--Change in subjective (general health perception, symptoms) and objective (clinical assessment, treadmill exercise, and radiological and echocardiographic indices) results between pacing modes before and after upgrading. RESULTS--75% preferred DDD, 68% found VVI least acceptable with 12% expressing no preference. Perceived general well-being and exercise capacity (p less than 0.01) and treadmill times (p less than 0.05) were improved in DDD mode but VVI and DDI modes were similar. Clinical, echocardiographic, radiological, and electrophysiological indices confirmed the absence of overt pacemaker syndrome, although mitral and tricuspid regurgitation was greatest in VVI mode (p less than 0.01). CONCLUSIONS--Most patients who were satisfied with long term pacing in VVI mode benefited from upgrading to DDD mode pacing suggesting the existence of "subclinical" pacemaker syndrome in up to 75% of such patients. The DDI mode offered little subjective or objective benefit over VVI mode in this population and should be reserved for patients with paroxysmal atrial arrhythmias. VVI mode pacing should be used only for patients with very intermittent symptomatic bradycardia or atrial fibrillation with a good chronotropic response during exercise. PMID:1739528

  3. Delirium: a disturbance of circadian integrity?

    PubMed

    Fitzgerald, James M; Adamis, Dimitrios; Trzepacz, Paula T; O'Regan, Niamh; Timmons, Suzanne; Dunne, Colum; Meagher, David J

    2013-10-01

    Delirium is a serious neuropsychiatric syndrome of acute onset that occurs in approximately one in five general hospital patients and is associated with serious adverse outcomes that include loss of adaptive function, persistent cognitive problems and increased mortality. Recent studies indicate a three-domain model for delirium that includes generalised cognitive impairment, disturbed executive cognition, and disruption of behaviours that are under circadian control such as sleep-wake cycle and motor activity levels. As a consequence, attention has focused upon the possible role of the circadian timing system (CTS) in the pathophysiology of delirium. We explored this possibility by reviewing evidence that (1) many symptoms that occur in delirium are influenced by circadian rhythms, (2) many features of recognised circadian rhythm disorders are similar to characteristic features of delirium, (3) common risk factors for delirium are known to disrupt circadian systems, (4) physiological disturbances of circadian systems have been noted in delirious patients, and (5) positive effects in the treatment of delirium have been demonstrated for melatonin and related agents that influence the circadian timing system. A programme of future studies that can help to clarify the relevance of circadian integrity to delirium is described. Such work can provide a better understanding of the pathophysiology of delirium while also identifying opportunities for more targeted therapeutic efforts. PMID:23916192

  4. [Circadian clocks and energy metabolism in rodents].

    PubMed

    Challet, Etienne

    2014-01-01

    Circadian rhythmicity is an important component of physiological processes which provides them with a 24-hour temporal organization and adjustment to cyclical changes in the environment. Circadian rhythms are controlled by a network of endogenous clocks, comprising the main clock in the suprachiasmatic nuclei of the hypothalamus and many secondary clocks in the brain and peripheral tissues. All aspects of energy metabolism, from food intake to intracellular signaling pathways, are strongly influenced by circadian rhythmicity. In turn, meal timing is an efficient synchronizer (time-giver) to set the phase of the peripheral clocks, while the suprachiasmatic clock is synchronized by ambient light. In certain nutritional conditions (i.e., low- or high-calory diets), metabolic factors remaining to be identified modulate the functioning of the suprachiasmatic clock. Animal models of obesity and diabetes show circadian alterations. Conversely, when circadian rhythmicity is disturbed, either due to genetically defective circadian clocks, or to circadian desynchronization (chronic light exposure or repeated meals at odd times of the cycle), lipid and glucose metabolism is deregulated. The metabolic impact of circadian desynchronization justifies the development of preventive or therapeutic strategies that could rely, among others, on dietary interventions combining timed meals and specific composition. PMID:25840453

  5. Circadian rhythms of locomotor activity in Drosophila

    Microsoft Academic Search

    André Klarsfeld; Jean-Christophe Leloup; François Rouyer

    2003-01-01

    Drosophila is by far the most advanced model to understand the complex biochemical interactions upon which circadian clocks rely. Most of the genes that have been characterized so far were isolated through genetic screens using the locomotor activity rhythms of the adults as a circadian output. In addition, new techniques are available to deregulate gene expression in specific cells, allowing

  6. Circadian Rhythms: In the Loop at Last

    NSDL National Science Digital Library

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

    2003-06-06

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

  7. Glaucoma Alters the Circadian Timing System

    Microsoft Academic Search

    Elise Drouyer; Ouria Dkhissi-Benyahya; Christophe Chiquet; Elizabeth Woldemussie; Guadalupe Ruiz; Larry A. Wheeler; Philippe Denis; Howard M. Cooper; Alain Chédotal

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are

  8. Running for time: circadian rhythms and melanoma.

    PubMed

    Markova-Car, Elitza P; Juriši?, Davor; Ili?, Nataša; Kraljevi? Paveli?, Sandra

    2014-09-01

    Circadian timing system includes an input pathway transmitting environmental signals to a core oscillator that generates circadian signals responsible for the peripheral physiological or behavioural events. Circadian 24-h rhythms regulate diverse physiologic processes. Deregulation of these rhythms is associated with a number of pathogenic conditions including depression, diabetes, metabolic syndrome and cancer. Melanoma is a less common type of skin cancer yet more aggressive often with a lethal ending. However, little is known about circadian control in melanoma and exact functional associations between core clock genes and development of melanoma skin cancer. This paper, therefore, comprehensively analyses current literature data on the involvement of circadian clock components in melanoma development. In particular, the role of circadian rhythm deregulation is discussed in the context of DNA repair mechanisms and influence of UV radiation and artificial light exposure on cancer development. The role of arylalkylamine N-acetyltransferase (AANAT) enzyme and impact of melatonin, as a major output factor of circadian rhythm, and its protective role in melanoma are discussed in details. We hypothesise that further understanding of clock genes' involvement and circadian regulation might foster discoveries in the field of melanoma diagnostics and treatment. PMID:24729125

  9. Metabolism and cancer: the circadian clock connection

    Microsoft Academic Search

    Saurabh Sahar; Paolo Sassone-Corsi

    2009-01-01

    Circadian rhythms govern a remarkable variety of metabolic and physiological functions. Accumulating epidemiological and genetic evidence indicates that the disruption of circadian rhythms might be directly linked to cancer. Intriguingly, several molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of the cell cycle, and alterations in clock function could lead to aberrant cellular

  10. The Circadian Clock Modulates Renal Sodium Handling

    PubMed Central

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

    2012-01-01

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

  11. Effects of Tetraethylammoni um on Potassium Currents in a Molluscan Neuron

    Microsoft Academic Search

    A. HERMANN; A. L. F. GORMAN

    1981-01-01

    The effects of tetraethylammoni um (TEA) on the delayed K + current and on the Ca2+-activated K + current of the Aplysia pacemaker neurons R-15 and L-6 were studied. The delayed outward K + current was measured in Ca2+-free ASW containing tetrodotoxin (TTX), using brief depolarizing clamp pulses. External TEA blocks the delayed K + current reversibly in a dose-

  12. Circadian Clock Gene Per2 Is Not Necessary for the Photoperiodic Response in Mice

    PubMed Central

    Ikegami, Keisuke; Iigo, Masayuki; Yoshimura, Takashi

    2013-01-01

    In mammals, light information received by the eyes is transmitted to the pineal gland via the circadian pacemaker, i.e., the suprachiasmatic nucleus (SCN). Melatonin secreted by the pineal gland at night decodes night length and regulates seasonal physiology and behavior. Melatonin regulates the expression of the ?-subunit of thyroid-stimulating hormone (TSH; Tshb) in the pars tuberalis (PT) of the pituitary gland. Long day-induced PT TSH acts on ependymal cells in the mediobasal hypothalamus to induce the expression of type 2 deiodinase (Dio2) and reduce type 3 deiodinase (Dio3) that are thyroid hormone-activating and hormone-inactivating enzymes, respectively. The long day-activated thyroid hormone T3 regulates seasonal gonadotropin-releasing hormone secretion. It is well established that the circadian clock is involved in the regulation of photoperiodism. However, the involvement of the circadian clock gene in photoperiodism regulation remains unclear. Although mice are generally considered non-seasonal animals, it was recently demonstrated that mice are a good model for the study of photoperiodism. In the present study, therefore, we examined the effect of changing day length in Per2 deletion mutant mice that show shorter wheel-running rhythms under constant darkness followed by arhythmicity. Although the amplitude of clock gene (Per1, Cry1) expression was greatly attenuated in the SCN, the expression profile of arylalkylamine N-acetyltransferase, a rate-limiting melatonin synthesis enzyme, was unaffected in the pineal gland, and robust photoperiodic responses of the Tshb, Dio2, and Dio3 genes were observed. These results suggested that the Per2 clock gene is not necessary for the photoperiodic response in mice. PMID:23505514

  13. Fatigue and Circadian Activity Rhythms in Breast Cancer Patients Before and After Chemotherapy: A Controlled Study.

    PubMed

    Liu, Lianqi; Rissling, Michelle; Neikrug, Ariel; Fiorentino, Lavinia; Natarajan, Loki; Faierman, Michelle; Sadler, Georgia Robins; Dimsdale, Joel E; Mills, Paul J; Parker, Barbara A; Ancoli-Israel, Sonia

    2013-01-01

    BACKGROUND: Breast cancer (BC) patients often experience cancer-related fatigue (CRF) before, during, and after their chemotherapy. Circadian rhythms are 24-hour cycles of behavior and physiology that are generated by internal pacemakers and entrained by zeitgebers (e.g., light). A few studies have suggested a relationship between fatigue and circadian rhythms in some clinical populations. METHODS: One hundred and forty-eight women diagnosed with stage I-III breast cancer and scheduled to receive at least four cycles of adjuvant or neoadjuvant chemotherapy, and 61 controls (cancer-free healthy women) participated in this study. Data were collected before (Baseline) and after four cycles of chemotherapy (Cycle-4). Fatigue was assessed with the Short Form of Multidimensional Fatigue Symptom Inventory (MFSI-SF); circadian activity rhythm (CAR) was recorded with wrist actigraphy (six parameters included: amplitude, acrophase, mesor, up-mesor, down-mesor and F-statistic). A mixed model analysis was used to examine changes in fatigue and CAR parameters compared to controls, and to examine the longitudinal relationship between fatigue and CAR parameters in BC patients. RESULTS: More severe CRF (total and subscale scores) and disrupted CAR (amplitude, mesor and F-statistic) were observed in BC patients compared to controls at both Baseline and Cycle-4 (all p's<0.05); BC patients also experienced more fatigue and decreased amplitude and mesor, as well as delayed up-mesor time at Cycle-4 compared to Baseline (all p's<0.05). The increased total MFSI-SF scores were significantly associated with decreased amplitude, mesor and F-statistic (all p's<0.006). CONCLUSION: CRF exists and CAR is disrupted even before the start of chemotherapy. The significant relationship between CRF and CAR indicate possible underlying connections. Re-entraining the disturbed CAR using effective interventions such as bright light therapy might also improve CRF. PMID:23412418

  14. Metabolic consequences of sleep and circadian disorders.

    PubMed

    Depner, Christopher M; Stothard, Ellen R; Wright, Kenneth P

    2014-07-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome, and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance, and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID:24816752

  15. The Circadian Clock Coordinates Ribosome Biogenesis

    PubMed Central

    Symul, Laura; Martin, Eva; Atger, Florian; Naef, Felix; Gachon, Frédéric

    2013-01-01

    Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis. PMID:23300384

  16. Circadian rhythms synchronize mitosis in Neurospora crassa

    PubMed Central

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

    2014-01-01

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

  17. Strategy for Safe Performance of Extrathoracic Magnetic Resonance Imaging at 1.5 Tesla in the Presence of Cardiac Pacemakers in Non-Pacemaker-Dependent Patients A Prospective Study With 115 Examinations

    Microsoft Academic Search

    Torsten Sommer; Claas P. Naehle; Alexander Yang; Volkert Zeijlemaker; Matthias Hackenbroch; Alexandra Schmiedel; Carsten Meyer; Katharina Strach; Dirk Skowasch; Christian Vahlhaus; Harold Litt; Hans Schild

    2011-01-01

    Background—The purpose of the present study was to evaluate a strategy for safe performance of extrathoracic magnetic resonance imaging (MRI) in non-pacemaker-dependent patients with cardiac pacemakers. Methods and Results—Inclusion criteria were presence of a cardiac pacemaker and urgent clinical need for an MRI examination. Pacemaker-dependent patients and those requiring examinations of the thoracic region were excluded. The study group consisted

  18. Direct Cellular Peptidomics of Hypothalamic Neurons Research highlights

    E-print Network

    Gillette, Martha U.

    enable suites of peptides from hypothalamic neurons to be identified. Analytical chemistry protocols, University of Illinois at Urbana-Champaign, Urbana, IL, USA c Dept. of Chemistry, University of Illinois, hunger/satiety and reproductive state to circadian rhythms and sleep. Hypothalamic nuclei

  19. Copper chelation and exogenous copper affect circadian clock phase resetting in the suprachiasmatic nucleus in vitro.

    PubMed

    Yamada, Y; Prosser, R A

    2014-01-01

    Light stimulates specialized retinal ganglion cells to release glutamate (Glu) onto circadian clock neurons of the suprachiasmatic nucleus (SCN). Glu resets the phase of the SCN circadian clock by activating N-methyl-d-aspartate receptors (NMDAR) causing either delays or advances in the clock phase, depending on early- or late-night stimulation, respectively. In addition, these Glu-induced phase shifts require tropomyosin receptor kinase B (TrkB) receptor activity. Previous studies show that copper (Cu) released at hippocampal synapses can inhibit NMDAR activity, and application of exogenous Cu likewise inhibits NMDAR activity. We investigated the effects of Cu in acute SCN brain slices prepared from C57BL/6Nhsd adult, male mice using treatments that decrease or increase available Cu levels in vitro and recorded neuronal activity on the following day. When bath-applied for 10 min at zeitgeber time (ZT) 16 (where ZT0=lights-on in the donor animal colony), the Cu-specific chelators tetrathiomolybdate (TTM) and bathocuproine disulfonate each induce ?2.5-3-h phase delays in circadian neuronal activity rhythms, similarly to Glu-induced phase delays. Co-application of 10 ?M CuCl2, but not 10 ?M CoCl? blocks TTM-induced phase delays. Furthermore, TTM causes phase advances when applied at ZT23. At both application times, TTM-induced phase shifts are blocked by NMDA or TrkB receptor antagonists. Surprisingly, bath-application of 10 ?M Cu alone also induces phase shifts in analogous experiments at ZT16 and ZT23. Inhibiting NMDAR does not block Cu-induced phase shifts. TrkB inhibition blocks Cu-induced phase delays but not phase advances. Thus, increasing and decreasing Cu availability appear to shift the SCN clock phase through different mechanisms, at least at the receptor level. We propose that Cu plays a role in the SCN circadian clock by modulating Glu signaling. PMID:24161278

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

    PubMed Central

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

    2010-01-01

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

  1. Circadian Modulation of Anxiety: A Role for Somatostatin in the Amygdala

    PubMed Central

    Albrecht, Anne; Thiere, Marlen; Bergado-Acosta, Jorge Ricardo; Poranzke, Janine; Müller, Bettina; Stork, Oliver

    2013-01-01

    Pharmacological evidence suggests that the neuropeptide somatostatin (SST) exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST-/-) mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST-/- mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates. Behavioral differences occurred independently of changes of intrinsically motivated activity in the home cage. A circadian regulation of SST mRNA and protein expression that was evident in the basolateral complex of the amygdala of wild type mice may provide a neuronal substrate for the observed behavior. However, fear memory towards auditory cue or the conditioning context displayed neither a time- nor genotype-dependent modulation. Together this indicates that SST, in a circadian manner and putatively via its regulation of expression in the amygdala, modulates behavior responding to mildly aversive conditions in mice. PMID:24376834

  2. Circadian regulation of adipose function

    PubMed Central

    Shostak, Anton; Husse, Jana; Oster, Henrik

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  4. Circadian regulators of intestinal lipid absorption.

    PubMed

    Hussain, M Mahmood; Pan, Xiaoyue

    2015-04-01

    Among all the metabolites present in the plasma, lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in lipid absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circadian clock genes and these genes might control circadian expression of different proteins involved in intestinal lipid absorption. Intestinal circadian clock genes are synchronized by signals emanating from the suprachiasmatic nuclei that constitute a master clock and from signals coming from other environmental factors, such as food availability. Disruptions in central clock, as happens due to disruptions in the sleep/wake cycle, affect intestinal function. Similarly, irregularities in temporal food intake affect intestinal function. These changes predispose individuals to various metabolic disorders, such as metabolic syndrome, obesity, diabetes, and atherosclerosis. Here, we summarize how circadian rhythms regulate microsomal triglyceride transfer protein, apoAIV, and nocturnin to affect diurnal regulation of lipid absorption. PMID:25057097

  5. Pacemaker extrusion in a severely demented patient. Device reimplantation via the femoral approach

    PubMed Central

    Pavlidis, Antonios N; Orfanidis, Zaharias; Giannakopoulos, Andreas; Poulimenos, Leonidas E; Kallistratos, Manolis S; Mpampageorgakas, Prodromos; Manolis, Athanasios J

    2011-01-01

    Extrusion of the generator is an infrequent complication following pacemaker implantation. Occlusion or stenosis of the deep venous system is common in elderly patients and can cause significant difficulties in transvenous pacing. The present study reports a rare case of pacemaker extrusion in an elderly patient with an inaccessible upper extremities deep venous system, requiring device reimplantation via the femoral route. PMID:21747659

  6. A Simulink Hybrid Heart Model for Quantitative Verification of Cardiac Pacemakers

    E-print Network

    Oxford, University of

    Mereacre Department of Computer Science University of Oxford, UK ABSTRACT We develop a novel hybrid heartA Simulink Hybrid Heart Model for Quantitative Verification of Cardiac Pacemakers Taolue Chen model in Simulink that is suitable for quantitative verification of implantable cardiac pacemakers

  7. Conceptual Design of GaN Betavoltaic Battery using in Cardiac Pacemaker

    Microsoft Academic Search

    M. Mohamadian; S. A. H. Feghhi; H. Afarideh

    Pacemaker is an electronic biomedical device which stimulates and regulates or amplify the human heartbeat by delivering weak electrical pulses to the cardiac muscle at regular intervals when its natural regulating mechanisms break down. The purpose of the present work is to introduce a kind of low power Betavoltaic battery using in nuclear powered cardiac pacemakers which have higher efficiency

  8. Using the Virtual Heart Model to validate the mode-switch pacemaker operation

    Microsoft Academic Search

    Zhihao Jiang; Allison Connolly; Rahul Mangharam

    2010-01-01

    Artificial pacemakers are one of the most widely-used implantable devices today, with millions implanted worldwide. The main purpose of an artificial pacemaker is to treat bradycardia, or slow heart beats, by pacing the atrium and ventricles at a faster rate. While the basic functionality of the device is fairly simple, there are many documented cases of death and injury due

  9. Quantitative Verification of Implantable Cardiac Pacemakers Taolue Chen Marco Diciolla Marta Kwiatkowska Alexandru Mereacre

    E-print Network

    Oxford, University of

    the electrocardiogram model of Clifford et al, which generates realistic normal and abnormal heart beat behaviours a methodology for deriving the composition of the heart and the pacemaker, based on discretisation. The main correctness properties we consider include checking that the pacemaker corrects Bradycardia (slow heart beat

  10. Effect of 1. 5 tesla nuclear magnetic resonance imaging scanner on implanted permanent pacemakers

    Microsoft Academic Search

    David L. Hayes; David R. Holmes Jr.; Joel E. Gray

    1987-01-01

    Patients with a permanent pacemaker are currently restricted from diagnostic nuclear magnetic resonance (NMR) imaging because of potential adverse effects on the pacemaker by the magnet. Previous work has shown that NMR imaging will result in asynchronous pacing of the pulse generator within a given distance of the magnet. The radiofrequency signal generated by the system may also result in

  11. PP2 prevents ?-adrenergic stimulation of cardiac pacemaker activity.

    PubMed

    Huang, Jianying; Lin, Yen-Chang; Hileman, Stan; Martin, Karen H; Hull, Robert; Yu, Han-Gang

    2014-06-01

    One of the main strategies for cancer therapy is to use tyrosine kinase inhibitors for inhibiting tumor proliferation. Increasing evidence has demonstrated the potential risks of cardiac arrhythmias (such as prolonged QT interval) of these drugs. We report here that a widely used selective inhibitor of Src tyrosine kinases, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), can inhibit and prevent ?-adrenergic stimulation of cardiac pacemaker activity. First, in dissected rat sinus node, PP2 inhibited and prevented the isoproterenol-induced increase of spontaneous beating rate. Second, in isolated rat sinus node myocytes, PP2 suppressed the hyperpolarization-activated "funny" current (traditionally called cardiac pacemaker current, I(f)) by negatively shifting the activation curve and decelerating activation kinetics. Third, in isolated rat sinus node myocytes, PP2 decreased the Src kinase activity, the cell surface expression, and tyrosine phosphorylation of hyperpolarization-activated, cyclic nucleotide-modulated channel 4 (HCN4) channel proteins. Finally, in human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed the enhancement of HCN4 channels by isoproterenol and inhibited 573x, a cyclic adenosine momophosphate-insensitive human HCN4 mutant. These results demonstrated that inhibition of Src kinase activity in heart by PP2 decreased and prevented ?-adrenergic stimulation of cardiac pacemaker activity. These effects are mediated, at least partially, by a cAMP-independent attenuation of channel activity and cell surface expression of HCN4, the main channel protein that controls the heart rate. PMID:24566462

  12. Characterisation of circadian rhythms of various duckweeds.

    PubMed

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

    2015-01-01

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

  13. Circadian Disruption: comparing humans with mice.

    PubMed

    Radetsky, Leora C; Rea, Mark S; Bierman, Andrew; Figueiro, Mariana G

    2013-10-01

    Disruption of the 24-h light-dark cycle has been implicated as an endocrine disruptor and linked to increased morbidity and mortality in animal studies. Previously reported measurements of circadian disruption in day-shift and rotating-shift nurses were compared with new mouse data where the light-dark patterns simulated shiftwork. Phasor magnitudes, a measure of circadian entrainment, were shown to be similar for humans and for mice when exposed to similar patterns of light and dark. Phasor analyses may be a useful method for quantitatively bridging ecological measurements of circadian disruption in human with parametric studies of health outcomes in a mouse model. PMID:23866054

  14. A train of blue light pulses delivered through closed eyelids suppresses melatonin and phase shifts the human circadian system

    PubMed Central

    Figueiro, Mariana G; Bierman, Andrew; Rea, Mark S

    2013-01-01

    A model of circadian phototransduction was published in 2005 to predict the spectral sensitivity of the human circadian system to narrow-band and polychromatic light sources by combining responses to light from the spectral-opponent “blue” versus “yellow” cone bipolar pathway with direct responses to light by the intrinsically photosensitive retinal ganglion cells. In the model, depolarizing “blue” responses, but not hyperpolarizing “yellow” responses, from the “blue” versus “yellow” pathway are combined with the intrinsically photosensitive retinal ganglion cell responses. Intrinsically photosensitive retinal ganglion cell neurons are known to be much slower to respond to light than the cone pathway, so an implication of the model is that periodic flashes of “blue” light, but not “yellow” light, would be effective for stimulating the circadian system. A within-subjects study was designed to test the implications of the model regarding retinal exposures to brief flashes of light. The study was also aimed at broadening the foundation for clinical treatment of circadian sleep disorders by delivering flashing light through closed eyelids while people were asleep. In addition to a dark control night, the eyelids of 16 subjects were exposed to three light-stimulus conditions in the phase delay portion of the phase response curve while they were asleep: (1) 2-second flashes of 111 W/m2 of blue (?max ? 480 nm) light once every minute for 1 hour, (2) 131 W/m2 of green (?max ? 527 nm) light, continuously on for 1 hour, and (3) 2-second flashes of the same green light once every minute for 1 hour. Inferential statistics showed that the blue flash light-stimulus condition significantly delayed circadian phase and significantly suppressed nocturnal melatonin. The results of this study further our basic understanding of circadian phototransduction and broaden the technical foundations for delivering light through closed eyelids during sleep for treating circadian sleep disorders. PMID:24124400

  15. Fibroblast Circadian Rhythms of PER2 Expression Depend on Membrane Potential and Intracellular Calcium

    PubMed Central

    Noguchi, Takako; Wang, Connie W.; Pan, Haiyun

    2012-01-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes circadian rhythms of cells and tissues throughout the body. In SCN neurons, rhythms of clock gene expression are suppressed by manipulations that hyperpolarize the plasma membrane or lower intracellular Ca2+. However, whether clocks in other cells also depend on membrane potential and calcium is unknown. In this study, we investigate the effects of membrane potential and intracellular calcium on circadian rhythms in mouse primary fibroblasts. Rhythms of clock gene expression were monitored using a PER2::LUC knockin reporter. We found that rhythms were lost or delayed at lower (hyperpolarizing) K+ concentrations. Bioluminescence imaging revealed that this loss of rhythmicity in cultures was due to loss of rhythmicity of single cells rather than desynchrony among cells. In lower Ca2+ concentrations, rhythms were advanced or had shorter periods. Buffering intracellular Ca2+ by the calcium chelator 1,2-Bis(2-aminophenoxy) ethane-N,N,N?,N?-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM) or manipulation of IP3-sensitive intracellular calcium stores by thapsigargin delayed rhythms. These results suggest that the circadian clock in fibroblasts, as in SCN neurons, is regulated by membrane potential and Ca2+. Changes in intracellular Ca2+ may mediate the effects of membrane potential that we observed. PMID:22734566

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

    E-print Network

    Silver, Rae

    -1-1, Higashi, Tsukuba, Ibaraki, 305-8562, Japan b Department of Psychology, Columbia University, 1190 Amsterdam 10027, USA d Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia from Charles River (Kingston, NY) were given food and water ad libitum. The animal colony room was kept

  17. [Early and late complications of endocardial pacemaker wires (author's transl)].

    PubMed

    Bücking, J; Voss, H; Stein, J; Hahner, U

    1980-06-01

    Comparison of early and late complications of 769 endocardial pacemaker wires implanted in the period between 1969 and 1973 with 861 wires implanted between 1974 and 1978 revealed a decline of the complication rate from 17% to 7.6%. The dislocation rate could be lowered from 6.2% to 1.6%. Other early complications (exist and entrance block) were not effected (3.5% as compared with 3.2%). Late complications declined from 6.2% to 2.9%. Of these the number of intravascular wire breakages constitutes a high proportion. The main reason for this improvement is the use of a flexible Flange-tip lead. A variation of testing the positional stability of the wire is described.--The indications for pacemaker implantation shifted from 3rd degree AV-Block to the diagnoses "pathological bradycardia" and "hypersensitive carotis sinus". The comparatively low complication rate permits the application of new types of wires only in a few selected patients until a sufficient number of cases and an adequate follow-up period have been reached for clinical evaluation of these wires. PMID:7445644

  18. Pacemaker dynamics in the full Morris-Lecar model

    NASA Astrophysics Data System (ADS)

    González-Miranda, J. M.

    2014-09-01

    This article reports the finding of pacemaker dynamics in certain region of the parameter space of the three-dimensional version of the Morris-Lecar model for the voltage oscillations of a muscle cell. This means that the cell membrane potential displays sustained oscillations in the absence of an external electrical stimulation. The development of this dynamic behavior is shown to be tied to the strength of the leak current contained in the model. The approach followed is mostly based on the use of linear stability analysis and numerical continuation techniques. In this way it is shown that the oscillatory dynamics is associated to the existence of two Hopf bifurcations, one subcritical and other supercritical. Moreover, it is explained that in the region of parameter values most commonly studied for this model such pacemaker dynamics is not displayed because of the development of two fold bifurcations, with the increase of the strength of the leak current, whose interaction with the Hopf bifurcations destroys the oscillatory dynamics.

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

    PubMed Central

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

    2004-01-01

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

  20. Circadian clocks, feeding time, and metabolic homeostasis

    PubMed Central

    Paschos, Georgios K.

    2015-01-01

    Metabolic processes exhibit diurnal variation from cyanobacteria to humans. The circadian clock is thought to have evolved as a time keeping system for the cell to optimize the timing of metabolic events according to physiological needs and environmental conditions. Circadian rhythms temporally separate incompatible cellular processes and optimize cellular and organismal fitness. A modern 24 h lifestyle can run at odds with the circadian rhythm dictated by our molecular clocks and create desynchrony between internal and external timing. It has been suggested that this desynchrony compromises metabolic homeostasis and may promote the development of obesity (Morris et al., 2012). Here we review the evidence supporting the association between circadian misalignment and metabolic homeostasis and discuss the role of feeding time.

  1. Mapping Circadian Output Pathways in Neurospora crassa 

    E-print Network

    Bennett, Lindsay Danielle

    2013-12-09

    . Our lab has focused on identifying output pathways from the clock, using the model organism Neurospora crassa. We have previously demonstrated the circadian regulation of the conserved Mitogen Activated Protein Kinase (MAPK) OS-2 pathway, a homolog...

  2. CIRCADIAN RHYTHMS Marking Time for a Kingdom

    NSDL National Science Digital Library

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

    2000-04-21

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

  3. Functional genomics of the avian circadian system 

    E-print Network

    Bailey, Michael J

    2006-04-12

    The genetic identification of molecular mechanisms responsible for circadian rhythm generation has advanced tremendously over the past 25 years. However the molecular identities of the avian clock remain largely unexplored. ...

  4. Neurobiology of circadian rhythm sleep disorders

    Microsoft Academic Search

    Prasanth Manthena; Phyllis C. Zee

    2006-01-01

    To adapt to a 24-hour environment, nearly all organisms, from mammals to single-celled organisms, have developed endogenous\\u000a mechanisms that generate nearly 24-hour (circadian) rhythms in physiology and behavior, the most notable being that of the\\u000a daily cycles of sleep and wake. Disruption of these circadian rhythms is often accompanied by disorders of sleep and wakefulness.\\u000a With the recent advances in

  5. Melanopsin in the circadian timing system

    Microsoft Academic Search

    Christian Beaulé; Barry Robinson; Elaine Waddington Lamont; Shimon Amir

    2003-01-01

    In mammals, circadian rhythms are generated by a light-entrainable oscillator located in the hypothalamic suprachiasmatic\\u000a nucleus (SCN). Light signals reach the SCN via a dedicated retinal pathway, the retinohypothalamic tract (RHT). One question\\u000a that continues to elude scientists is whether the circadian system has its own dedicated photoreceptor or photoreceptors.\\u000a It is well established that conventional photoreceptors, rods and cones,

  6. Circadian Metabolic Rhythms in Obese Children

    Microsoft Academic Search

    Jehan-François Desjeux; Catherine Gernez-Lestradet; Ingeborg Deschamps; Sylvine Machinot; Frédérique Rolland; Henri Lestradet

    1982-01-01

    Obese children display constant hyperinsulinism and, frequently, hyperphagia. In animals, lesions of the hypothalamic system affect simultaneously the circadian rhythm of insulin secretion and of food intake. In this study, circadian metabolic rhythm was examined in obese and non-obese children, by two different protocols. (1) Oral glucose tolerance tests (OGTT) were carried out at 9 a.m. and 3 p.m. on

  7. Circadian rhythms of crawling and swimming in the nudibranch mollusc Melibe leonina.

    PubMed

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

    2014-12-01

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

  8. Personalized medicine for pathological circadian dysfunctions

    PubMed Central

    Skelton, Rachel L.; Kornhauser, Jon M.; Tate, Barbara A.

    2015-01-01

    The recent approval of a therapeutic for a circadian disorder has increased interest in developing additional medicines for disorders characterized by circadian disruption. However, previous experience demonstrates that drug development for central nervous system (CNS) disorders has a high failure rate. Personalized medicine, or the approach to identifying the right treatment for the right patient, has recently become the standard for drug development in the oncology field. In addition to utilizing Companion Diagnostics (CDx) that identify specific genetic biomarkers to prescribe certain targeted therapies, patient profiling is regularly used to enrich for a responsive patient population during clinical trials, resulting in fewer patients required for statistical significance and a higher rate of success for demonstrating efficacy and hence receiving approval for the drug. This personalized medicine approach may be one mechanism that could reduce the high clinical trial failure rate in the development of CNS drugs. This review will discuss current circadian trials, the history of personalized medicine in oncology, lessons learned from a recently approved circadian therapeutic, and how personalized medicine can be tailored for use in future clinical trials for circadian disorders to ultimately lead to the approval of more therapeutics for patients suffering from circadian abnormalities. PMID:26150790

  9. Sleep and circadian rhythm disruption in schizophrenia†

    PubMed Central

    Wulff, Katharina; Dijk, Derk-Jan; Middleton, Benita; Foster, Russell G.; Joyce, Eileen M.

    2012-01-01

    Background Sleep disturbances comparable with insomnia occur in up to 80% of people with schizophrenia, but very little is known about the contribution of circadian coordination to these prevalent disruptions. Aims A systematic exploration of circadian time patterns in individuals with schizophrenia with recurrent sleep disruption. Method We examined the relationship between sleep-wake activity, recorded actigraphically over 6 weeks, along with ambient light exposure and simultaneous circadian clock timing, by collecting weekly 48 h profiles of a urinary metabolite of melatonin in 20 out-patients with schizophrenia and 21 healthy control individuals matched for age, gender and being unemployed. Results Significant sleep/circadian disruption occurred in all the participants with schizophrenia. Half these individuals showed severe circadian misalignment ranging from phase-advance/delay to non-24 h periods in sleep-wake and melatonin cycles, and the other half showed patterns from excessive sleep to highly irregular and fragmented sleep epochs but with normally timed melatonin production. Conclusions Severe circadian sleep/wake disruptions exist despite stability in mood, mental state and newer antipsychotic treatment. They cannot be explained by the individuals' level of everyday function. PMID:22194182

  10. A computational study of the interdependencies between neuronal impulse pattern, noise effects and synchronization.

    PubMed

    Postnova, Svetlana; Finke, Christian; Jin, Wuyin; Schneider, Horst; Braun, Hans A

    2010-01-01

    Alterations of individual neurons dynamics and associated changes of the activity pattern, especially the transition from tonic firing (single-spikes) to bursts discharges (impulse groups), play an important role for neuronal information processing and synchronization in many physiological processes (sensory encoding, information binding, hormone release, sleep-wake cycles) as well as in disease (Parkinson, epilepsy). We have used Hodgkin-Huxley-type model neurons with subthreshold oscillations to examine the impact of noise on neuronal encoding and thereby have seen significant differences depending on noise implementation as well as on the neuron's dynamic state. The importance of the individual neurons' dynamics is further elucidated by simulation studies with electrotonically coupled model neurons which revealed mutual interdependencies between the alterations of the network's coupling strength and neurons' activity patterns with regard to synchronization. Remarkably, a pacemaker-like activity pattern which revealed to be much more noise sensitive than the bursting patterns also requires much higher coupling strengths for synchronization. This seemingly simple pattern is obviously governed by more complex dynamics than expected from a conventional pacemaker which may explain why neurons more easily synchronize in the bursting than in the tonic firing mode. PMID:19948218

  11. Circadian Changes in Intraocular Pressure

    Microsoft Academic Search

    Amish B. Doshi; John H. K. Liu; Robert N. Weinreb

    \\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a Intraocular pressure (IOP) follows a circadian rhythm\\u000a \\u000a \\u000a • \\u000a \\u000a While the suprachiasmatic nucleus controls these rhythms, an intrinsic oscillator may be present within the eye\\u000a \\u000a \\u000a • \\u000a \\u000a Dysregulation of 24-hour IOP may be responsible for some cases of glaucomatous optic neuropathy\\u000a \\u000a \\u000a • \\u000a \\u000a IOP is highest in the habitual positions during the nocturnal period\\u000a \\u000a \\u000a • \\u000a \\u000a Prostaglandin analogs and carbonic anhydrase inhibitors more

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

    Microsoft Academic Search

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

    1993-01-01

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

  13. The circadian clock controls the expression pattern of the circadian input photoreceptor, phytochrome B

    E-print Network

    Millar, Andrew J.

    and physiological responses are regulated by light throughout the entire life cycle of higher plants. To sense that the abundance of PHYB RNA retains this circadian regulation and use a PHYB::Luc fusion protein to show weak circadian rhythmicity, if any. These data suggest that photoreceptor gene expression patterns may

  14. Regional Difference in Dynamical Property of Sinoatrial Node Pacemaking: Role of Na+ Channel Current

    PubMed Central

    Kurata, Yasutaka; Matsuda, Hiroyuki; Hisatome, Ichiro; Shibamoto, Toshishige

    2008-01-01

    To elucidate the regional differences in sinoatrial node pacemaking mechanisms, we investigated 1), bifurcation structures during current blocks or hyperpolarization of the central and peripheral cells, 2), ionic bases of regional differences in bifurcation structures, and 3), the role of Na+ channel current (INa) in peripheral cell pacemaking. Bifurcation analyses were performed for mathematical models of the rabbit sinoatrial node central and peripheral cells; equilibrium points, periodic orbits, and their stability were determined as functions of parameters. Structural stability against applications of acetylcholine or electrotonic modulations of the atrium was also evaluated. Blocking L-type Ca2+ channel current (ICa,L) stabilized equilibrium points and abolished pacemaking in both the center and periphery. Critical acetylcholine concentration and gap junction conductance for pacemaker cessation were higher in the periphery than in the center, being dramatically reduced by blocking INa. Under hyperpolarized conditions, blocking INa, but not eliminating ICa,L, abolished peripheral cell pacemaking. These results suggest that 1), ICa,L is responsible for basal pacemaking in both the central and peripheral cells, 2), the peripheral cell is more robust in withstanding hyperpolarizing loads than the central cell, 3), INa improves the structural stability to hyperpolarizing loads, and 4), INa-dependent pacemaking is possible in hyperpolarized peripheral cells. PMID:18390617

  15. The behavior of dual-chamber pacemakers exposed to a conducted low-frequency disruptive signal.

    PubMed

    Babouri, A; Hedjiedj, A; Guendouz, L; Andretzko, J P

    2006-08-01

    This paper presents a study of the behavior of dual-chamber cardiac pacemakers submitted to low-frequency conducted disruptions. The disruptive signal is sinusoidal, operating at 50 Hz, 60 Hz, 10 kHz and 25 kHz. The behavior of the pacemakers is described by statistical data obtained with a telemetry system and by visualization of the pacemaker signal during the application of the interfering signal. The pacemakers were tested in two configurations. The first one consists of direct application of the interfering signal between the pacemaker terminals. In the second, these attempts are completed by in vitro tests using an electromagnetic model which allow us to take into account the interface which constitutes the human body. The pacemaker under test is inserted into a gelatine phantom mimicking the electrical conductivity of tissues. This study allowed us to define the pacemaker detection thresholds for the two test configurations. For the in vitro approach, which constitutes a complementary approach to a realistic implantation situation, oversensing is noticed for 10 kHz and 25 kHz interfering signal frequencies. Detection thresholds vary from a few tens to a few hundreds of mV, depending on the interfering signal frequency, the device and its programmed detection sensitivities. PMID:16772671

  16. Guinea Pig Kisspeptin Neurons Are Depolarized by Leptin via Activation of TRPC Channels

    PubMed Central

    Qiu, Jian; Fang, Yuan; Bosch, Martha A.

    2011-01-01

    Hypothalamic kisspeptin neurons are critical for driving reproductive function, but virtually nothing is known about their endogenous electrophysiological properties and the effects of leptin on their excitability. Therefore, we used the slice preparation from female guinea pigs to study the endogenous conductances and the effects of leptin on kisspeptin neurons. We targeted the arcuate kisspeptin neurons using visualized-patch whole-cell recording and identified kisspeptin neurons using immuocytochemical staining for kisspeptin or single cell RT-PCR. We also harvested dispersed arcuate neurons for analysis of expression of channel transcripts. Kisspeptin neurons exhibited a relatively negative resting membrane potential, and eighty percent of the neurons expressed a pacemaker current (h-current) and a T-type Ca2+ current. Furthermore, the glutamate receptor agonist N-methyl D-aspartic acid depolarized and induced burst firing in kisspeptin neurons. Leptin activated an inward current that depolarized kisspeptin neurons and increased (burst) firing, but leptin hyperpolarized NPY neurons. Lanthanum, a TRPC-4,-5 channel activator, potentiated the leptin-induced inward current by 170%. The leptin-activated current reversed near ?15 mV and was abrogated by the relatively selective TRPC channel blocker 2-APB. The leptin effects were also blocked by a Janus kinase inhibitor, a phosphatidylinositol 3 kinase inhibitor, and a phospholipase C? inhibitor. In addition, the majority of these neurons expressed TRPC1 and -5 and phospholipase C?1 based on single cell RT-PCR. Therefore, guinea pig kisspeptin neurons express endogenous pacemaker currents, and leptin excites these neurons via activation of TRPC channels. The leptin excitatory effects on kisspeptin neurons may be critical for governing the excitatory drive to GnRH neurons during different nutritional states. PMID:21285322

  17. Circadian Rhythms in Anesthesia and Critical Care Medicine: Potential importance of circadian disruptions

    PubMed Central

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

    2015-01-01

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

  18. PDF and cAMP enhance PER stability in Drosophila clock neurons.

    PubMed

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

    2014-04-01

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

  19. Barley Hv CIRCADIAN CLOCK ASSOCIATED 1 and Hv PHOTOPERIOD H1 Are Circadian Regulators That Can Affect Circadian Rhythms in Arabidopsis

    PubMed Central

    Martí, María C.; Laurie, David A.; Greenland, Andy J.; Hall, Anthony; Webb, Alex A. R.

    2015-01-01

    Circadian clocks regulate many aspects of plant physiology and development that contribute to essential agronomic traits. Circadian clocks contain transcriptional feedback loops that are thought to generate circadian timing. There is considerable similarity in the genes that comprise the transcriptional and translational feedback loops of the circadian clock in the plant Kingdom. Functional characterisation of circadian clock genes has been restricted to a few model species. Here we provide a functional characterisation of the Hordeum vulgare (barley) circadian clock genes Hv CIRCADIAN CLOCK ASSOCIATED 1 (HvCCA1) and Hv PHOTOPERIODH1, which are respectively most similar to Arabidopsis thaliana CIRCADIAN CLOCK ASSOCIATED 1 (AtCCA1) and PSEUDO RESPONSE REGULATOR 7 (AtPRR7). This provides insight into the circadian regulation of one of the major crop species of Northern Europe. Through a combination of physiological assays of circadian rhythms in barley and heterologous expression in wild type and mutant strains of A. thaliana we demonstrate that HvCCA1 has a conserved function to AtCCA1. We find that Hv PHOTOPERIOD H1 has AtPRR7-like functionality in A. thaliana and that the effects of the Hv photoperiod h1 mutation on photoperiodism and circadian rhythms are genetically separable. PMID:26076005

  20. Clinical utility of a magnetic resonance-conditional pacemaker in a patient with cardiac sarcoidosis.

    PubMed

    Ishibashi, Kazuya; Takeda, Mitsuo; Yamahara, Yasuhiro

    2013-01-01

    We herein present a case of cardiac sarcoidosis with atrioventricular (AV) block that was evaluated using magnetic resonance imaging (MRI) before and after pacemaker implantation. An echocardiogram showed wall thinning in the basal septum. MRI showed late gadolinium enhancement in the interventricular septum and right ventricle. Fluorine-18-fluorodeoxyglucose positron emission tomography (PET) demonstrated abnormal uptake in the same area. An MR-conditional pacemaker was implanted to treat AV block. Steroid treatment resulted in the remission of the cardiac lesions and AV block, as confirmed by PET and MRI. MR-conditional pacemakers are thus considered to have great advantages in treating cardiac sarcoidosis with AV block. PMID:23774544

  1. In vitro investigation of eddy current effect on pacemaker operation generated by low frequency magnetic field.

    PubMed

    Babouri, A; Hedjeidj, A

    2007-01-01

    This paper presents in vitro investigation of the eddy current induction effects to the cardiac pacemaker exposed to low frequency magnetic fields. The method used in this study is based to the interaction by inductive coupling through the loop formed by the pacemaker and its leads and the surrounding medium. This interaction results in an induced electromotive force between the terminals of the pacemaker which can potentially disturb the operation of this last. In this article we present experimental results, analytical calculations and numerical simulations using the finite element method. PMID:18003302

  2. The use of fluorescent proteins to analyze circadian rhythms.

    PubMed

    Shor, Ekaterina; Hassidim, Miriam; Green, Rachel M

    2014-01-01

    Compared with luciferase which is widely used as a reporter for circadian rhythms in Arabidopsis thaliana, available fluorescent markers are generally too stable to allow circadian oscillations to be measured. However, we have developed a technique to use the nuclear localization of circadian-controlled transcription factors fused to a fluorescent reporter as a means of measuring circadian rhythms. This technique has the advantage of being suitable for analyzing rhythms at the level of individual cells and in living plants. PMID:24792054

  3. Circadian disruption in experimental cancer processes.

    PubMed

    Filipski, Elisabeth; Lévi, Francis

    2009-12-01

    The circadian timing system (CTS) coordinated by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of behavior, physiology, as well as cellular metabolism and proliferation. Altered circadian rhythms predict for poor survival in cancer patients. An increased incidence of several cancers has been reported in flight attendants and in shift workers. To explore the contribution of the CTS to tumor growth, we developed experimental models of disrupted or enhanced circadian coordination through stereotaxic destruction of the SCN, modifications of photoperiodic or feeding synchronizers and/or the administration of pharmacologic agents. SCN ablation or exposure to experimental chronic jetlag (CJL, consisting of an 8-hour advance of the light-dark cycle every 2 days) caused alterations in circadian physiology and significantly accelerated tumor growth. CJL suppressed or altered the rhythms of clock gene and cell cycle gene expression in mouse liver. It increased p53 and decreased c-Myc expression, a result in line with the promotion of diethylnitrosamine -initiated hepatocarcinogenesis in jet-lagged mice. The accelerating effect of CJL on tumor growth was counterbalanced by the regular timing of food access over the 24-h. Meal timing prevented the circadian disruption produced by CJL and slowed down tumor growth. In synchronized mice, meal timing reinforced host circadian coordination, phase-shifted the transcriptional rhythms of clock genes in the liver of tumor-bearing mice and slowed down cancer progression. These results support the role of the CTS in cancer progression and call for the development of therapeutic strategies aimed at preventing or treating circadian clock dysfunctions. PMID:20042408

  4. Deactivation of Pacemakers and Implantable Cardioverter-Defibrillators

    PubMed Central

    Kramer, Daniel B.; Mitchell, Susan L.; Brock, Dan W.

    2013-01-01

    Cardiac implantable electrical devices (CIEDs), including pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs), are the most effective treatment for life-threatening arrhythmias. Patients or their surrogates may request device deactivation to avoid prolongation of the dying process or in other settings, such as after device-related complications or with changes in their health care goals. Despite published guidelines outlining theoretical and practical aspects of this common clinical scenario, significant uncertainty remains for both patients and health care providers regarding the ethical and legal status of CIED deactivation. This review outlines the ethical and legal principles supporting CIED deactivation at patients’ request, centered upon patient autonomy and authority over their own medical treatment. The empirical literature describing stakeholder views and experiences surrounding CIED deactivation is described, along with lessons for future research and practice guidance surrounding the care of patients with CIEDs. PMID:23217433

  5. Ventricular pacing on the prognosis of patients with pacemaker implantation.

    PubMed

    Zheng, Liuying; Du, Xinping

    2014-06-01

    Excessive right ventricular apex pacing has significant adverse effects on the cardiac function and hence, it is necessary to clinically optimize pacing parameters and advocate suitable physiological pacing to safeguard the cardiac function after pacemaker implant. Minimizing ventricular pacing is an atrioventricular node priority function, to encourage ventricular self conduction and to reduce unnecessary right ventricular pacing. Minimized ventricular pacing reduces ventricular pacing by encouraging self atrioventricular conduction function and extending the AV interval. This study is a prospective cohort study to evaluate the changes of cardiac function in patients and serum amino-terminal natriuretic peptide (NT-proBNP) before and after pacing, and the risk of atrial fibrillation with different CUM% VP. The study has shown that the cardiac function will deteriorate with an increase in pacing rate. PMID:24242189

  6. 2014 ANNUAL REPORT CENTER FOR SLEEP & CIRCADIAN NEUROBIOLOGY

    E-print Network

    Bushman, Frederic

    2014 ANNUAL REPORT CENTER FOR SLEEP & CIRCADIAN NEUROBIOLOGY #12;#12;TABLE OF CONTENTS Message from 56 Publications 64 Annual Report 2014 #12;Center for Sleep and Circadian Neurobiology2 Center for Sleep and Circadian Neurobiology2 Message from the Director ALLAN I. PACK, MBChB, PhD Our Center

  7. Edinburgh Research Explorer Stochastic properties of the plant circadian clock

    E-print Network

    Millar, Andrew J.

    of molecular noise in single cells on the behaviour of the circadian clock in the plant model speciesEdinburgh Research Explorer Stochastic properties of the plant circadian clock Citation, 'Stochastic properties of the plant circadian clock' Journal of the Royal Society Interface., 10.1098/rsif

  8. A novel animal model linking adiposity to altered circadian rhythms

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  9. Clockwork green—the circadian oscillator in Arabidopsis

    Microsoft Academic Search

    Jan C. Schöning; Corinna Streitner; Dorothee Staiger

    2006-01-01

    Although rhythmic leaf movement in a higher plant was the first physiological process recognised to be under circadian control, our understanding of the molecular drives underlying circadian rhythms in plants is still limited. Genetic screens for mutants impaired with regard to circadian rhythmicity have identified components critical for clock function in the model plant Arabidopsis thaliana, providing a snapshot of

  10. Prospective influences of circadian clocks in adipose tissue and metabolism

    Microsoft Academic Search

    Gregory M. Sutton; Bruce A. Bunnell; Andrey A. Ptitsyn; Z. Elizabeth Floyd; Jeffrey M. Gimble

    2010-01-01

    Circadian rhythms make a critical contribution to endocrine functions that involve adipose tissue. These contributions are made at the systemic, organ and stem cell levels. The transcription factors and enzymes responsible for the maintenance of circadian rhythms in adipose depots and other peripheral tissues that are metabolically active have now been identified. Furthermore, the circadian regulation of glucose and lipid

  11. Computational Reconstruction of Pacemaking and Intrinsic Electroresponsiveness in Cerebellar Golgi Cells

    PubMed Central

    Solinas, Sergio; Forti, Lia; Cesana, Elisabetta; Mapelli, Jonathan; De Schutter, Erik; D'Angelo, Egidio

    2007-01-01

    The Golgi cells have been recently shown to beat regularly in vitro (Forti et al., 2006. J. Physiol. 574, 711–729). Four main currents were shown to be involved, namely a persistent sodium current (I Na-p), an h current (I h), an SK-type calcium-dependent potassium current (I K-AHP), and a slow M-like potassium current (I K-slow). These ionic currents could take part, together with others, also to different aspects of neuronal excitability like responses to depolarizing and hyperpolarizing current injection. However, the ionic mechanisms and their interactions remained largely hypothetical. In this work, we have investigated the mechanisms of Golgi cell excitability by developing a computational model. The model predicts that pacemaking is sustained by subthreshold oscillations tightly coupled to spikes. I Na-p and I K-slow emerged as the critical determinants of oscillations. I h also played a role by setting the oscillatory mechanism into the appropriate membrane potential range. I K-AHP, though taking part to the oscillation, appeared primarily involved in regulating the ISI following spikes. The combination with other currents, in particular a resurgent sodium current (I Na-r) and an A-current (I K-A), allowed a precise regulation of response frequency and delay. These results provide a coherent reconstruction of the ionic mechanisms determining Golgi cell intrinsic electroresponsiveness and suggests important implications for cerebellar signal processing, which will be fully developed in a companion paper (Solinas et al., 2008. Front. Neurosci. 2:4). PMID:18946520

  12. [Preoperative prophylactic pacemakers: apropos of their indication in a disputed case].

    PubMed

    Fuentes Rodríguez, R; Sebastianes Marfil, M C; Mato Ponce, M; Morales Guerrero, J; Torres Morera, L M

    2001-01-01

    The criteria for preoperative use of pacemakers are not unanimously agreed upon. Certain cases require careful assessment to weigh potential benefits against inherent risks in placing the device. Although external transcutaneous pacemakers, whose use circumvents the risks of transvenous insertion, have been available for years, such devices are not always appropriate, depending on the flow disorder involved or the type of surgery that will be performed. We report the case of a 75-year-old woman who was a candidate for surgery requiring general anesthesia (lumboperitoneal shunt due to chronic adult hydrocephaly). Although her condition did not initially call for prophylactic use of a pacemaker before surgery, changes soon developed that necessitated insertion of a temporary transvenous device for surgery and insertion of a permanent pacemaker the day after surgery. PMID:11234605

  13. Torsade de pointes in a patient with complete atrioventricular block and pacemaker failure, misdiagnosed with epilepsy.

    PubMed

    Cai, Si-Yu; Ye, Shen-Feng; Wu, Xiang; Xiang, Mei-Xiang; Wang, Jian-An

    2015-01-01

    A case of torsade de pointes (TdP) with complete atrioventricular block and pacemaker failure that was misdiagnosed as epilepsy is presented herein. An 82-year-old female with recurrent seizure-like attacks showed epileptiform discharge during an electroencephalogram recording. A long QT interval and severe hypokalemia induced runs of TdP, which was related to pacemaker lead fracture, was detected during Holter recording and accompanied with episodes of seizures. After a DDD pacemaker with a new ventricular lead was replaced, there was no recurrence of any seizure-like attacks. Bradycardia-mediated TdP associated with complete atrioventricular block should not be missed in patients with recurrent seizure-like attacks even after pacemaker implantation. PMID:25771702

  14. Safety precautions in the management of patients with pacemakers when electrocautery operations are performed.

    PubMed

    Erdman, S; Levinsky, L; Servadio, C; Stoupel, E; Levy, M J

    1988-10-01

    The hazards related to ten patients who underwent 11 urologic surgical procedures during a 36 month period were taken into consideration. Electrocautery was used in all instances and there were no complications. All of the pacemakers were preset for ventricular pacing and sensing inhibited or multiprogrammable and were reprogrammed during the operation to ventricular pacing fixed rate mode or magnet mode, with very satisfactory outcome. To avoid life-threatening situations arising from pacemaker inhibition or ventricular fibrillation during cautery for transuretheral resection, three basic factors were considered: 1, appropriate type of pacemaker; 2, the proper grounding of all medical electronic equipment used during the procedure, and 3, the directing of the complete flow of the electrocautery circuits substantially below the level of the pacemaker unit. PMID:2458629

  15. [Circadian rhythm of the renin-angiotensin-aldosterone system: a summary of our research studies].

    PubMed

    Cugini, P; Lucia, P

    2004-01-01

    The renin-angiotensin-aldosterone system (RAAS) is characterized by a circadian rhythm (CR) whose acrophase is detectable early in the morning. The prorenin and angiotensin converting enzyme (ACE) show a CR as well. However, while the prorenin is in phase with the RAAS the ACE shows its circadian acrophase in the afternoon suggesting a negative feed-back. The RAAS CR is influenced by many factors. Its mesor is modified by sodium intake. The physical activity and rest affect both the mesor and acrophase. The variations in mesor amplitude and acrophase in aged subjects are conditioned by sex and physical activity. Moreover, the RAAS CR seems to be influenced by the race. In addition, it is abolished by the beta-adrenergic blockade, suggesting the existence of an adrenergic clock. Interestingly, the RAAS CR seems not to be a pacemaker for the blood pressure CR, whose acrophase is early in the afternoon. The RAAS CR is not substantially modified has in essential hypertension. However, the CR of plasma renin activity is disappeared in the low-renin essential hypertension, while the CR of plasma aldosterone is detectable. On the contrary, the aldosterone CR is not detectable in ascitic liver cirrhosis; but, it is restored when the ascites is removed by peritoneal-jugular shunt. No significant variation of the RAAS CR seems to occur in obesity and Cushing's syndrome. The RAAS CR has disappeared in Conn's disease as well as in Bartter's syndrome and Liddle's syndrome. The administration of indomethacine in Bartter's syndrome and of triamterene in Liddle's syndrome is able to restore the RAAS CR. Finally, the RAAS CR is not detectable in the heart or kidney transplanted patients; such a phenomenon could be attributed to cyclosporine and corticosteroids administration and to the denervation of the transplanted organs. PMID:15553256

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

    PubMed

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

    2012-03-01

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

  17. miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock.

    PubMed

    Alvarez-Saavedra, Matías; Antoun, Ghadi; Yanagiya, Akiko; Oliva-Hernandez, Reynaldo; Cornejo-Palma, Daniel; Perez-Iratxeta, Carolina; Sonenberg, Nahum; Cheng, Hai-Ying M

    2011-02-15

    Mammalian circadian rhythms are synchronized to the external time by daily resetting of the suprachiasmatic nucleus (SCN) in response to light. As the master circadian pacemaker, the SCN coordinates the timing of diverse cellular oscillators in multiple tissues. Aberrant regulation of clock timing is linked to numerous human conditions, including cancer, cardiovascular disease, obesity, various neurological disorders and the hereditary disorder familial advanced sleep phase syndrome. Additionally, mechanisms that underlie clock resetting factor into the sleep and physiological disturbances experienced by night-shift workers and travelers with jet lag. The Ca(2+)/cAMP response element-binding protein-regulated microRNA, miR-132, is induced by light within the SCN and attenuates its capacity to reset, or entrain, the clock. However, the specific targets that are regulated by miR-132 and underlie its effects on clock entrainment remained elusive until now. Here, we show that genes involved in chromatin remodeling (Mecp2, Ep300, Jarid1a) and translational control (Btg2, Paip2a) are direct targets of miR-132 in the mouse SCN. Coordinated regulation of these targets underlies miR-132-dependent modulation of Period gene expression and clock entrainment: the mPer1 and mPer2 promoters are bound to and transcriptionally activated by MeCP2, whereas PAIP2A and BTG2 suppress the translation of the PERIOD proteins by enhancing mRNA decay. We propose that miR-132 is selectively enriched for chromatin- and translation-associated target genes and is an orchestrator of chromatin remodeling and protein translation within the SCN clock, thereby fine-tuning clock entrainment. These findings will further our understanding of mechanisms governing clock entrainment and its involvement in human diseases. PMID:21118894

  18. A model of cardiac tissue as a conductive system with interacting pacemakers and refractory time

    E-print Network

    Alexander Loskutov; Sergei Rybalko; Ekaterina Zhuchkova

    2002-12-10

    A model of the heart tissue as a conductive system with two interacting pacemakers and a refractory time, is proposed. In the parametric space of the model the phase locking areas are investigated in detail. Obtained results allow us to predict the behaviour of excitable systems with two pacemakers depending on the type and intensity of their interaction and the initial phase. Comparison of the described phenomena with intrinsic pathologies of cardiac rhythms is presented.

  19. A Fully Implantable Pacemaker for the Mouse: From Battery to Wireless Power

    PubMed Central

    Zellmer, Erik R.; Weinheimer, Carla J.; MacEwan, Matthew R.; Cui, Sophia X.; Nerbonne, Jeanne M.; Efimov, Igor R.

    2013-01-01

    Animal models have become a popular platform for the investigation of the molecular and systemic mechanisms of pathological cardiovascular physiology. Chronic pacing studies with implantable pacemakers in large animals have led to useful models of heart failure and atrial fibrillation. Unfortunately, molecular and genetic studies in these large animal models are often prohibitively expensive or not available. Conversely, the mouse is an excellent species for studying molecular mechanisms of cardiovascular disease through genetic engineering. However, the large size of available pacemakers does not lend itself to chronic pacing in mice. Here, we present the design for a novel, fully implantable wireless-powered pacemaker for mice capable of long-term (>30 days) pacing. This design is compared to a traditional battery-powered pacemaker to demonstrate critical advantages achieved through wireless inductive power transfer and control. Battery-powered and wireless-powered pacemakers were fabricated from standard electronic components in our laboratory. Mice (n?=?24) were implanted with endocardial, battery-powered devices (n?=?14) and epicardial, wireless-powered devices (n?=?10). Wireless-powered devices were associated with reduced implant mortality and more reliable device function compared to battery-powered devices. Eight of 14 (57.1%) mice implanted with battery-powered pacemakers died following device implantation compared to 1 of 10 (10%) mice implanted with wireless-powered pacemakers. Moreover, device function was achieved for 30 days with the wireless-powered device compared to 6 days with the battery-powered device. The wireless-powered pacemaker system presented herein will allow electrophysiology studies in numerous genetically engineered mouse models as well as rapid pacing-induced heart failure and atrial arrhythmia in mice. PMID:24194832

  20. Initial Experience of Implanted Pacemakers with Intracardiac Haemodynamic Sensor: Evaluation of Sensor Safety

    Microsoft Academic Search

    N. Galizio; J. Gonzalez; R. Chirife; H. Fraguas; J. Barra; S. Graf; E. Forteza; F. Gregorio

    In the present animal model study, TVI sensor operation did not interfere with conventional pacemaker functions of implanted\\u000a Sophós pacemakers. These results look promising since this sensor could play an important part in haemodynamic monitoring:\\u000a for physiological rate adaptation, for beat-tobeat capture confirmation, in patients with neurocardiogenic syncope, for the\\u000a follow-up of patients with heart failure, to indicate the best

  1. The oral cavity is not a primary source for implantable pacemaker or cardioverter defibrillator infections

    PubMed Central

    2013-01-01

    Background To test the hypothesis that the oral cavity is a potential source for implantable pacemaker and cardioverter defibrillators infections, the bacterial diversity on explanted rhythm heart management devices was investigated and compared to the oral microbiome. Methods A metagenomic approach was used to analyze the bacterial diversity on the surfaces of non-infected and infected pacemakers. The DNA from surfaces swaps of 24 non-infected and 23 infected pacemaker were isolated and subjected to bacterial-specific DNA amplification, single strand conformation polymorphism- (SSCP) and sequencing analysis. Species-specific primer sets were used to analyze for any correlation between bacterial diversity on pacemakers and in the oral cavity. Results DNA of bacterial origin was detected in 21 cases on infected pacemakers and assigned to the bacterial phylotypes Staphylococcus epidermidis, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus schleiferi and Stapyhlococcus. In 17 cases bacterial DNA was found on pacemakers with no clinical signs of infections. On the basis of the obtained sequence data, the phylotypes Propionibacterium acnes, Staphylococcus and an uncultured bacterium were identified. Propionibacterium acnes and Staphylococcus epidermidis were the only bacteria detected in pacemeaker (n?=?25) and oral samples (n?=?11). Conclusions The frequency of the coincidental detection of bacteria on infected devices and in the oral cavity is low and the detected bacteria are highly abundant colonizers of non-oral human niches. The transmission of oral bacteria to the lead or device of implantable pacemaker or cardioverter defibrillators is unlikely relevant for the pathogenesis of pacemaker or cardioverter defibrillators infections. PMID:23575037

  2. [Right heart failure resulting from pacemaker lead-induced tricuspid valve regurgitation].

    PubMed

    Schroeter, T; Strotdrees, E; Doll, N; Mohr, F W

    2011-06-01

    Pacemaker lead-induced tricuspid valve regurgitation is a severe and often underdiagnosed complication due to the widely variable time interval between implantation and the development of severe tricuspid valve insufficiency with ensuing right heart failure. Complete explantation of inactive pacemaker leads is necessary to avoid permanent damage to right heart structures. If performed in a timely fashion, regression of tricuspid insufficiency can be achieved without additional cardiac procedures. PMID:21547560

  3. Simplified Interpretation of the Pacemaker Potential as a Tool For Teaching Membrane Potentials

    NSDL National Science Digital Library

    Sven Kurbel (Osijek Medical Faculty Department of Physiology)

    2003-09-01

    Most courses of physiology start by teaching about membrane potentials in different cells. Many of our students find these ideas difficult to understand. Often they try to memorize facts rather than understand mechanisms. The most difficult task may be interpretation of the pacemaker potential generation in sinoatrial (SA) cells. This illumination attempts to improve studentsÂ? understanding of membrane potentials by giving them a simplified interpretation of pacemaker potential generation before they have group discussions.

  4. Identification of the location of the colonic pacemakers: a histologic study.

    PubMed

    Shafik, Ahmed; El-Sibai, Olfat; Shafik, Ismail A; Shafik, Ali A

    2005-01-01

    A recent electrophysiologic study has suggested the existence of 4 pacemakers in the colon which generate the electric waves that are responsible for the colonic motor activity. These pacemakers are located at the cecal pole, the cecocolonic junction, the mid third of the transverse colon and at the colosigmoid junction. We investigated the hypothesis that these pacemaker sites contain ICCs in great numbers and that the electric waves generated from these sites are transmitted by a chain of ICCs to the remaining colon. Specimens were taken from the 4 electrophysiologically defined pacemaker sites and the remaining colon of 24 cadavers. They were subjected to c-kit immunohistochemistry tests. Controls for antisera specificity consisted of tissue incubation with normal rabbit serum substituted for the primary antiserum. The morphometric study was performed by submitting the immunohistochemically-stained sections to image analysis in order to determine the area percent of immuno-reactivity in comparison to the total area of fields examined in the sections. Data obtained from the image analyzer were statistically analyzed. Immunohistochemical and morphometric studies have shown that the 4 electrophysiologically defined pacemaker sites contained a significantly higher proportion of ICCs than the remaining colon, the ICCs at these sites being multipolar and forming a network surrounded by a fibrous tissue wall. In the remaining colon, the ICCs were bipolar and arranged in a linear fashion. The study revealed the existence of a network of ICCs at the 4 pacemaker sites forming the 'pacemaker nodes' (PMNs). In the rest of the colon, a chain of ICCs extended in the colonic wall in a linear fashion forming the 'pacemaker bundles' (PMBs). We postulate that the colonic electric waves start at the PMNs and spread in the colon along the PMBs. PMID:15769656

  5. Interference of apex locator, pulp tester and diathermy on pacemaker function

    PubMed Central

    Sriman, Narayanan; Prabhakar, V.; Bhuvaneswaran, J.S.; Subha, N.

    2015-01-01

    Aim: The purpose of this study was to evaluate the effects of three electronic apex locators (EAL), electric pulp tester (EPT) and diathermy on pacemaker function in vitro. Materials and Methods: Three EALs: Root ZX (J. Morita Co., Tustin, CA, U.S.A.), Propex (Dentsply), Mini Apex locator (SybronEndo, Anaheim, CA, USA), EPT (Parkell pulp vitality tester Farmingdale, NY, USA) and Diathermy (Neomed 250 B) were tested for any interference with one pacemaker (A medtronic kappa KVDD901-serial number: PLE734632S). Directly connecting the pacemaker lead with the EAL/EPT/diathermy operating on a flat bench top, the telemetry wand was held directly over the pacemaker to monitor the pacing pattern for a period of 30 s. Pacemaker activity was continuously recorded on the telemetric programmer and electro gram (EGM) readings examined for pacer inhibition, noise reversion or inappropriate pacemaker pulses. Results: All the three apex locators showed no pacing interference or background noise during its function or at rest. The EGM readings of EPT showed varying levels of background noise in between pacing however, this did not affect the normal pacing pattern and the pacing interval remained constant. EGM readings of diathermy showed an increase in the pacing interval (irregular pacing pattern) followed by complete inhibition of the pacing system. Conclusion: The tested EALs do not interfere with cardiac pacemaker function. The tested EPT showed varying levels of background noise but does not interfere with cardiac pacemaker function. Use of Diathermy interfered with the normal pacing, leading to complete inhibition of the pacing system. PMID:25657520

  6. Disseminated Mycobacterium chelonae infection causing pacemaker lead endocarditis in an immunocompetent host.

    PubMed

    Hooda, Amit; Pati, Purinder K; John, Bobby; George, Paul V; Michael, Joy Sarojini

    2014-01-01

    Pacemaker infection with Mycobacterium chelonae has not been reported previously. We report the first case of pacemaker lead endocarditis due to M. chelonae, which was successfully treated with multidrug regimen. M. chelonae is regarded as an environmental bacterium and its pathogenicity has been recognised recently. The present case illustrates its ability as a primary invader should not be underestimated, especially in an immunocompetent patient with indwelling devices. Epidemiology and management of this rare cause of culture-negative endocarditis is discussed. PMID:25535221

  7. Coordination of the maize transcriptome by a conserved circadian clock

    PubMed Central

    2010-01-01

    Background The plant circadian clock orchestrates 24-hour rhythms in internal physiological processes to coordinate these activities with daily and seasonal changes in the environment. The circadian clock has a profound impact on many aspects of plant growth and development, including biomass accumulation and flowering time. Despite recent advances in understanding the circadian system of the model plant Arabidopsis thaliana, the contribution of the circadian oscillator to important agronomic traits in Zea mays and other cereals remains poorly defined. To address this deficit, this study investigated the transcriptional landscape of the maize circadian system. Results Since transcriptional regulation is a fundamental aspect of circadian systems, genes exhibiting circadian expression were identified in the sequenced maize inbred B73. Of the over 13,000 transcripts examined, approximately 10 percent displayed circadian expression patterns. The majority of cycling genes had peak expression at subjective dawn and dusk, similar to other plant circadian systems. The maize circadian clock organized co-regulation of genes participating in fundamental physiological processes, including photosynthesis, carbohydrate metabolism, cell wall biogenesis, and phytohormone biosynthesis pathways. Conclusions Circadian regulation of the maize genome was widespread and key genes in several major metabolic pathways had circadian expression waveforms. The maize circadian clock coordinated transcription to be coincident with oncoming day or night, which was consistent with the circadian oscillator acting to prepare the plant for these major recurring environmental changes. These findings highlighted the multiple processes in maize plants under circadian regulation and, as a result, provided insight into the important contribution this regulatory system makes to agronomic traits in maize and potentially other C4 plant species. PMID:20576144

  8. Analysis of Gene Regulatory Networks in the Mammalian Circadian Rhythm

    PubMed Central

    Yan, Jun; Wang, Haifang; Liu, Yuting; Shao, Chunxuan

    2008-01-01

    Circadian rhythm is fundamental in regulating a wide range of cellular, metabolic, physiological, and behavioral activities in mammals. Although a small number of key circadian genes have been identified through extensive molecular and genetic studies in the past, the existence of other key circadian genes and how they drive the genomewide circadian oscillation of gene expression in different tissues still remains unknown. Here we try to address these questions by integrating all available circadian microarray data in mammals. We identified 41 common circadian genes that showed circadian oscillation in a wide range of mouse tissues with a remarkable consistency of circadian phases across tissues. Comparisons across mouse, rat, rhesus macaque, and human showed that the circadian phases of known key circadian genes were delayed for 4–5 hours in rat compared to mouse and 8–12 hours in macaque and human compared to mouse. A systematic gene regulatory network for the mouse circadian rhythm was constructed after incorporating promoter analysis and transcription factor knockout or mutant microarray data. We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes. The analysis of the network structure revealed the paths through which light, food, and heat can entrain the circadian clock and identified that NR3C1 and FKBP/HSP90 complexes are central to the control of circadian genes through diverse environmental signals. Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm. PMID:18846204

  9. Blockade of the NPY Y5 receptor potentiates circadian responses to light: complementary in vivo and in vitro studies.

    PubMed

    Yannielli, P C; Brewer, J McKinley; Harrington, M E

    2004-02-01

    Neuropeptide Y (NPY) is delivered to the suprachiasmatic nuclei (SCN) circadian pacemaker via an input from the thalamic intergeniculate leaflet. NPY can inhibit light-induced responses of the circadian system of Syrian hamsters. Here we studied whether an antagonist to NPY receptors can be used to potentiate photic phase shifts late in the subjective night. First we determined by in situ hybridization that both NPY Y1 and Y5 receptor mRNA are expressed in the SCN of Syrian hamsters. Second, similar to our previous findings at Zeitgeber time 14 (ZT 14, where ZT 12 was the time of lights off), we found that NPY applied at ZT 18.5 onto the SCN region of brain slices maintained in vitro could block NMDA-induced phase advances of the spontaneous firing rate rhythm, and this blocking effect was probably mediated by the Y5 receptor, since co-application of Y5 receptor antagonists completely reversed the effect of NPY, while application of a Y1 receptor antagonist had no effect under the same conditions. Third, we found that co-treatment with a Y5 receptor antagonist in vivo (s.c., 10 mg/kg) not only reversed the effect of NPY applied to the SCN in vivo through a cannula but also significantly potentiated the light-induced phase advance in the absence of NPY. This is the first report of a NPY receptor antagonist having such an effect, and indicates that NPY Y5 receptor antagonists could be clinically useful for potentiating circadian system responses to light. PMID:15009136

  10. A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

    PubMed Central

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

    2013-01-01

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

  11. Bursting, Pacemaking Neurons and Central Pattern Generators (1) Pinsky-Rinzel rhythmic burster via calcium influx

    E-print Network

    Miller, Paul

    alt.m. [Ca] 15ms 200Hz 100-500ms ICa K(Ca)I IK(Ca) Two-compartment model (soma and dendrite) with ping. Soma fires regularly. Dendrites produce regular Ca-spikes (like Na-spikes but slower). gc current iCa,T to escape inhibition and start firing. Time to switch is determined by recovery time of i

  12. Experimental and theoretical investigation of implantable cardiac pacemaker exposed to low frequency magnetic field.

    PubMed

    Babouri, A; Hedjeidj, A; Guendouz, L

    2009-04-01

    This paper presents in vitro investigation of an implantable cardiac pacemaker exposed to low frequency magnetic fields. The method used in this study is based on the interaction by inductive coupling through the loop formed by the pacemaker and its loads and the surrounding medium. This interaction results in an induced electromotive force between the terminals of the pacemaker, which can potentially disturb its operation. The studied frequencies are 50/60 Hz and 10/25 kHz. The experimental tests were carried out on several cardiac pacemakers, single chamber, and dual chamber. The results show a window effect of the detection circuits of cardiac pacemakers for the four studied frequencies. The modelling of the test bed requires studying the effects of the induced currents generated by the application of a magnetic field. Analytical calculations and Numerical simulations were carried out. We modelled the interactions of the magnetic field with a simplified representation of pacemaker embedded in the medium. The comparison of the results in the air and in vitro enabled us to make an equivalent electric model. The results obtained in experimental and theoretical studies allowed us to validate the test bed. The method applied is valid for other medical implants such as cardiac defibrillators, implant hearing aids system...etc. PMID:19125341

  13. The East Asian Summer Monsoon in pacemaker experiments driven by ENSO

    NASA Astrophysics Data System (ADS)

    Ding, Hui; Greatbatch, Richard J.; Lu, Jian; Cash, Ben

    2015-03-01

    The variability of the East Asian summer monsoon (EASM) is studied using a pacemaker technique driven by ENSO in an atmospheric general circulation model (AGCM) coupled to a slab mixed layer model. In the pacemaker experiments, sea surface temperature (SST) is constrained to observations in the eastern equatorial Pacific through a q- flux that measures the contribution of ocean dynamics to SST variability, while the AGCM is coupled to the slab model. An ensemble of pacemaker experiments is analyzed using a multivariate EOF analysis to identify the two major modes of variability of the EASM. The results show that the pacemaker experiments simulate a substantial amount (around 45 %) of the variability of the first mode (the Pacific-Japan pattern) in ERA40 from 1979 to 1999. Different from previous work, the pacemaker experiments also simulate a large part (25 %) of the variability of the second mode, related to rainfall variability over northern China. Furthermore, we find that the lower (850 hPa) and the upper (200 hPa) tropospheric circulation of the first mode display the same degree of reproducibility whereas only the lower part of the second mode is reproducible. The basis for the success of the pacemaker experiments is the ability of the experiments to reproduce the observed relationship between El Niño Southern Oscillation (ENSO) and the EASM.

  14. Circadian oscillations of cytosolic and chloroplastic free calcium in plants

    NASA Technical Reports Server (NTRS)

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

    1995-01-01

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

  15. Optimal Implementations for Reliable Circadian Clocks

    NASA Astrophysics Data System (ADS)

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-09-01

    Circadian rhythms are acquired through evolution to increase the chances for survival through synchronizing with the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. We find by using a phase model with multiple inputs that achieving the maximal limit of regularity and entrainability entails many inherent features of the circadian mechanism. At the molecular level, we demonstrate the role sharing of two light inputs, phase advance and delay, as is well observed in mammals. At the behavioral level, the optimal phase-response curve inevitably contains a dead zone, a time during which light pulses neither advance nor delay the clock. We reproduce the results of phase-controlling experiments entrained by two types of periodic light pulses. Our results indicate that circadian clocks are designed optimally for reliable clockwork through evolution.

  16. Effect of Light on Human Circadian Physiology

    PubMed Central

    Duffy, Jeanne F.; Czeisler, Charles A.

    2009-01-01

    Synopsis The circadian system in animals and humans, being near but not exactly 24-hours in cycle length, must be reset on a daily basis in order to remain in synchrony with external environmental time. This process of entrainment is achieved in most mammals through regular exposure to light and darkness. In this chapter, we review the results of studies conducted in our laboratory and others over the past 25 years in which the effects of light on the human circadian timing system were investigated. These studies have revealed, how the timing, intensity, duration, and wavelength of light affect the human biological clock. Our most recent studies also demonstrate that there is much yet to learn about the effects of light on the human circadian timing system. PMID:20161220

  17. Studying circadian rhythms in Drosophila melanogaster

    PubMed Central

    Tataroglu, Ozgur; Emery, Patrick

    2014-01-01

    Circadian rhythms have a profound influence on most bodily functions: from metabolism to complex behaviors. They ensure that all these biological processes are optimized with the time-of-day. They are generated by endogenous molecular oscillators that have a period that closely, but not exactly, matches day length. These molecular clocks are synchronized by environmental cycles such as light intensity and temperature. Drosophila melanogaster has been a model organism of choice to understand genetically, molecularly and at the level of neural circuits how circadian rhythms are generated, how they are synchronized by environmental cues, and how they drive behavioral cycles such as locomotor rhythms. This review will cover a wide range of techniques that have been instrumental to our understanding of Drosophila circadian rhythms, and that are essential for current and future research. PMID:24412370

  18. [Molecular oscillatory machinery of circadian rhythms].

    PubMed

    Yamaguchi, Yoshiaki; Okamura, Hitoshi

    2012-07-01

    Many metabolic and physiological processes display daily rhythms oscillated by the internal circadian clock system. This rhythm is generated by interlocked transcription-(post) translation feedback loops of clock genes: the core oscillatory loop, being composed of CLOCK/BMAL1 heterodimer activating the expressions of PER and CRY that directly repress CLOCK/BMAL1, is accompanied by accessory loops consisted with REV-ERB nuclear receptor repressing Bmal1 or with DBP competing with E4BP4 on D-box site. These clock proteins are regulated by phosphorylation and ubiquitination (PER/CRY), and acetylation (CLOCK/BMAL1). Recently, a deacetylating protein SIRT1 mediated metabolic pathway is discovered to be interlocked with core oscillatory loop via Nampt expression, a late-limiting enzyme in NAD+ salvage pathway. Since many key-step enzymes of metabolisms are regulated by the circadian clock, circadian clock system may intimately link to cellular metabolism. PMID:22844791

  19. Structural Insights into a Circadian Oscillator

    NSDL National Science Digital Library

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

    2008-10-31

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

  20. Optimal implementations for reliable circadian clocks.

    PubMed

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-09-01

    Circadian rhythms are acquired through evolution to increase the chances for survival through synchronizing with the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. We find by using a phase model with multiple inputs that achieving the maximal limit of regularity and entrainability entails many inherent features of the circadian mechanism. At the molecular level, we demonstrate the role sharing of two light inputs, phase advance and delay, as is well observed in mammals. At the behavioral level, the optimal phase-response curve inevitably contains a dead zone, a time during which light pulses neither advance nor delay the clock. We reproduce the results of phase-controlling experiments entrained by two types of periodic light pulses. Our results indicate that circadian clocks are designed optimally for reliable clockwork through evolution. PMID:25238386

  1. Circadian clock: linking epigenetics to aging.

    PubMed

    Orozco-Solis, Ricardo; Sassone-Corsi, Paolo

    2014-06-01

    Circadian rhythms are generated by an intrinsic cellular mechanism that controls a large array of physiological and metabolic processes. There is erosion in the robustness of circadian rhythms during aging, and disruption of the clock by genetic ablation of specific genes is associated with aging-related features. Importantly, environmental conditions are thought to modulate the aging process. For example, caloric restriction is a very strong environmental effector capable of delaying aging. Intracellular pathways implicating nutrient sensors, such as SIRTs and mTOR complexes, impinge on cellular and epigenetic mechanisms that control the aging process. Strikingly, accumulating evidences indicate that these pathways are involved in both the modulation of the aging process and the control of the clock. Hence, innovative therapeutic strategies focused at controlling the circadian clock and the nutrient sensing pathways might beneficially influence the negative effects of aging. PMID:25033025

  2. Molecular components of the mammalian circadian clock

    PubMed Central

    Buhr, Ethan D.; Takahashi, Joseph S.

    2013-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  4. Transcription factors involved in retinogenesis are co-opted by the circadian clock following photoreceptor differentiation

    PubMed Central

    Laranjeiro, Ricardo; Whitmore, David

    2014-01-01

    The circadian clock is known to regulate a wide range of physiological and cellular processes, yet remarkably little is known about its role during embryo development. Zebrafish offer a unique opportunity to explore this issue, not only because a great deal is known about key developmental events in this species, but also because the clock starts on the very first day of development. In this study, we identified numerous rhythmic genes in zebrafish larvae, including the key transcriptional regulators neurod and cdx1b, which are involved in neuronal and intestinal differentiation, respectively. Rhythmic expression of neurod and several additional transcription factors was only observed in the developing retina. Surprisingly, these rhythms in expression commenced at a stage of development after these transcription factors are known to have played their essential role in photoreceptor differentiation. Furthermore, this circadian regulation was maintained in adult retina. Thus, once mature photoreceptors are formed, multiple retinal transcription factors fall under circadian clock control, at which point they appear to play a new and important role in regulating rhythmic elements in the phototransduction pathway. PMID:24924194

  5. Circadian clock components in the rat neocortex: daily dynamics, localization and regulation.

    PubMed

    Rath, Martin F; Rohde, Kristian; Fahrenkrug, Jan; Møller, Morten

    2013-03-01

    The circadian master clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the clock of the SCN is driven by a transcriptional/posttranslational autoregulatory network with clock gene products as core elements. Recent investigations have shown the presence of peripheral clocks in extra-hypothalamic areas of the central nervous system. However, knowledge on the clock gene network in the cerebral cortex is limited. We here show that the mammalian clock genes Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Nr1d1 and Dbp are expressed in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene expression in the neocortex is dependent on the SCN. In situ hybridization and immunohistochemistry showed that products of the canonical clock gene Per2 are located in perikarya throughout all areas of the neocortex. These findings show that local circadian oscillators driven by the SCN reside within neurons of the neocortex. PMID:22527123

  6. Circadian rhythms in the green sunfish retina.

    PubMed

    Dearry, A; Barlow, R B

    1987-05-01

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

  7. Circadian rhythms in the green sunfish retina

    PubMed Central

    1987-01-01

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

  8. Ecological measurements of light exposure, activity, and circadian disruption.

    PubMed

    Miller, D; Bierman, A; Figueiro, Mg; Schernhammer, Es; Rea, Ms

    2010-09-01

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

  9. Melatonin is required for the circadian regulation of sleep.

    PubMed

    Gandhi, Avni V; Mosser, Eric A; Oikonomou, Grigorios; Prober, David A

    2015-03-18

    Sleep is an evolutionarily conserved behavioral state whose regulation is poorly understood. A classical model posits that sleep is regulated by homeostatic and circadian mechanisms. Several factors have been implicated in mediating the homeostatic regulation of sleep, but molecules underlying the circadian mechanism are unknown. Here we use animals lacking melatonin due to mutation of arylalkylamine N-acetyltransferase 2 (aanat2) to show that melatonin is required for circadian regulation of sleep in zebrafish. Sleep is dramatically reduced at night in aanat2 mutants maintained in light/dark conditions, and the circadian regulation of sleep is abolished in free-running conditions. We find that melatonin promotes sleep downstream of the circadian clock as it is not required to initiate or maintain circadian rhythms. Additionally, we provide evidence that melatonin may induce sleep in part by promoting adenosine signaling, thus potentially linking circadian and homeostatic control of sleep. PMID:25754820

  10. Circadian and Circalunar Clock Interactions in a Marine Annelid

    PubMed Central

    Zantke, Juliane; Ishikawa-Fujiwara, Tomoko; Arboleda, Enrique; Lohs, Claudia; Schipany, Katharina; Hallay, Natalia; Straw, Andrew D.; Todo, Takeshi; Tessmar-Raible, Kristin

    2013-01-01

    Summary Life is controlled by multiple rhythms. Although the interaction of the daily (circadian) clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly) clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1?/?. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function. PMID:24075994

  11. Altitudinal variation in the circadian rhythm of oviposition in Drosophila ananassae.

    PubMed

    Khare, P V; Satralkar, M K; Vanlalnghaka, C; Keny, V L; Kasture, M S; Shivagaje, A J; Barnabas, R J; Joshi, D S

    2005-01-01

    The effect of altitude on four basic properties of the pacemaker controlling the circadian rhythm of oviposition in two strains of Drosophila ananassae was determined. The high altitude (HA) strain from Badrinath (5123 m above sea level) had a low amplitude peak in the forenoon while the low altitude (LA) strain from Firozpur (179 m a.s.l.) had a high amplitude peak after the lights-off of LD 12:12 cycles. Free running periods in continuous darkness were about 22.6 and 27.4 h in the HA and LA strains, respectively. The light pulse phase response curve (PRC) for the HA strain showed a low amplitude and a dead zone of 8h; the ratio for the advance to delay region (A/D) was less than 1, while the PRC for the LA strain had a high amplitude, which was devoid of a dead zone and showed a ratio of A/D > 1. The magnitude of the delay phase shifts at CT 18 evoked by light pulses of 1 h duration, but varying light intensity was significantly different in the HA and LA strain, which suggests that the photic sensitivity of the clock photoreceptors mediating the phase shifts had been affected by the altitude. PMID:15865320

  12. Percutaneous coronary intervention delays pacemaker implantation in coronary artery disease patients with established bradyarrhythmias

    PubMed Central

    Zhong, Lihua; Gao, Yanhui; Xia, Hongyuan; Li, Xueqi; Wei, Shipeng

    2013-01-01

    BACKGROUND: Pacemakers have long been used to assist the heart under pathological conditions, and they are the first choice in the treatment of systematic bradyarrhythmias. However, the effect of percutaneous coronary intervention (PCI) in patients with coronary artery disease as well as bradyarrhythmias remains unknown. METHODS: In the present study, 42 patients with chest pain and/or abnormal stress test results were surveyed. Before coronary angiography, patients underwent complete examination, including a 24 h dynamic electrocardiogram, which was used to diagnose bradyarrhythmias that were not suitable for pacemaker implantation due to a lack of arrhythmia-related symptoms. All patients underwent PCI but did not undergo pacemaker implantation. Forty-one patients with chest pain and/or abnormal stress test results, as well as symptom-free bradyarrhythmias, were selected as the control group. All of the patients in the control group were committed to treatments without PCI. RESULTS: During a mean (±SD) of 3.3±0.5 years of follow-up (range 2.5 to 4.5 years), 24 of 42 patients who received PCI underwent pacemaker implantation for arrhythmia-related symptoms, eight were shown by Holter monitoring to have worsened but still exhibited no symptoms, and the remainder did not show any changes according to the examinations performed. In the control group, 31 patients underwent pacemaker implantation for arrhythmia-related symptoms, eight were shown by Holter monitoring to have worsened but still exhibited no symptoms, and two did not show any changes according to the examinations performed. Nevertheless, the rates of pacemaker implantation each year (from the first to the third year) between the two groups were 7.1% versus 39.0% (P=0.001); 33.3% versus 63.4% (P=0.006); and 57.1% versus 75.6%, (P=0.075), respectively. CONCLUSIONS: The present study found that PCI delayed the demand for pacemaker implantation among coronary artery disease patients. PMID:24294031

  13. Ectopic jejunal pacemakers and gastric emptying after Roux gastrectomy: Effect of intestinal pacing

    SciTech Connect

    Karlstrom, L.; Kelly, K.A. (Mayo Clinic, Rochester, MN (USA))

    1989-11-01

    The aims of this study were to determine whether ectopic pacemakers are present after meals in the Roux limbs of dogs after vagotomy and Roux gastrectomy, whether these pacemakers slow gastric emptying of liquids or solids, and whether abolishing the pacemakers with electric pacing might speed any slow emptying that occurs. In six dogs that underwent vagotomy and Roux gastrectomy and in four dogs that underwent vagotomy and Billroth gastrectomy (controls), myoelectric activity of the Roux limb or duodenum was measured during gastric emptying of a 500 kcal mixed meal of 99mTc-labeled cooked egg and 111In-labeled milk. Roux dogs were tested with and without pacing of the Roux limb. Roux dogs showed ectopic pacemaker in the Roux limb that drove the pacesetter potentials of the limb in a reverse, or orad, direction during 57%