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Sample records for circadian pacemaker neurons

  1. 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

    2015-06-03

    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.

  2. Calcium responses of circadian pacemaker neurons of the cockroach Rhyparobia maderae to acetylcholine and histamine.

    PubMed

    Baz, El-Sayed; Wei, Hongying; Grosshans, Johannes; Stengl, Monika

    2013-05-01

    The accessory medulla (aMe) is the pacemaker that controls circadian activity rhythms in the cockroach Rhyparobia maderae. Not much is known about the classical neurotransmitters of input pathways to the cockroach circadian system. The circadian pacemaker center receives photic input from the compound eye, via unknown excitatory and GABAergic inhibitory entrainment pathways. In addition, neuropeptidergic inputs couple both pacemaker centers. A histamine-immunoreactive centrifugal neuron connects the ventral aMe with projection areas in the lateral protocerebrum and may provide non-photic inputs. To identify neurotransmitters of input pathways to the circadian clock with Fura-2-dependent Ca(2+) imaging, primary cell cultures of the adult aMe were stimulated with acetylcholine (ACh), as the most prominent excitatory, and histamine, as common inhibitory neurotransmitter. In most of aMe neurons, ACh application caused dose-dependent increases in intracellular Ca(2+) levels via ionotropic nicotinic ACh receptors. These ACh-dependent rises in Ca(2+) were mediated by mibefradil-sensitive voltage-activated Ca(2+) channels. In contrast, histamine application decreased intracellular Ca(2+) levels in only a subpopulation of aMe cells via H2-type histamine receptor chloride channels. Thus, our data suggest that ACh is part of the light entrainment pathway while histamine is involved in a non-photic input pathway to the ventral circadian clock of the Madeira cockroach.

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

    PubMed

    Ling, Jinli; Dubruille, Raphaëlle; Emery, Patrick

    2012-11-21

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

  4. Phase Shifting Capacity of the Circadian Pacemaker Determined by the SCN Neuronal Network Organization

    PubMed Central

    vanderLeest, Henk Tjebbe; Rohling, Jos H. T.; Michel, Stephan; Meijer, Johanna H.

    2009-01-01

    Background In mammals, a major circadian pacemaker that drives daily rhythms is located in the suprachiasmatic nuclei (SCN), at the base of the hypothalamus. The SCN receive direct light input via the retino-hypothalamic tract. Light during the early night induces phase delays of circadian rhythms while during the late night it leads to phase advances. The effects of light on the circadian system are strongly dependent on the photoperiod to which animals are exposed. An explanation for this phenomenon is currently lacking. Methodology and Principal Findings We recorded running wheel activity in C57 mice and observed large amplitude phase shifts in short photoperiods and small shifts in long photoperiods. We investigated whether these different light responses under short and long days are expressed within the SCN by electrophysiological recordings of electrical impulse frequency in SCN slices. Application of N-methyl-D-aspartate (NMDA) induced sustained increments in electrical activity that were not significantly different in the slices from long and short photoperiods. These responses led to large phase shifts in slices from short days and small phase shifts in slices from long days. An analysis of neuronal subpopulation activity revealed that in short days the amplitude of the rhythm was larger than in long days. Conclusions The data indicate that the photoperiodic dependent phase responses are intrinsic to the SCN. In contrast to earlier predictions from limit cycle theory, we observed large phase shifting responses in high amplitude rhythms in slices from short days, and small shifts in low amplitude rhythms in slices from long days. We conclude that the photoperiodic dependent phase responses are determined by the SCN and propose that synchronization among SCN neurons enhances the phase shifting capacity of the circadian system. PMID:19305510

  5. Reciprocal cholinergic and GABAergic modulation of the small ventrolateral pacemaker neurons of Drosophila's circadian clock neuron network.

    PubMed

    Lelito, Katherine R; Shafer, Orie T

    2012-04-01

    The relatively simple clock neuron network of Drosophila is a valuable model system for the neuronal basis of circadian timekeeping. Unfortunately, many key neuronal classes of this network are inaccessible to electrophysiological analysis. We have therefore adopted the use of genetically encoded sensors to address the physiology of the fly's circadian clock network. Using genetically encoded Ca(2+) and cAMP sensors, we have investigated the physiological responses of two specific classes of clock neuron, the large and small ventrolateral neurons (l- and s-LN(v)s), to two neurotransmitters implicated in their modulation: acetylcholine (ACh) and γ-aminobutyric acid (GABA). Live imaging of l-LN(v) cAMP and Ca(2+) dynamics in response to cholinergic agonist and GABA application were well aligned with published electrophysiological data, indicating that our sensors were capable of faithfully reporting acute physiological responses to these transmitters within single adult clock neuron soma. We extended these live imaging methods to s-LN(v)s, critical neuronal pacemakers whose physiological properties in the adult brain are largely unknown. Our s-LN(v) experiments revealed the predicted excitatory responses to bath-applied cholinergic agonists and the predicted inhibitory effects of GABA and established that the antagonism of ACh and GABA extends to their effects on cAMP signaling. These data support recently published but physiologically untested models of s-LN(v) modulation and lead to the prediction that cholinergic and GABAergic inputs to s-LN(v)s will have opposing effects on the phase and/or period of the molecular clock within these critical pacemaker neurons.

  6. Strong attachment of circadian pacemaker neurons on modified ultrananocrystalline diamond surfaces.

    PubMed

    Voss, Alexandra; Wei, HongYing; Zhang, Yi; Turner, Stuart; Ceccone, Giacomo; Reithmaier, Johann Peter; Stengl, Monika; Popov, Cyril

    2016-07-01

    Diamond is a promising material for a number of bio-applications, including the fabrication of platforms for attachment and investigation of neurons and of neuroprostheses, such as retinal implants. In the current work ultrananocrystalline diamond (UNCD) films were deposited by microwave plasma chemical vapor deposition, modified by UV/O3 treatment or NH3 plasma, and comprehensively characterized with respect to their bulk and surface properties, such as crystallinity, topography, composition and chemical bonding nature. The interactions of insect circadian pacemaker neurons with UNCD surfaces with H-, O- and NH2-terminations were investigated with respect to cell density and viability. The fast and strong attachment achieved without application of adhesion proteins allowed for advantageous modification of dispersion protocols for the preparation of primary cell cultures. Centrifugation steps, which are employed for pelletizing dispersed cells to separate them from dispersing enzymes, easily damage neurons. Now centrifugation can be avoided since dispersed neurons quickly and strongly attach to the UNCD surfaces. Enzyme solutions can be easily washed off without losing many of the dispersed cells. No adverse effects on the cell viability and physiological responses were observed as revealed by calcium imaging. Furthermore, the enhanced attachment of the neurons, especially on the modified UNCD surfaces, was especially advantageous for the immunocytochemical procedures with the cell cultures. The cell losses during washing steps were significantly reduced by one order of magnitude in comparison to controls. In addition, the integration of a titanium grid structure under the UNCD films allowed for individual assignment of physiologically characterized neurons to immunocytochemically stained cells. Thus, employing UNCD surfaces free of foreign proteins improves cell culture protocols and immunocytochemistry with cultured cells. The fast and strong attachment of

  7. 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

    2015-03-04

    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.

  8. Electrical Hyperexcitation of Lateral Ventral Pacemaker Neurons Desynchronizes Downstream Circadian Oscillators in the Fly Circadian Circuit and Induces Multiple Behavioral Periods

    PubMed Central

    Nitabach, Michael N.; Wu, Ying; Sheeba, Vasu; Lemon, William C.; Strumbos, John; Zelensky, Paul K.; White, Benjamin H.; Holmes, Todd C.

    2008-01-01

    Coupling of autonomous cellular oscillators is an essential aspect of circadian clock function but little is known about its circuit requirements. Functional ablation of the pigment-dispersing factor-expressing lateral ventral subset (LNV ) of Drosophila clock neurons abolishes circadian rhythms of locomotor activity. The hypothesis that LNVs synchronize oscillations in downstream clock neurons was tested by rendering the LNVs hyperexcitable via transgenic expression of a low activation threshold voltage-gated sodium channel. When the LNVs are made hyperexcitable, free-running behavioral rhythms decompose into multiple independent superimposed oscillations and the clock protein oscillations in the dorsal neuron 1 and 2 subgroups of clock neurons are phase-shifted. Thus, regulated electrical activity of the LNVs synchronize multiple oscillators in the fly circadian pacemaker circuit. PMID:16407545

  9. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

    PubMed Central

    Issa, Abdul-Raouf; Seugnet, Laurent; Klarsfeld, André

    2017-01-01

    Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila. PMID:28072817

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

    PubMed

    Saifullah, A S M; Tomioka, Kenji

    2002-05-01

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

  11. 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

  12. Nonphotic entrainment of the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Rimmer, D. W.; Dijk, D. J.; Kronauer, R. E.; Rizzo, J. F. 3rd; Czeisler, C. A.

    1998-01-01

    In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

  13. Caffeine increases light responsiveness of the mouse circadian pacemaker.

    PubMed

    van Diepen, Hester C; Lucassen, Eliane A; Yasenkov, Roman; Groenen, Inske; Ijzerman, Adriaan P; Meijer, Johanna H; Deboer, Tom

    2014-11-01

    Caffeine is the most commonly used psychoactive stimulant worldwide. It reduces sleep and sleepiness by blocking access to the adenosine receptor. The level of adenosine increases during sleep deprivation, and is thought to induce sleepiness and initiate sleep. Light-induced phase shifts of the rest-activity circadian rhythms are mediated by light-responsive neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus, where the circadian clock of mammals resides. Previous studies have shown that sleep deprivation reduces circadian clock phase-shifting capacity and decreases SCN neuronal activity. In addition, application of adenosine agonists and antagonists mimics and blocks, respectively, the effect of sleep deprivation on light-induced phase shifts in behaviour, suggesting a role for adenosine. In the present study, we examined the role of sleep deprivation in and the effect of caffeine on light responsiveness of the SCN. We performed in vivo electrical activity recordings of the SCN in freely moving mice, and showed that the sustained response to light of SCN neuronal activity was attenuated after 6 h of sleep deprivation prior to light exposure. Subsequent intraperitoneal application of caffeine was able to restore the response to light. Finally, we performed behavioural recordings in constant conditions, and found enhanced period lengthening during chronic treatment with caffeine in drinking water in constant light conditions. The data suggest that increased homeostatic sleep pressure changes circadian pacemaker functioning by reducing SCN neuronal responsiveness to light. The electrophysiological and behavioural data together provide evidence that caffeine enhances clock sensitivity to light.

  14. The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus.

    PubMed

    Albers, H Elliott; Walton, James C; Gamble, Karen L; McNeill, John K; Hummer, Daniel L

    2017-01-01

    Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.

  15. 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.

  16. The Drosophila Receptor Protein Tyrosine Phosphatase LAR Is Required for Development of Circadian Pacemaker Neuron Processes That Support Rhythmic Activity in Constant Darkness But Not during Light/Dark Cycles

    PubMed Central

    Agrawal, Parul

    2016-01-01

    In Drosophila, a transcriptional feedback loop that is activated by CLOCK-CYCLE (CLK-CYC) complexes and repressed by PERIOD-TIMELESS (PER-TIM) complexes keeps circadian time. The timing of CLK-CYC activation and PER-TIM repression is regulated post-translationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Although kinases that control PER, TIM, and CLK levels, activity, and/or subcellular localization have been identified, less is known about phosphatases that control clock protein dephosphorylation. To identify clock-relevant phosphatases, clock-cell-specific RNAi knockdowns of Drosophila phosphatases were screened for altered activity rhythms. One phosphatase that was identified, the receptor protein tyrosine phosphatase leukocyte-antigen-related (LAR), abolished activity rhythms in constant darkness (DD) without disrupting the timekeeping mechanism in brain pacemaker neurons. However, expression of the neuropeptide pigment-dispersing factor (PDF), which mediates pacemaker neuron synchrony and output, is eliminated in the dorsal projections from small ventral lateral (sLNv) pacemaker neurons when Lar expression is knocked down during development, but not in adults. Loss of Lar function eliminates sLNv dorsal projections, but PDF expression persists in sLNv and large ventral lateral neuron cell bodies and their remaining projections. In contrast to the defects in lights-on and lights-off anticipatory activity seen in flies that lack PDF, Lar RNAi knockdown flies anticipate the lights-on and lights-off transition normally. Our results demonstrate that Lar is required for sLNv dorsal projection development and suggest that PDF expression in LNv cell bodies and their remaining projections mediate anticipation of the lights-on and lights-off transitions during a light/dark cycle. SIGNIFICANCE STATEMENT In animals, circadian clocks drive daily rhythms in physiology, metabolism, and behavior via transcriptional feedback loops. Because key circadian

  17. Circadian rhythms in neuronal activity propagate through output circuits

    PubMed Central

    Cavey, Matthieu; Collins, Ben; Bertet, Claire; Blau, Justin

    2016-01-01

    24hr rhythms in behavior are organized by a network of circadian pacemaker neurons. Rhythmic activity in this network is generated by intrinsic rhythms in clock neuron physiology and communication between clock neurons. However, it is poorly understood how the activity of a small number of pacemaker neurons is translated into rhythmic behavior of the whole animal. To understand this, we screened for signals that could identify circadian output circuits in Drosophila. We found that Leucokinin neuropeptide (LK) and its receptor (LK-R) are required for normal behavioral rhythms. This LK/LK-R circuit connects pacemaker neurons to brain areas that regulate locomotor activity and sleep. Our experiments revealed that pacemaker neurons impose rhythmic activity and excitability on LK and LK-R expressing neurons. We also found pacemaker neuron-dependent activity rhythms in DH44-expressing neurons, a second circadian output pathway. We conclude that rhythmic clock neuron activity propagates to multiple downstream circuits to orchestrate behavioral rhythms. PMID:26928065

  18. Circadian rhythms in neuronal activity propagate through output circuits.

    PubMed

    Cavey, Matthieu; Collins, Ben; Bertet, Claire; Blau, Justin

    2016-04-01

    Twenty-four hour rhythms in behavior are organized by a network of circadian pacemaker neurons. Rhythmic activity in this network is generated by intrinsic rhythms in clock neuron physiology and communication between clock neurons. However, it is poorly understood how the activity of a small number of pacemaker neurons is translated into rhythmic behavior of the whole animal. To understand this, we screened for signals that could identify circadian output circuits in Drosophila melanogaster. We found that leucokinin neuropeptide (LK) and its receptor (LK-R) were required for normal behavioral rhythms. This LK/LK-R circuit connects pacemaker neurons to brain areas that regulate locomotor activity and sleep. Our experiments revealed that pacemaker neurons impose rhythmic activity and excitability on LK- and LK-R-expressing neurons. We also found pacemaker neuron-dependent activity rhythms in a second circadian output pathway controlled by DH44 neuropeptide-expressing neurons. We conclude that rhythmic clock neuron activity propagates to multiple downstream circuits to orchestrate behavioral rhythms.

  19. Mutual entrainment of bilaterally distributed circadian pacemaker.

    PubMed

    Page, T L; Caldarola, P C; Pittendrigh, C S

    1977-03-01

    The interactions between the bilaterally distributed components of the circadin system that controls the locomotor activity rhythm of the cockroach Leucophaea maderae were investigated in a series of surgical lesion experiments. Complete excision of one optic lobe (either right or left) or its surgical isolation from the central nervous system had no effect on the animals' ability to free-run in constant darkness nor was there any indication, as judged by postoperative pi values of any difference between left and right lobe pacemakers. However, these surgical procedures consistently resulted in a significant increase in tau over preoperative value while optic nerve section had no effect on tau. The propostion is developed that the left and right pacemakers in the two optic lobes are mutally coupled and that the compound pacemaker's period is shorter than either of its constituent pacemakers. It was also found that the integrity of either compound eye is sufficient to assure entrainment of both left and right pacemakers.

  20. Mutual entrainment of bilaterally distributed circadian pacemaker.

    PubMed Central

    Page, T L; Caldarola, P C; Pittendrigh, C S

    1977-01-01

    The interactions between the bilaterally distributed components of the circadin system that controls the locomotor activity rhythm of the cockroach Leucophaea maderae were investigated in a series of surgical lesion experiments. Complete excision of one optic lobe (either right or left) or its surgical isolation from the central nervous system had no effect on the animals' ability to free-run in constant darkness nor was there any indication, as judged by postoperative pi values of any difference between left and right lobe pacemakers. However, these surgical procedures consistently resulted in a significant increase in tau over preoperative value while optic nerve section had no effect on tau. The propostion is developed that the left and right pacemakers in the two optic lobes are mutally coupled and that the compound pacemaker's period is shorter than either of its constituent pacemakers. It was also found that the integrity of either compound eye is sufficient to assure entrainment of both left and right pacemakers. Images PMID:265571

  1. 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.

  2. Pacemaking Property of RVLM Presympathetic Neurons

    PubMed Central

    Accorsi-Mendonça, Daniela; da Silva, Melina P.; Souza, George M. P. R.; Lima-Silveira, Ludmila; Karlen-Amarante, Marlusa; Amorim, Mateus R.; Almado, Carlos E. L.; Moraes, Davi J. A.; Machado, Benedito H.

    2016-01-01

    Despite several studies describing the electrophysiological properties of RVLM presympathetic neurons, there is no consensus in the literature about their pacemaking property, mainly due to different experimental approaches used for recordings of neuronal intrinsic properties. In this review we are presenting a historical retrospective about the pioneering studies and their controversies on the intrinsic electrophysiological property of auto-depolarization of these cells in conjunction with recent studies from our laboratory documenting that RVLM presympathetic neurons present pacemaking capacity. We also discuss whether increased sympathetic activity observed in animal models of neurogenic hypertension (CIH and SHR) are dependent on changes in the intrinsic electrophysiological properties of these cells or due to changes in modulatory inputs from neurons of the respiratory network. We also highlight the key role of INaP as the major current contributing to the pacemaking property of RVLM presympathetic neurons. PMID:27713705

  3. A delayed rectifier current is modulated by the circadian pacemaker in Bulla.

    PubMed

    Michel, S; Manivannan, K; Zaritsky, J J; Block, G D

    1999-04-01

    Basal retinal neurons of the marine mollusc Bulla gouldiana continue to express a circadian modulation of their membrane conductance for at least two cycles in cell culture. Voltage-dependent currents of these pacemaker cells were recorded using the whole-cell perforated patch-clamp technique to characterize outward currents and investigate their putative circadian modulation. Three components of the outward potassium current were identified. A transient outward current (IA) was activated after depolarization from holding potentials greater than -30 mV, inactivated with a time constant of 50 ms, and partially blocked by 4-aminopyridine (1-5 mM). A Ca(2+)-dependent potassium current (IK(Ca)) was activated by depolarization to potentials more positive than -10 mV and was blocked by removing Ca2+ from the bath or by applying the Ca2+ channel blockers Cd2+ (0.1-0.2 mM) and Ni2+ (1-5 mM). A sustained Ca(2+)-independent current component including the delayed rectifier current (IK) was recorded at potentials positive to -20 mV in the absence of extracellular Na+ and Ca2+ and was partially blocked by tetraethylammonium chloride (TEA, 30mM). Whole-cell currents recorded before and after the projected dawn and normalized to the cell capacitance revealed a circadian modulation of the delayed rectifier current (IK). However, the IA and IK(Ca) currents were not affected by the circadian pacemaker.

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

    PubMed

    Ushirogawa, H; Abe, Y; Tomioka, K

    1997-10-01

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

  5. Phase shifting two coupled circadian pacemakers - Implications for jet lag

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

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

  6. Asynchronous response of coupled pacemaker neurons

    PubMed Central

    Dodla, Ramana; Wilson, Charles J.

    2009-01-01

    We study a network model of two conductance-based pacemaker neurons of differing natural frequency, coupled with either mutual excitation or inhibition, and receiving shared random inhibitory synaptic input. The networks may phase-lock spike-to-spike for strong mutual coupling. But the shared input can desynchronize the locked spike-pairs by selectively eliminating the lagging spike or modulating its timing with respect to the leading spike depending on their separation time window. Such loss of synchrony is also found in a large network of sparsely coupled heterogeneous spiking neurons receiving shared input. PMID:19257636

  7. 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

  8. Putative pacemakers in the eyestalk and brain of the crayfish Procambarus clarkii show circadian oscillations in levels of mRNA for crustacean hyperglycemic hormone.

    PubMed

    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.

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

    PubMed Central

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

    2013-01-01

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

  10. Decreased human circadian pacemaker influence after 100 days in space: a case study

    NASA Technical Reports Server (NTRS)

    Monk, T. H.; Kennedy, K. S.; Rose, L. R.; Linenger, J. M.

    2001-01-01

    OBJECTIVE: The objectives of this study were (1) to assess the circadian rhythms and sleep of a healthy, 42-year-old male astronaut experiencing microgravity (weightlessness) for nearly 5 months while living aboard Space Station Mir as it orbited Earth and (2) to determine the effects of prolonged space flight on the endogenous circadian pacemaker, as indicated by oral temperature and subjective alertness rhythms, and their ramifications for sleep, alertness, and performance. METHODS: For three 12- to 14-day blocks of time (spread throughout the mission), oral temperatures were taken and subjective alertness was self-rated five times per day. Sleep diaries and performance tests were also completed daily during each block. RESULTS: Examination of the subject's circadian alertness and oral temperature rhythms suggested that the endogenous circadian pacemaker seemed to function quite well up to 90 days in space. Thereafter (on days 110-122), the influence of the endogenous circadian pacemaker on oral temperature and subjective alertness circadian rhythms was considerably weakened, with consequent disruptions in sleep. CONCLUSIONS: Space missions lasting more than 3 months might result in diminished circadian pacemaker influence in astronauts, leading to eventual sleep problems.

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

    PubMed Central

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

    2011-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

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

  13. COMPARISON OF AMPLITUDE RECOVERY DYNAMICS OF TWO LIMIT CYCLE OSCILLATOR MODELS OF THE HUMAN CIRCADIAN PACEMAKER

    PubMed Central

    Indic, Premananda; Forger, Daniel B.; St. Hilaire, Melissa A.; Dean, Dennis A.; Brown, Emery N.; Kronauer, Richard E.; Klerman, Elizabeth B.; Jewett, Megan E.

    2013-01-01

    At an organism level, the mammalian circadian pacemaker is a two-dimensional system. For these two dimensions, phase (relative timing) and amplitude of the circadian pacemaker are commonly used. Both the phase and the amplitude (A) of the human circadian pacemaker can be observed within multiple physiological measures—including plasma cortisol, plasma melatonin, and core body temperature (CBT)—all of which are also used as markers of the circadian system. Although most previous work has concentrated on changes in phase of the circadian system, critically timed light exposure can significantly reduce the amplitude of the pacemaker. The rate at which the amplitude recovers to its equilibrium level after reduction can have physiological significance. Two mathematical models that describe the phase and amplitude dynamics of the pacemaker have been reported. These models are essentially equivalent in predictions of phase and in predictions of amplitude recovery for small changes from an equilibrium value (A = 1), but are markedly different in the prediction of recovery rates when A < 0.6. To determine which dynamic model best describes the amplitude recovery observed in experimental data; both models were fit to CBT data using a maximum likelihood procedure and compared using Akaike’s Information Criterion (AIC). For all subjects, the model with the lower recovery rate provided a better fit to data in terms of AIC, supporting evidence that the amplitude recovery of the endogenous pacemaker is slow at low amplitudes. Experiments derived from model predictions are proposed to test the influence of low amplitude recovery on the physiological and neurobehavioral functions. PMID:16147894

  14. Circadian Neuron Feedback Controls the Drosophila Sleep-Activity Profile

    PubMed Central

    Guo, Fang; Yu, Junwei; Jung, Hyung Jae; Abruzzi, Katharine C.; Luo, Weifei; Griffith, Leslie C.; Rosbash, Michael

    2016-01-01

    SUMMARY Little is known about the ability of Drosophila circadian neurons to promote sleep. We show here with optogenetic manipulations and video recording that a subset of dorsal clock neurons (DN1s) are potent sleep-promoting cells, releasing glutamate to directly inhibit key pacemaker neurons. These pacemakers promote morning arousal by activating these same DN1s, implying that there is a late-day feedback circuit to drive siesta and nighttime sleep. To address more plastic aspects of the sleep program, we used a novel calcium assay to monitor and compared the real-time DN1 activity of freely behaving males and females. It revealed a dramatic sexual dimorphism, which parallels the well-known difference in daytime sleep. DN1 activity is also enhanced by elevated temperature, consistent with its known effect on sleep. These new approaches indicate that the DN1s have a major impact on the fly sleep-wake profile and integrate environmental information with the circadian molecular program. PMID:27479324

  15. Dynamic resetting of the human circadian pacemaker by intermittent bright light

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

  16. Circadian rhythms in healthy aging--effects downstream from the pacemaker

    NASA Technical Reports Server (NTRS)

    Monk, T. H.; Kupfer, D. J.

    2000-01-01

    Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).

  17. Modeling the emergence of circadian rhythms in a clock neuron network.

    PubMed

    Diambra, Luis; Malta, Coraci P

    2012-01-01

    Circadian rhythms in pacemaker cells persist for weeks in constant darkness, while in other types of cells the molecular oscillations that underlie circadian rhythms damp rapidly under the same conditions. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms leading to damped or self-sustained oscillations remain largely unknown. There exist many mathematical models that reproduce the circadian rhythms in the case of a single cell of the Drosophila fly. However, not much is known about the mechanisms leading to coherent circadian oscillation in clock neuron networks. In this work we have implemented a model for a network of interacting clock neurons to describe the emergence (or damping) of circadian rhythms in Drosophila fly, in the absence of zeitgebers. Our model consists of an array of pacemakers that interact through the modulation of some parameters by a network feedback. The individual pacemakers are described by a well-known biochemical model for circadian oscillation, to which we have added degradation of PER protein by light and multiplicative noise. The network feedback is the PER protein level averaged over the whole network. In particular, we have investigated the effect of modulation of the parameters associated with (i) the control of net entrance of PER into the nucleus and (ii) the non-photic degradation of PER. Our results indicate that the modulation of PER entrance into the nucleus allows the synchronization of clock neurons, leading to coherent circadian oscillations under constant dark condition. On the other hand, the modulation of non-photic degradation cannot reset the phases of individual clocks subjected to intrinsic biochemical noise.

  18. Entrainment of the human circadian pacemaker to longer-than-24-h days

    PubMed Central

    Gronfier, Claude; Wright, Kenneth P.; Kronauer, Richard E.; Czeisler, Charles A.

    2007-01-01

    Entrainment of the circadian pacemaker to the light:dark cycle is necessary for rhythmic physiological functions to be appropriately timed over the 24-h day. Nonentrainment results in sleep, endocrine, and neurobehavioral impairments. Exposures to intermittent bright light pulses have been reported to phase shift the circadian pacemaker with great efficacy. Therefore, we tested the hypothesis that a modulated light exposure (MLE) with bright light pulses in the evening would entrain subjects to a light:dark cycle 1 h longer than their own circadian period (τ). Twelve subjects underwent a 65-day inpatient study. Individual subject's circadian period was determined in a forced desynchrony protocol. Subsequently, subjects were released into 30 longer-than-24-h days (daylength of τ + 1 h) in one of three light:dark conditions: (i) ≈25 lux; (ii) ≈100 lux; and (iii) MLE: ≈25 lux followed by ≈100 lux, plus two 45-min bright light pulses of ≈9,500 lux near the end of scheduled wakefulness. We found that lighting levels of ≈25 lux were insufficient to entrain all subjects tested. Exposure to ≈100 lux was sufficient to entrain subjects, although at a significantly wider phase angle compared with baseline. Exposure to MLE was able to entrain the subjects to the imposed sleep–wake cycles but at a phase angle comparable to baseline. These results suggest that MLE can be used to entrain the circadian pacemaker to non-24-h days. The implications of these findings are important because they could be used to treat circadian misalignment associated with space flight and circadian rhythm sleep disorders such as shift-work disorder. PMID:17502598

  19. 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.

  20. Glial fibrillary acidic protein (GFAP) shows circadian oscillations in crayfish Procambarus clarkii putative pacemakers.

    PubMed

    Rodríguez-Muñoz, María de la Paz; Escamilla-Chimal, Elsa G

    2015-01-01

    Although several studies of glia have examined glial fibrillary acid protein (GFAP) and its relationship to the circadian rhythms of different organisms, they have not explored the daily GFAP oscillations in the putative pacemakers of the crayfish Procambarus clarkii or in other crustaceans. In this study we investigated the daily variations in GFAP concentrations in the eyestalk and brain, which are considered to be putative pacemakers in adult P. clarkii. In both structures, the glial GFAP was quantified using the indirect enzyme-linked immunosorbent assay (ELISA), and double labeling immunofluorescence was used to detect it and its co-localization with protein Period (PER), an important component of the circadian clock, in various regions of both structures. The ELISA results were analyzed using Cosinor and one-way ANOVA with Bonferroni and Scheffé's post hoc tests. The results of this analysis showed that the GFAP levels present circadian oscillations in both structures. Moreover, GFAP was localized in different structures of the eyestalk and brain; however, co-localization with PER occurred only in the lamina ganglionaris, specifically in the cartridges of the eyestalk and in some of the cluster 9 brain cells. These results suggest that as in other invertebrates and vertebrates, glial cells could be involved in the circadian system of P. clarkii; however, thus far we cannot know whether the glial cells are only effectors, participate in afferent pathways, or are part of the circadian clock.

  1. 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.

  2. Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Dijk, D. J.; Kronauer, R.; Brown, E.; Czeisler, C.

    2000-01-01

    Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

  3. Drosophila ATF-2 regulates sleep and locomotor activity in pacemaker neurons.

    PubMed

    Shimizu, Hideyuki; Shimoda, Masami; Yamaguchi, Terumi; Seong, Ki-Hyeon; Okamura, Tomoo; Ishii, Shunsuke

    2008-10-01

    Stress-activated protein kinases such as p38 regulate the activity of transcription factor ATF-2. However, the physiological role of ATF-2, especially in the brain, is unknown. Here, we found that Drosophila melanogaster ATF-2 (dATF-2) is expressed in large ventral lateral neurons (l-LN(v)s) and also, to a much lesser extent, in small ventral lateral neurons, the pacemaker neurons. Only l-LN(v)s were stained with the antibody that specifically recognizes phosphorylated dATF-2, suggesting that dATF-2 is activated specifically in l-LN(v)s. The knockdown of dATF-2 in pacemaker neurons using RNA interference decreased sleep time, whereas the ectopic expression of dATF-2 increased sleep time. dATF-2 knockdown decreased the length of sleep bouts but not the number of bouts. The ATF-2 level also affected the sleep rebound after sleep deprivation and the arousal threshold. dATF-2 negatively regulated locomotor activity, although it did not affect the circadian locomotor rhythm. The degree of dATF-2 phosphorylation was greater in the morning than at night and was enhanced by forced locomotion via the dp38 pathway. Thus, dATF-2 is activated by the locomotor while it increases sleep, suggesting a role for dATF-2 as a regulator to connect sleep with locomotion.

  4. Emergence of Noise-Induced Oscillations in the Central Circadian Pacemaker

    PubMed Central

    Buhr, Ethan D.; Liu, Andrew C.; Zhang, Eric E.; Ralph, Martin R.; Kay, Steve A.; Forger, Daniel B.; Takahashi, Joseph S.

    2010-01-01

    Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization. PMID:20967239

  5. Pacemaker

    MedlinePlus

    ... the Risks Lifestyle Clinical Trials Links Related Topics Arrhythmia Atrial Fibrillation Heart Block Implantable Cardioverter Defibrillators Long ... a normal rate. Pacemakers are used to treat arrhythmias (ah-RITH-me-ahs). Arrhythmias are problems with ...

  6. Quantifying human circadian pacemaker response to brief, extended, and repeated light stimuli over the phototopic range.

    PubMed

    Kronauer, R E; Forger, D B; Jewett, M E

    1999-12-01

    The authors' previous models have been able to describe accurately the effects of extended (approximately 5 h) bright-light (>4000 lux) stimuli on the phase and amplitude of the human circadian pacemaker, but they are not sufficient to represent the surprising human sensitivity to both brief pulses of bright light and light of more moderate intensities. Therefore, the authors have devised a new model in which a dynamic stimulus processor (Process L) intervenes between the light stimuli and the traditional representation of the circadian pacemaker as a self-sustaining limit-cycle oscillator (Process P). The overall model incorporating Process L and Process P is intended to allow the prediction of phase shifts to photic stimuli of any temporal pattern (extended and brief light episodes) and any light intensity in the photopic range. Two time constants emerge in the Process L model: the characteristic duration for necessary bright-light pulses to achieve their full effect (5-10 min) and the characteristic stimulus-free (dark) interval that can be tolerated without incurring an excessive penalty in phase shifting (30-80 min). The effect of reducing light intensity is incorporated in Process L as an extension of the time necessary for the light pulse to be fully realized (a power-law relation between time and intensity). This new model generates a number of new testable hypotheses, including the surprising prediction that 24-h cycles consisting of 8 h of darkness and 16 h of only approximately 3.5 lux would be capable of entraining a large fraction of the adult population (approximately 45%). Experimental data on the response of the human circadian system to lower light intensities and briefer stimuli are needed to allow for further refinement and validation of the model proposed here.

  7. Functions of corazonin and histamine in light entrainment of the circadian pacemaker in the Madeira cockroach, Rhyparobia maderae.

    PubMed

    Arendt, Andreas; Baz, El-Sayed; Stengl, Monika

    2017-04-01

    The circadian pacemaker of the Madeira cockroach, Rhyparobia (Leucophaea) maderae, is located in the accessory medulla (AME). Ipsi- and contralateral histaminergic compound eyes are required for photic entrainment. Light pulses delay locomotor activity rhythm during the early night and advance it during the late night. Thus, different neuronal pathways might relay either light-dependent delays or advances to the clock. Injections of neuroactive substances combined with running-wheel assays suggested that GABA, pigment-dispersing factor, myoinhibitory peptides (MIPs), and orcokinins (ORCs) were part of both entrainment pathways, whereas allatotropin (AT) only delayed locomotor rhythms at the early night. To characterize photic entrainment further, histamine and corazonin were injected. Histamine injections resulted in light-like phase delays and advances, indicating that the neurotransmitter of the compound eyes participates in both entrainment pathways. Because injections of corazonin only advanced during the late subjective night, it was hypothesized that corazonin is only part of the advance pathway. Multiple-label immunocytochemistry in combination with neurobiotin backfills demonstrated that a single cell expressed corazonin in the optic lobes that belonged to the group of medial AME interneurons. It colocalized GABA and MIP but not AT or ORC immunoreactivity. Corazonin-immunoreactive (-ir) terminals overlapped with projections of putatively light-sensitive interneurons from the ipsi- and contralateral compound eye. Thus, we hypothesize that the corazonin-ir medial neuron integrates ipsi- and contralateral light information as part of the phase-advancing light entrainment pathway to the circadian clock. J. Comp. Neurol. 525:1250-1272, 2017. © 2016 Wiley Periodicals, Inc.

  8. 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

  9. 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

  10. 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.

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

    NASA Technical Reports Server (NTRS)

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

    1998-01-01

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

  12. The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms.

    PubMed

    Yao, Zepeng; Bennett, Amelia J; Clem, Jenna L; Shafer, Orie T

    2016-12-13

    In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network.

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

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  14. Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm.

    PubMed

    Mieda, Michihiro; Ono, Daisuke; Hasegawa, Emi; Okamoto, Hitoshi; Honma, Ken-Ichi; Honma, Sato; Sakurai, Takeshi

    2015-03-04

    The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. Here, we report that mice with a Bmal1 deletion specific to arginine vasopressin (AVP)-producing neurons showed marked lengthening in the free-running period and activity time of behavior rhythms. When exposed to an abrupt 8-hr advance of the light/dark cycle, these mice reentrained faster than control mice did. In these mice, the circadian expression of genes involved in intercellular communications, including Avp, Prokineticin 2, and Rgs16, was drastically reduced in the dorsal SCN, where AVP neurons predominate. In slices, dorsal SCN cells showed attenuated PER2::LUC oscillation with highly variable and lengthened periods. Thus, Bmal1-dependent oscillators of AVP neurons may modulate the coupling of the SCN network, eventually coupling morning and evening behavioral rhythms, by regulating expression of multiple factors important for the network property of these neurons.

  15. Stress-induced changes in circadian rhythms of body temperature and activity in rats are not caused by pacemaker changes.

    PubMed

    Meerlo, P; van den Hoofdakker, R H; Koolhaas, J M; Daan, S

    1997-02-01

    Previous work has shown that social stress in rats (i.e., defeat by an aggressive male conspecific) causes a variety of behavioral and physiological changes including alterations in the daily rhythms of body temperature and activity. To study the role of the circadian pacemaker in these stress-induced changes, three experiments were performed, successively addressing pacemaker period, phase, and sensitivity to light. In all experiments, rats were subjected to social stress by placing them in the home cage of a dominant conspecific for 1 h. This was done on 2 consecutive days, between the second and fifth hours of the activity phase. Experimental animals were attacked by the resident and lost the fight as indicated by submissive behavior. Control animals were placed in an unfamiliar but clean and empty cage for 1 h. In Experiment 1, the effects of social stress on the period of the free-running activity rhythm were studied. Rats were individually housed under constant dim red light. Activity was measured with infrared detectors. Social defeat caused a reduction of activity for a number of days, but the period of the free-running rhythm was not affected. In Experiment 2, the authors studied whether social defeat induced acute phase shifts. Body temperature and activity were measured by means of radiotelemetry with intraperitoneally implanted transmitters. After the social interactions, experimental animals were kept under constant dim red light. Social stress caused a profound reduction in the amplitude of the body temperature and activity rhythm, but no significant phase shifts occurred. In Experiment 3, the authors studied whether social defeat affected the circadian pacemaker's sensitivity to light given that the size of light-induced phase shifts is thought to reflect pacemaker amplitude. Again, body temperature and activity were measured by means of telemetry. After double social defeat, animals were kept under continuous dim red light. One day after the second

  16. 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; Ślimak, 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 α3, β4, and α5 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, α3β4-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

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

    PubMed

    Tohidi, Vahid; Nadim, Farzan

    2009-05-20

    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 (frequency of approximately 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 I(Ca) and the hyperpolarization-activated inward current I(h) 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 suprathreshold bursting frequency can be shifted in the same direction by either direct current injection or by using the dynamic-clamp technique to inject artificial conductances for I(h) or I(Ca). Together, these results suggest that membrane resonance of pacemaker neurons can be strongly correlated with the CPG oscillation frequency.

  18. 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

  19. High sensitivity of spontaneous spike frequency to sodium leak current in a Lymnaea pacemaker neuron.

    PubMed

    Lu, T Z; Kostelecki, W; Sun, C L F; Dong, N; Pérez Velázquez, J L; Feng, Z-P

    2016-12-01

    The spontaneous rhythmic firing of action potentials in pacemaker neurons depends on the biophysical properties of voltage-gated ion channels and background leak currents. The background leak current includes a large K(+) and a small Na(+) component. We previously reported that a Na(+) -leak current via U-type channels is required to generate spontaneous action potential firing in the identified respiratory pacemaker neuron, RPeD1, in the freshwater pond snail Lymnaea stagnalis. We further investigated the functional significance of the background Na(+) current in rhythmic spiking of RPeD1 neurons. Whole-cell patch-clamp recording and computational modeling approaches were carried out in isolated RPeD1 neurons. The whole-cell current of the major ion channel components in RPeD1 neurons were characterized, and a conductance-based computational model of the rhythmic pacemaker activity was simulated with the experimental measurements. We found that the spiking rate is more sensitive to changes in the Na(+) leak current as compared to the K(+) leak current, suggesting a robust function of Na(+) leak current in regulating spontaneous neuronal firing activity. Our study provides new insight into our current understanding of the role of Na(+) leak current in intrinsic properties of pacemaker neurons.

  20. 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.

  1. MicroRNA-92a is a circadian modulator of neuronal excitability in Drosophila

    PubMed Central

    Chen, Xiao; Rosbash, Michael

    2017-01-01

    Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability. In addition, mir-92a levels within PDF cells respond to light pulses and also affect the phase shift response. Translating ribosome affinity purification (TRAP) and in vitro luciferase reporter assay indicate that mir-92a suppresses expression of sirt2, which is homologous to human sir2 and sirt3. sirt2 RNAi also phenocopies mir-92a overexpression. These experiments indicate that sirt2 is a functional mir-92a target and that mir-92a modulates PDF neuronal excitability via suppressing SIRT2 levels in a rhythmic manner. PMID:28276426

  2. Autaptic pacemaker mediated propagation of weak rhythmic activity across small-world neuronal networks

    NASA Astrophysics Data System (ADS)

    Yilmaz, Ergin; Baysal, Veli; Ozer, Mahmut; Perc, Matjaž

    2016-02-01

    We study the effects of an autapse, which is mathematically described as a self-feedback loop, on the propagation of weak, localized pacemaker activity across a Newman-Watts small-world network consisting of stochastic Hodgkin-Huxley neurons. We consider that only the pacemaker neuron, which is stimulated by a subthreshold periodic signal, has an electrical autapse that is characterized by a coupling strength and a delay time. We focus on the impact of the coupling strength, the network structure, the properties of the weak periodic stimulus, and the properties of the autapse on the transmission of localized pacemaker activity. Obtained results indicate the existence of optimal channel noise intensity for the propagation of the localized rhythm. Under optimal conditions, the autapse can significantly improve the propagation of pacemaker activity, but only for a specific range of the autaptic coupling strength. Moreover, the autaptic delay time has to be equal to the intrinsic oscillation period of the Hodgkin-Huxley neuron or its integer multiples. We analyze the inter-spike interval histogram and show that the autapse enhances or suppresses the propagation of the localized rhythm by increasing or decreasing the phase locking between the spiking of the pacemaker neuron and the weak periodic signal. In particular, when the autaptic delay time is equal to the intrinsic period of oscillations an optimal phase locking takes place, resulting in a dominant time scale of the spiking activity. We also investigate the effects of the network structure and the coupling strength on the propagation of pacemaker activity. We find that there exist an optimal coupling strength and an optimal network structure that together warrant an optimal propagation of the localized rhythm.

  3. Heterogeneity induces rhythms of weakly coupled circadian neurons

    NASA Astrophysics Data System (ADS)

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H. T.

    2016-02-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle.

  4. Acceleratory synapses on pacemaker neurons in the heart ganglion of a stomatopod, Squilla oratoria.

    PubMed

    Watanabe, A; Obara, S; Akiyama, T

    1969-08-01

    The pacemaker neurons of the heart ganglion are innervated from the CNS through two pairs of acceleratory nerves. The effect of acceleratory nerve stimulation was examined with intracellular electrodes from the pacemaker cells. The major effects on the pacemaker potential were an increase in the rate of rise of the spontaneous depolarization and in the duration of the plateau. The aftereffect of stimulation could last for minutes. No clear excitatory postsynaptic potential (EPSP) was observed, however. On high frequency stimulation, a small depolarizing response (the initial response) was sometimes observed, but the major postsynaptic event was the following slow depolarization, or the enhancement of the pacemaker potential (the late response). With hyperpolarization the initial response did not significantly change its amplitude, but the late response disappeared, showing that the latter has the property of the local response. The membrane conductance did not increase with acceleratory stimulation. The injection of depolarizing current increased the rate of rise of the spontaneous depolarization, but only slightly in comparison with acceleratory stimulation, and did not increase the burst duration. It is concluded that the acceleratory effect is not mediated by the EPSP but is due to a direct action of the transmitter on the pacemaker membrane.

  5. Acceleratory Synapses on Pacemaker Neurons in the Heart Ganglion of a Stomatopod, Squilla oratoria

    PubMed Central

    Watanabe, Akira; Obara, Shosaku; Akiyama, Toyohiro

    1969-01-01

    The pacemaker neurons of the heart ganglion are innervated from the CNS through two pairs of acceleratory nerves. The effect of acceleratory nerve stimulation was examined with intracellular electrodes from the pacemaker cells. The major effects on the pacemaker potential were an increase in the rate of rise of the spontaneous depolarization and in the duration of the plateau. The aftereffect of stimulation could last for minutes. No clear excitatory postsynaptic potential (EPSP) was observed, however. On high frequency stimulation, a small depolarizing response (the initial response) was sometimes observed, but the major postsynaptic event was the following slow depolarization, or the enhancement of the pacemaker potential (the late response). With hyperpolarization the initial response did not significantly change its amplitude, but the late response disappeared, showing that the latter has the property of the local response. The membrane conductance did not increase with acceleratory stimulation. The injection of depolarizing current increased the rate of rise of the spontaneous depolarization, but only slightly in comparison with acceleratory stimulation, and did not increase the burst duration. It is concluded that the acceleratory effect is not mediated by the EPSP but is due to a direct action of the transmitter on the pacemaker membrane. PMID:5796369

  6. Circadian Regulation of Olfactory Receptor Neurons in the Cockroach Antenna

    PubMed Central

    Saifullah, A.S.M.; Page, Terry L.

    2013-01-01

    In the cockroach, olfactory sensitivity as measured by the amplitude of the electroantennogram (EAG) is regulated by the circadian system. We wished to determine how this rhythm in antennal response was reflected in the activity of individual olfactory receptor neurons. The amplitude of the electroantennogram (EAG) and the activity of olfactory receptor neurons (ORNs) in single olfactory sensilla were recorded simultaneously for 3–5 days in constant darkness from an antenna of the cockroach Leucophaea maderae. Both EAG amplitude and the spike frequency of the ORNs exhibited circadian rhythms with peak amplitude/activity occurring in the subjective day. The phases of the rhythms were dependent on the phase of the prior light cycle and thus were entrainable by light. Ablation of the optic lobes abolished the rhythm in EAG amplitude as has been previously reported. In contrast, the rhythm in ORN response persisted following surgery. These results indicated that a circadian clock outside the optic lobes can regulate the responses of olfactory receptor neurons and further that this modulation of the ORN response is not dependent on the circadian rhythm in EAG amplitude. PMID:19346451

  7. The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker

    PubMed Central

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

    2013-01-01

    Rev-erbα is a ubiquitously expressed orphan nuclear receptor which functions as a constitutive transcriptional repressor and is expressed in vertebrates according to a robust circadian rhythm. We report here that two Rev-erbα mRNA isoforms, namely Rev-erbα1 and Rev-erbα2, are generated through alternative promoter usage and that both show a circadian expression pattern in an in vitro system using serum-shocked fibroblasts. Both promoter regions P1 (Rev-erbα1) and P2 (Rev-erbα2) contain several E-box DNA sequences, which function as response elements for the core circadian-clock components: CLOCK and BMAL1. The CLOCK–BMAL1 heterodimer stimulates the activity of both P1 and P2 promoters in transient transfection assay by 3–6-fold. This activation was inhibited by the overexpression of CRY1, a component of the negative limb of the circadian transcriptional loop. Critical E-box elements were mapped within both promoters. This regulation is conserved in vertebrates since we found that the CLOCK–BMAL1 heterodimer also regulates the zebrafish Rev-erbα gene. In line with these data Rev-erbα circadian expression was strongly impaired in the livers of Clock mutant mice and in the pineal glands of zebrafish embryos treated with Clock and Bmal1 antisense oligonucleotides. Together these data demonstrate that CLOCK is a critical regulator of Rev-erbα circadian gene expression in evolutionarily distant vertebrates and suggest a role for Rev-erbα in the circadian clock output. PMID:15591021

  8. Dissecting differential gene expression within the circadian neuronal circuit of Drosophila

    PubMed Central

    Nagoshi, Emi; Sugino, Ken; Kula, Ela; Okazaki, Etsuko; Tachibana, Taro; Nelson, Sacha; Rosbash, Michael

    2013-01-01

    Behavioral circadian rhythms are controlled by a neuronal circuit consisting of diverse neuronal subgroups. To understand the molecular mechanisms underlying the roles of neuronal subgroups within the Drosophila circadian circuit, we used cell-type specific gene-expression profiling and identified a large number of genes specifically expressed in all clock neurons or in two important subgroups. Moreover, we identified and characterized two circadian genes, which are expressed specifically in subsets of clock cells and affect different aspects of rhythms. The transcription factor Fer2 is expressed in ventral lateral neurons; it is required for the specification of lateral neurons and therefore their ability to drive locomotor rhythms. The Drosophila melanogaster homolog of the vertebrate circadian gene nocturnin is expressed in a subset of dorsal neurons and mediates the circadian light response. The approach should also enable the molecular dissection of many different Drosophila neuronal circuits. PMID:19966839

  9. 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.

  10. Inhibitory Synapses on Pacemaker Neurons in the Heart Ganglion of a Stomatopod, Squilla oratoria

    PubMed Central

    Watanabe, Akira; Obara, Shosaku; Akiyama, Toyohiro

    1968-01-01

    The pacemaker neurons of the Squilla heart ganglion are innervated from the CNS through three pairs of extrinsic nerves. One of them, the α-nerve, is inhibitory to the heart beat. The effect of α-nerve stimulation on the pacemaker potential was examined with intracellular electrodes. Without extrinsic nerve stimulation the membrane potential of the pacemaker cell fluctuated spontaneously. On application of a tetanic train of stimuli to the α-nerve the membrane potential was shifted and fixed to a steady level, which with K2SO4-filled electrodes was near the peak of hyperpolarization after a spontaneous burst, but was less negative with KCl-filled electrodes. The shift of the membrane potential was due to the summated IPSP's. By changing the level of the membrane potential with injection of the polarizing current the IPSP could be reversed in sign, and the size of the IPSP was linearly correlated with the membrane potential level. During inhibition the membrane conductance increased. The increase depended on divalent cation concentrations in the outside medium. In Ca-rich saline the IPSP was greatly enhanced. In Mg-rich saline it was suppressed. The amplitude of antidromic spikes was reduced during inhibition especially when the spike frequency was high. PMID:5722085

  11. Inhibitory synapses on pacemaker neurons in the heart ganglion of a stomatopod, Squilla oratoria.

    PubMed

    Watanabe, A; Obara, S; Akiyama, T

    1968-12-01

    The pacemaker neurons of the Squilla heart ganglion are innervated from the CNS through three pairs of extrinsic nerves. One of them, the alpha-nerve, is inhibitory to the heart beat. The effect of alpha-nerve stimulation on the pacemaker potential was examined with intracellular electrodes. Without extrinsic nerve stimulation the membrane potential of the pacemaker cell fluctuated spontaneously. On application of a tetanic train of stimuli to the alpha-nerve the membrane potential was shifted and fixed to a steady level, which with K(2)SO(4)-filled electrodes was near the peak of hyperpolarization after a spontaneous burst, but was less negative with KCl-filled electrodes. The shift of the membrane potential was due to the summated IPSP's. By changing the level of the membrane potential with injection of the polarizing current the IPSP could be reversed in sign, and the size of the IPSP was linearly correlated with the membrane potential level. During inhibition the membrane conductance increased. The increase depended on divalent cation concentrations in the outside medium. In Ca-rich saline the IPSP was greatly enhanced. In Mg-rich saline it was suppressed. The amplitude of antidromic spikes was reduced during inhibition especially when the spike frequency was high.

  12. Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture

    PubMed Central

    Yu, Xiao; Zecharia, Anna; Zhang, Zhe; Yang, Qianzi; Yustos, Raquel; Jager, Polona; Vyssotski, Alexei L.; Maywood, Elizabeth S.; Chesham, Johanna E.; Ma, Ying; Brickley, Stephen G.; Hastings, Michael H.; Franks, Nicholas P.; Wisden, William

    2014-01-01

    Summary Circadian clocks allow anticipation of daily environmental changes [1]. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body [1]. Although some peripheral clocks have established roles [1], it is unclear what local brain clocks do [2, 3]. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset [4–6]; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness [7–11]. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3 [12]) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN. PMID:25454592

  13. Central and peripheral circadian clocks in mammals.

    PubMed

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

    2012-01-01

    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.

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

    PubMed

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

    2014-06-17

    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.

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

    PubMed

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

    2008-08-15

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

  16. Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances

    PubMed Central

    Khaliq, Zayd M.; Bean, Bruce P.

    2010-01-01

    Dopaminergic neurons in the ventral tegmental area (VTA) fire spontaneously in a pacemaker-like manner. We analyzed the ionic currents that drive pacemaking in dopaminergic VTA neurons, studied in mouse brain slices. Pacemaking was not inhibited by blocking hyperpolarization-activated cation current (Ih) or blocking all calcium current by Mg2+ replacement of Ca2+. Tetrodotoxin (TTX) stopped spontaneous activity and usually resulted in stable resting potentials near −60 mV to −55 mV, 10–15 mV below the action potential threshold. When external sodium was replaced by N-methyl-D-glucamine (NMDG) with TTX present, cells hyperpolarized by an average of −11 mV, suggesting a significant resting sodium conductance not sensitive to TTX. Voltage-clamp experiments using slow (10 mV/s) ramps showed a steady-state, steeply voltage-dependent current blocked by TTX that activates near −60 mV, as well as a sodium “background” current with little voltage-sensitivity, revealed by NMDG replacement for sodium with TTX present. We quantified these two components of sodium current during the pacemaking trajectory using action potential clamp. The initial phase of depolarization, up to about −55 mV, is driven mainly by non-voltage-dependent sodium background current. Above −55 mV, TTX-sensitive voltage-dependent “persistent” Na current helps drive the final phase of depolarization to the spike threshold. Voltage-dependent calcium current is small at all subthreshold voltages. The pacemaking mechanism in VTA neurons differs from that in substantia nigra pars compacta (SNc) neurons, where subthreshold calcium current plays a dominant role. In addition, we found that non-voltage-dependent background sodium current is much smaller in SNc neurons than VTA neurons. PMID:20505107

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

    PubMed Central

    Yamada-Hanff, Jason

    2013-01-01

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

  18. Kinetic properties and functional dynamics of sodium channels during repetitive spiking in a slow pacemaker neuron

    PubMed Central

    Milescu, Lorin S.; Yamanishi, Tadashi; Ptak, Krzysztof; Smith, Jeffrey C.

    2010-01-01

    We examined the kinetic properties of voltage-gated Na+ channels and their contribution to the repetitive spiking activity of medullary raphé neurons, which exhibit slow pacemaking and strong spiking adaptation. The study is based on a combination of whole-cell patch clamp, modeling and real-time computation. Na+ currents were recorded from neurons in brain slices obtained from male and female neonatal rats, using voltage-clamp protocols designed to reduce space-clamp artifacts and to emphasize functionally relevant kinetic features. A detailed kinetic model was formulated to explain the broad range of transient and stationary voltage-dependent properties exhibited by Na+ currents. The model was tested by injecting via dynamic clamp a model-based current as a substitute for the native TTX-sensitive Na+ currents, which were pharmacologically blocked. The model-based current reproduced well the native spike shape and spiking frequency. The dynamics of Na+ channels during repetitive spiking were indirectly examined through this model. By comparing the spiking activities generated with different kinetic models in dynamic clamp experiments, we determined that state-dependent slow inactivation contributes significantly to spiking adaptation. Through real-time manipulation of the model-based current, we established that suprathreshold Na+ current mainly controls spike shape, whereas subthreshold Na+ current modulates spiking frequency and contributes to the pacemaking mechanism. Since the model-based current was injected in the soma, the results also suggest that somatic Na+ channels are sufficient to establish the essential spiking properties of raphé neurons in vitro. PMID:20826674

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

    PubMed

    Abe, Y; Ushirogawa, H; Tomioka, K

    1997-10-01

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

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

    SciTech Connect

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

    1997-05-01

    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 outlet, ranged from 600 to 4,200 W/kg, causing temperature rises from 0.3 to 2.2 C, respectively. Irradiation at an SAR of 4,200 W/kg caused a biphasic change in the firing rate, i.e., a transient decrease in the firing rate followed by a gradual increase to a new level that was 68 {+-} 21% above control. The biphasic changes in the firing rate were reproduced by heating under the condition that the magnitude (2 C) and the rate of temperature rise were equal to those produced by the irradiation. The addition of 0.05 mM of ouabain caused the disappearance of transient responses of the neuron to the irradiation. It was shown that the rate of temperature rise played an important role in the development of a transient neuronal response. The threshold stimulus for a transient response of the BP-4 neutron found in warming experiments was a temperature rise of 0.0025 C/s.

  1. Electrical properties of the pacemaker neurons in the heart ganglion of a stomatopod, Squilla oratoria.

    PubMed

    Watanabe, A; Obara, S; Akiyama, T; Yumoto, K

    1967-03-01

    In the Squilla heart ganglion, the pacemaker is located in the rostral group of cells. After spontaneous firing ceased, the electrophysiological properties of these cells were examined with intracellular electrodes. Cells respond to electrical stimuli with all-or-none action potentials. Direct stimulation by strong currents decreases the size of action potentials. Comparison with action potentials caused by axonal stimulation and analysis of time relations indicate that with stronger currents the soma membrane is directly stimulated whereas with weaker currents the impulse first arises in the axon and then invades the soma. Spikes evoked in a neuron spread into all other neurons. Adjacent cells are interconnected by electrotonic connections. Histologically axons are tied with the side-junction. B spikes of adjacent cells are blocked simultaneously by hyperpolarization or by repetitive stimulation. Experiments show that under such circumstances the B spike is not directly elicited from the A spike but is evoked by invasion of an impulse or electrotonic potential from adjacent cells. On rostral stimulation a small prepotential precedes the main spike. It is interpreted as an action potential from dendrites.

  2. Electrical Properties of the Pacemaker Neurons in the Heart Ganglion of a Stomatopod, Squilla oratoria

    PubMed Central

    Watanabe, Akira; Obara, Shosaku; Akiyama, Toyohiro; Yumoto, Katsuto

    1967-01-01

    In the Squilla heart ganglion, the pacemaker is located in the rostral group of cells. After spontaneous firing ceased, the electrophysiological properties of these cells were examined with intracellular electrodes. Cells respond to electrical stimuli with all-or-none action potentials. Direct stimulation by strong currents decreases the size of action potentials. Comparison with action potentials caused by axonal stimulation and analysis of time relations indicate that with stronger currents the soma membrane is directly stimulated whereas with weaker currents the impulse first arises in the axon and then invades the soma. Spikes evoked in a neuron spread into all other neurons. Adjacent cells are interconnected by electrotonic connections. Histologically axons are tied with the side-junction. B spikes of adjacent cells are blocked simultaneously by hyperpolarization or by repetitive stimulation. Experiments show that under such circumstances the B spike is not directly elicited from the A spike but is evoked by invasion of an impulse or electrotonic potential from adjacent cells. On rostral stimulation a small prepotential precedes the main spike. It is interpreted as an action potential from dendrites. PMID:6034505

  3. Contribution of Drosophila TRPA1-expressing neurons to circadian locomotor activity patterns.

    PubMed

    Lee, Youngseok

    2013-01-01

    In both vertebrates and invertebrates, Transient Receptor Potential (TRP) channels are expressed in sensory neurons and mediate environmental stimuli such as light, sound, temperature, and taste. Some of these channels, however, are expressed only in the brain and their functions remain incompletely understood. Using the GAL4/UAS binary system with a line in which the GAL4 had been knocked into the trpA1 locus in Drosophila, we recently reported new insights into TRPA1 localization and function, including its expression in approximately 15% of all circadian neurons. TRPA1 is expressed in lateral posterior neurons (LPNs), which are known to be highly sensitive to entrainment by temperature cycles. Here, I used the bacterial sodium channel, NaChBac, to examine the effects of altering the electrical properties of trpA1 neurons on circadian rhythms. My results indicate that circadian activity of the flies in the morning, daytime, and evening was affected in a temperature-dependent manner following TRPA1 neuronal activation. Remarkably, TRPA1 neuron activation in flies kept at 18°C impacted the morning peak of circadian activity even though TRPA1 is not expressed in morning cells. Taken together, these results suggest that the activation of TRPA1-expressing neurons may differentially coordinate light/dark circadian entrainment, depending on the temperature.

  4. Developmental change in the contribution of voltage-gated Ca(2+) channels to the pacemaking of deep cerebellar nuclei neurons.

    PubMed

    Alviña, K; Tara, E; Khodakhah, K

    2016-05-13

    The activity of the deep cerebellar nuclei (DCN) neurons conveys the bulk of the output of the cerebellum. To generate these motor signals, DCN neurons integrate synaptic inputs with their own spontaneous activity. We have previously reported that N-type voltage-gated Ca(2+) channels modulate the spontaneous activity of the majority of juvenile DCN neurons in vitro. Specifically, pharmacologically blocking N-type Ca(2+) channels increases their firing rate causing DCN cells to burst. Adult DCN neurons however, behaved differently. To further investigate this change, we have studied here the effect of cadmium on the firing rate of DCN neurons in acute cerebellar slices obtained from adult (>2 months old) or juvenile (12-21 days old) rats and mice. Strikingly, and in contrast to juvenile DCN cells, cadmium did not affect the pacemaking of adult DCN cells. The activity of Purkinje cells (PCs) however was transformed into high-frequency bursting, regardless the age. Further, we questioned whether these findings could be due to an artifact associated with the added difficulty of preparing adult DCN slices. Hence we proceeded to examine the spontaneous activity of DCN neurons in anesthetized juvenile and adult rats and mice in vivo. When cadmium was injected into the DCN in vivo no significant change in firing rate was observed, conversely to most juvenile DCN neurons which showed high-frequency bursts after cadmium injection. In these same animals, PCs pacemaking showed no developmental difference. Thus our results demonstrate a remarkable age-dependent functional modification in the regulation of DCN neurons pacemaking.

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

    PubMed Central

    Ha, Joon; Kuznetsov, Alexey

    2013-01-01

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

  6. Glia-related circadian plasticity in the visual system of Diptera

    PubMed Central

    Górska-Andrzejak, Jolanta

    2012-01-01

    The circadian changes in morphology of the first visual neuropil or lamina of Diptera represent an example of the neuronal plasticity controlled by the circadian clock (circadian plasticity). It is observed in terminals of the compound eye photoreceptor cells, the peripheral oscillators expressing the clock genes. However, it has been found also in their postsynaptic partners, the L1 and L2 monopolar cells, in which the activity of the clock genes have not yet been detected. The circadian input that the L1 and L2 receive seems to originate not only from the retina photoreceptors and from the circadian pacemaker neurons located in the brain, but also from the glial cells that express the clock genes and thus contain circadian oscillators. This paper summarizes the morphological and biochemical rhythms in glia of the optic lobe, shows how they contribute to circadian plasticity, and discusses how glial clocks may modulate circadian rhythms in the lamina. PMID:23986707

  7. Circadian Regulation of Cellular Physiology

    PubMed Central

    Peek, C.B; Ramsey, K.M; Levine, D.C; Marcheva, B; Perelis, M; Bass, J

    2015-01-01

    The circadian clock synchronizes behavioral and physiological processes on a daily basis in anticipation of the light–dark cycle. In mammals, molecular clocks are present in both the central pacemaker neurons and in nearly all peripheral tissues. Clock transcription factors in metabolic tissues coordinate metabolic fuel utilization and storage with alternating periods of feeding and fasting corresponding to the rest–activity cycle. In vitro and in vivo biochemical approaches have led to the discovery of mechanisms underlying the interplay between the molecular clock and the metabolic networks. For example, recent studies have demonstrated that the circadian clock controls rhythmic synthesis of the cofactor nicotinamide adenine dinucleotide (NAD+) and activity of NAD+-dependent sirtuin deacetylase enzymes to regulate mitochondrial function across the circadian cycle. In this chapter, we review current state-of-the-art methods to analyze circadian cycles in mitochondrial bioenergetics, glycolysis, and nucleotide metabolism in both cell-based and animal models. PMID:25707277

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

    PubMed Central

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

    2012-01-01

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

  9. Fluorescence circadian imaging reveals a PDF-dependent transcriptional regulation of the Drosophila molecular clock

    PubMed Central

    Sabado, Virginie; Vienne, Ludovic; Nunes, José Manuel; Rosbash, Michael; Nagoshi, Emi

    2017-01-01

    Circadian locomotor behaviour is controlled by a pacemaker circuit composed of clock-containing neurons. To interrogate the mechanistic relationship between the molecular clockwork and network communication critical to the operation of the Drosophila circadian pacemaker circuit, we established new fluorescent circadian reporters that permit single-cell recording of transcriptional and post-transcriptional rhythms in brain explants and cultured neurons. Live-imaging experiments combined with pharmacological and genetic manipulations demonstrate that the neuropeptide pigment-dispersing factor (PDF) amplifies the molecular rhythms via time-of-day- and activity-dependent upregulation of transcription from E-box-containing clock gene promoters within key pacemaker neurons. The effect of PDF on clock gene transcription and the known role of PDF in enhancing PER/TIM stability occur via independent pathways downstream of the PDF receptor, the former through a cAMP-independent mechanism and the latter through a cAMP-PKA dependent mechanism. These results confirm and extend the mechanistic understanding of the role of PDF in controlling the synchrony of the pacemaker neurons. More broadly, our results establish the utility of the new live-imaging tools for the study of molecular-neural interactions important for the operation of the circadian pacemaker circuit. PMID:28134281

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

    PubMed

    Tseng, Hua-an; Nadim, Farzan

    2010-08-11

    Many oscillatory networks involve neurons that exhibit intrinsic rhythmicity but possess a large variety of voltage-gated currents that interact in a complex fashion, making it difficult to determine which factors control frequency. Yet these neurons often have preferred (resonance) frequencies that can be close to the network frequency. Because the preferred frequency results from the dynamics of ionic currents, it can be assumed to depend on parameters that determine the neuron's oscillatory waveform shape. The pyloric network frequency in the crab Cancer borealis is correlated with the preferred frequency of its bursting pacemaker neurons anterior burster and pyloric dilator (PD). We measured the preferred frequency of the PD neuron in voltage clamp, which allows control of the oscillation voltage range and waveforms (sine waves and realistic oscillation waveforms), and showed that (1) the preferred frequency depends on the voltage range of the oscillating voltage waveform; (2) the slope of the waveform near its peak has a strongly negative correlation with the preferred frequency; and (3) correlations between parameters of the PD neuron oscillation waveform and its preferred frequency can be used to predict shifts in the network frequency. As predicted by these results, dynamic clamp shifts of the upper or lower voltage limits of the PD neuron waveform during ongoing oscillations changed the network frequency, consistent with the predictions from the preferred frequency. These results show that the voltage waveform of oscillatory neurons can be predictive of their preferred frequency and thus the network oscillation frequency.

  11. Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking

    PubMed Central

    Militi, Stefania; Maywood, Elizabeth S.; Sandate, Colby R.; Chesham, Johanna E.; Parsons, Michael J.; Vibert, Jennifer L.; Joynson, Greg M.; Partch, Carrie L.; Hastings, Michael H.; Nolan, Patrick M.

    2016-01-01

    The suprachiasmatic nucleus (SCN) defines 24 h of time via a transcriptional/posttranslational feedback loop in which transactivation of Per (period) and Cry (cryptochrome) genes by BMAL1–CLOCK complexes is suppressed by PER–CRY complexes. The molecular/structural basis of how circadian protein complexes function is poorly understood. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT-SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of Per2Edo/Edo mice by 1.5 h. Structural and biophysical analyses revealed that Edo alters the packing of the highly conserved interdomain linker of the PER2 PAS core such that, although PER2Edo complexes with clock proteins, its vulnerability to degradation mediated by casein kinase 1ε (CSNK1E) is increased. The functional relevance of this mutation is revealed by the ultrashort (<19 h) but robust circadian rhythms in Per2Edo/Edo; Csnk1eTau/Tau mice and the SCN. These periods are unprecedented in mice. Thus, Per2Edo reveals a direct causal link between the molecular structure of the PER2 PAS core and the pace of SCN circadian timekeeping. PMID:26903623

  12. [Multilayered control of the Mammalian circadian system].

    PubMed

    Ode, Koji L; Ueda, Hiroki R

    2014-06-01

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

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

    PubMed Central

    Tseng, Hua-an; Nadim, Farzan

    2010-01-01

    Many oscillatory networks involve neurons that exhibit intrinsic rhythmicity, but possess a large variety of voltage-gated currents which interact in a complex fashion making it difficult to determine which factors control frequency. Yet, these neurons often have preferred (resonance) frequencies that can be close to the network frequency. Because the preferred frequency results from the dynamics of ionic currents, it can be assumed to depend on parameters that determine the neuron’s oscillatory waveform shape. The pyloric network frequency in the crab Cancer borealis is correlated with the preferred frequency of its bursting pacemaker neurons AB and PD. We measure the preferred frequency of the PD neuron in voltage-clamp, which allows control of the oscillation voltage range and waveforms (sine waves and realistic oscillation waveforms), and showthat1) the preferred frequency depends on the voltage range of the oscillating voltage waveform; 2) the slope of the waveform near its peak has a strongly negative correlation with the preferred frequency; and 3) correlations between parameters of the PD neuron oscillation waveform and its preferred frequency can be used to predict shifts in the network frequency. As predicted by these results, dynamic clamp shifts of the upper or lower voltage limits of the PD neuron waveform during ongoing oscillations changed the network frequency, consistent with the predictions from the preferred frequency. These results show that the voltage waveform of oscillatory neurons can be predictive of their preferred frequency and thus the network oscillation frequency. PMID:20702710

  14. A constant light-genetic screen identifies KISMET as a regulator of circadian photoresponses.

    PubMed

    Dubruille, Raphaëlle; Murad, Alejandro; Rosbash, Michael; Emery, Patrick

    2009-12-01

    Circadian pacemakers are essential to synchronize animal physiology and behavior with the dayrationight cycle. They are self-sustained, but the phase of their oscillations is determined by environmental cues, particularly light intensity and temperature cycles. In Drosophila, light is primarily detected by a dedicated blue-light photoreceptor: CRYPTOCHROME (CRY). Upon light activation, CRY binds to the pacemaker protein TIMELESS (TIM) and triggers its proteasomal degradation, thus resetting the circadian pacemaker. To understand further the CRY input pathway, we conducted a misexpression screen under constant light based on the observation that flies with a disruption in the CRY input pathway remain robustly rhythmic instead of becoming behaviorally arrhythmic. We report the identification of more than 20 potential regulators of CRY-dependent light responses. We demonstrate that one of them, the chromatin-remodeling enzyme KISMET (KIS), is necessary for normal circadian photoresponses, but does not affect the circadian pacemaker. KIS genetically interacts with CRY and functions in PDF-negative circadian neurons, which play an important role in circadian light responses. It also affects daily CRY-dependent TIM oscillations in a peripheral tissue: the eyes. We therefore conclude that KIS is a key transcriptional regulator of genes that function in the CRY signaling cascade, and thus it plays an important role in the synchronization of circadian rhythms with the dayrationight cycle.

  15. Circadian Modulation of Dopamine Levels and Dopaminergic Neuron Development Contributes to Attention Deficiency and Hyperactive Behavior

    PubMed Central

    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

    2015-01-01

    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 β 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

  16. 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 β 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.

  17. Dynamic, Nonlinear Feedback Regulation of Slow Pacemaking by A-Type Potassium Current in Ventral Tegmental Area Neurons

    PubMed Central

    Khaliq, Zayd M.; Bean, Bruce P.

    2010-01-01

    We analyzed ionic currents that regulate pacemaking in dopaminergic neurons of the mouse ventral tegmental area by comparing voltage trajectories during spontaneous firing with ramp-evoked currents in voltage clamp. Most recordings were made in brain slice, with key experiments repeated using acutely dissociated neurons, which gave identical results. During spontaneous firing, net ionic current flowing between spikes was calculated from the time derivative of voltage multiplied by cell capacitance, signal-averaged over many firing cycles to enhance resolution. Net inward interspike current had a distinctive nonmonotonic shape, reaching a minimum (generally <1 pA) between −60 and −55 mV. Under voltage clamp, ramps over subthreshold voltages elicited a time- and voltage-dependent outward current that peaked near −55 mV. This current was undetectable with 5 mV/s ramps and increased steeply with depolarization rate over the range (10 –50 mV/s) typical of natural pacemaking. Ramp-evoked subthreshold current was resistant to α-dendrotoxin, paxilline, apamin, and tetraethylammonium but sensitive to 4-aminopyridine and 0.5 mM Ba2+, consistent with A-type potassium current (IA). Same-cell comparison of currents elicited by various ramp speeds with natural spontaneous depolarization showed how the steep dependence of IA on depolarization rate results in small net inward currents during pacemaking. These results reveal a mechanism in which subthreshold IA is near zero at steady state, but is engaged at depolarization rates >10 mV/s to act as a powerful, supralinear feedback element. This feedback mechanism explains how net ionic current can be constrained to <1–2 pA but reliably inward, thus enabling slow, regular firing. PMID:18945898

  18. Phenotyping Circadian Rhythms in Mice.

    PubMed

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-09-01

    Circadian rhythms take place with a periodicity of 24 hr, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the "central pacemaker" of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hr as manifest when an animal is placed into constant dark or "free-running" conditions. Simple measurements of an organism's activity in free-running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their homecage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are presented here including the process of entrainment, determination of tau (period length) in free-running conditions, determination of circadian periodicity in response to light disruption (e.g., jet lag studies), and evaluation of clock plasticity in non-24-hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of environmental surroundings.

  19. Inverse Relationship between Basal Pacemaker Neuron Activity and Aversive Long-Term Memory Formation in Lymnaea stagnalis

    PubMed Central

    Dong, Nancy; Feng, Zhong-Ping

    2017-01-01

    Learning and memory formation are essential physiological functions. While quiescent neurons have long been the focus of investigations into the mechanisms of memory formation, there is increasing evidence that spontaneously active neurons also play key roles in this process and possess distinct rules of activity-dependent plasticity. In this study, we used a well-defined aversive learning model of aerial respiration in the mollusk Lymnaea stagnalis (L. stagnalis) to study the role of basal firing activity of the respiratory pacemaker neuron Right Pedal Dorsal 1 (RPeD1) as a determinant of aversive long-term memory (LTM) formation. We investigated the relationship between basal aerial respiration behavior and RPeD1 firing activity, and examined aversive LTM formation and neuronal plasticity in animals exhibiting different basal aerial respiration behavior. We report that animals with higher basal aerial respiration behavior exhibited early responses to operant conditioning and better aversive LTM formation. Early behavioral response to the conditioning procedure was associated with biphasic enhancements in the membrane potential, spontaneous firing activity and gain of firing response, with an early phase spanning the first 2 h after conditioning and a late phase that is observed at 24 h. Taken together, we provide the first evidence suggesting that lower neuronal activity at the time of learning may be correlated with better memory formation in spontaneously active neurons. Our findings provide new insights into the diversity of cellular rules of plasticity underlying memory formation. PMID:28101006

  20. 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.

  1. Organization of Circadian Behavior Relies on Glycinergic Transmission.

    PubMed

    Frenkel, Lia; Muraro, Nara I; Beltrán González, Andrea N; Marcora, María S; Bernabó, Guillermo; Hermann-Luibl, Christiane; Romero, Juan I; Helfrich-Förster, Charlotte; Castaño, Eduardo M; Marino-Busjle, Cristina; Calvo, Daniel J; Ceriani, M Fernanda

    2017-04-04

    The small ventral lateral neurons (sLNvs) constitute a central circadian pacemaker in the Drosophila brain. They organize daily locomotor activity, partly through the release of the neuropeptide pigment-dispersing factor (PDF), coordinating the action of the remaining clusters required for network synchronization. Despite extensive efforts, the basic principles underlying communication among circadian clusters remain obscure. We identified classical neurotransmitters released by sLNvs through disruption of specific transporters. Adult-specific RNAi-mediated downregulation of the glycine transporter or impairment of glycine synthesis in LNv neurons increased period length by nearly an hour without affecting rhythmicity of locomotor activity. Electrophysiological recordings showed that glycine reduces spiking frequency in circadian neurons. Interestingly, downregulation of glycine receptor subunits in specific sLNv targets impaired rhythmicity, revealing involvement of glycine in information processing within the network. These data identify glycinergic inhibition of specific targets as a cue that contributes to the synchronization of the circadian network.

  2. Circadian and homeostatic regulation of structural synaptic plasticity in hypocretin neurons.

    PubMed

    Appelbaum, Lior; Wang, Gordon; Yokogawa, Tohei; Skariah, Gemini M; Smith, Stephen J; Mourrain, Philippe; Mignot, Emmanuel

    2010-10-06

    Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse number in HCRT axons. This rhythm is regulated primarily by the circadian clock but is also affected by sleep deprivation. Furthermore, NPTX2, a protein implicated in AMPA receptor clustering, modulates circadian synaptic changes. In zebrafish, nptx2b is a rhythmic gene that is mostly expressed in hypothalamic and pineal gland cells. Arrhythmic transgenic nptx2b overexpression (hcrt:NPTX2b) increases synapse number and abolishes rhythmicity in HCRT axons. Finally, hcrt:NPTX2b fish are resistant to the sleep-promoting effects of melatonin. This behavioral effect is consistent with NPTX2b-mediated increased activity of HCRT circuitry. These data provide real-time in vivo evidence of circadian and homeostatic regulation of structural synaptic plasticity.

  3. Dynamic interactions mediated by nonredundant signaling mechanisms couple circadian clock neurons.

    PubMed

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

    2013-11-20

    Interactions among suprachiasmatic nucleus (SCN) neurons are required for robust circadian rhythms entrained to local time. To investigate these signaling mechanisms, we developed a 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 6-12 hr apart after in vivo exposure to long days. Once they are 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 is in an antiphase configuration, but opposes synchrony under steady-state conditions. Further, VIP acts together with GABAA signaling to couple the network in an antiphase configuration, but promotes synchrony under steady-state conditions by counteracting the actions of GABAA signaling. Thus, SCN neurons interact through nonredundant coupling mechanisms influenced by the state of the network.

  4. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Boyle, R.

    2012-01-01

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

  5. The Drosophila Circadian Clock Gates Sleep through Time-of-Day Dependent Modulation of Sleep-Promoting Neurons

    PubMed Central

    Cavanaugh, Daniel J.; Vigderman, Abigail S.; Dean, Terry; Garbe, David S.; Sehgal, Amita

    2016-01-01

    Study Objectives: Sleep is under the control of homeostatic and circadian processes, which interact to determine sleep timing and duration, but the mechanisms through which the circadian system modulates sleep are largely unknown. We therefore used adult-specific, temporally controlled neuronal activation and inhibition to identify an interaction between the circadian clock and a novel population of sleep-promoting neurons in Drosophila. Methods: Transgenic flies expressed either dTRPA1, a neuronal activator, or Shibirets1, an inhibitor of synaptic release, in small subsets of neurons. Sleep, as determined by activity monitoring and video tracking, was assessed before and after temperature-induced activation or inhibition using these effector molecules. We compared the effect of these manipulations in control flies and in mutant flies that lacked components of the molecular circadian clock. Results: Adult-specific activation or inhibition of a population of neurons that projects to the sleep-promoting dorsal Fan-Shaped Body resulted in bidirectional control over sleep. Interestingly, the magnitude of the sleep changes were time-of-day dependent. Activation of sleep-promoting neurons was maximally effective during the middle of the day and night, and was relatively ineffective during the day-to-night and night-to-day transitions. These time-ofday specific effects were absent in flies that lacked functional circadian clocks. Conclusions: We conclude that the circadian system functions to gate sleep through active inhibition at specific times of day. These data identify a mechanism through which the circadian system prevents premature sleep onset in the late evening, when homeostatic sleep drive is high. Citation: Cavanaugh DJ, Vigderman AS, Dean T, Garbe DS, Sehgal A. The Drosophila circadian clock gates sleep through time-of-day dependent modulation of sleep-promoting neurons. SLEEP 2016;39(2):345–356. PMID:26350473

  6. Cell Autonomy and Synchrony of Suprachiasmatic Nucleus Circadian Oscillators

    PubMed Central

    Mohawk, Jennifer A.; Takahashi, Joseph S.

    2013-01-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this Review, we will highlight recent advances in our understanding of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

  7. Mauthner cell-initiated electromotor behavior is mediated via NMDA and metabotropic glutamatergic receptors on medullary pacemaker neurons in a gymnotid fish.

    PubMed

    Curti, S; Falconi, A; Morales, F R; Borde, M

    1999-10-15

    Weakly electric fish generate meaningful electromotor behaviors by specific modulations of the discharge of their medullary pacemaker nucleus from which the rhythmic command for each electric organ discharge (EOD) arises. Certain electromotor behaviors seem to involve the activation of specific neurotransmitter receptors on particular target cells within the nucleus, i.e., on pacemaker or on relay cells. This paper deals with the neural basis of the electromotor behavior elicited by activation of Mauthner cells in Gymnotus carapo. This behavior consists of an abrupt and prolonged increase in the rate of the EOD. The effects of specific glutamate agonists and antagonists on basal EOD frequency and on EOD accelerations induced by Mauthner cell activation were assessed. Injections of both ionotropic (AMPA, kainate, and NMDA) and metabotropic (trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid) glutamate agonists induced increases in EOD rate that were maximal when performed close to the soma of pacemaker cells. In contrast, injections in the proximity of relay cells were ineffective. Therefore, pacemaker neurons are probably endowed with diverse glutamate receptor subtypes, whereas relay cells are probably not. The Mauthner cell-evoked electromotor behavior was suppressed by injections of AP-5 and (+/-)-amino-4-carboxy-methyl-phenylacetic acid, NMDA receptor and metabotropic glutamate receptor antagonists, respectively. Thus, this electromotor behavior relies on the activation of the NMDA and metabotropic glutamate receptor subtypes of pacemaker cells. Our study gives evidence for the synergistic effects of NMDA and metabotropic receptor activation and shows how a simple circuit can produce specific electromotor outputs.

  8. Circadian Rhythms in Rho1 Activity Regulate Neuronal Plasticity and Network Hierarchy.

    PubMed

    Petsakou, Afroditi; Sapsis, Themistoklis P; Blau, Justin

    2015-08-13

    Neuronal plasticity helps animals learn from their environment. However, it is challenging to link specific changes in defined neurons to altered behavior. Here, we focus on circadian rhythms in the structure of the principal s-LNv clock neurons in Drosophila. By quantifying neuronal architecture, we observed that s-LNv structural plasticity changes the amount of axonal material in addition to cycles of fasciculation and defasciculation. We found that this is controlled by rhythmic Rho1 activity that retracts s-LNv axonal termini by increasing myosin phosphorylation and simultaneously changes the balance of pre-synaptic and dendritic markers. This plasticity is required to change clock network hierarchy and allow seasonal adaptation. Rhythms in Rho1 activity are controlled by clock-regulated transcription of Puratrophin-1-like (Pura), a Rho1 GEF. Since spinocerebellar ataxia is associated with mutations in human Puratrophin-1, our data support the idea that defective actin-related plasticity underlies this ataxia.

  9. The Organization of the Suprachiasmatic Circadian Pacemaker of the Rat and Its Regulation by Neurotransmitters and Modulators

    DTIC Science & Technology

    1994-02-02

    of suprachiasmatic neuronal activity and sensitivity. Invited presentation at the World Federation of Sleep Research Societies meeting on the...Cellular Consequences of Sleep , Maui, HI, March, 1993. Ding, J.M. and Gillette, M.U. 1993. Glutamate induces light-like phase shifts in the rat SCN in brain...described for cyclic adenosine monophosphate (Prosser and Gillette, 1989). cyclic guanosine monophosphate (Prosser et al.. 1989) and melatonin

  10. Pacemaker (image)

    MedlinePlus

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

  11. Light Activates Output from Evening Neurons and Inhibits Output from Morning Neurons in the Drosophila Circadian Clock

    PubMed Central

    Picot, Marie; Cusumano, Paola; Klarsfeld, André; Ueda, Ryu; Rouyer, François

    2007-01-01

    Animal circadian clocks are based on multiple oscillators whose interactions allow the daily control of complex behaviors. The Drosophila brain contains a circadian clock that controls rest–activity rhythms and relies upon different groups of PERIOD (PER)–expressing neurons. Two distinct oscillators have been functionally characterized under light-dark cycles. Lateral neurons (LNs) that express the pigment-dispersing factor (PDF) drive morning activity, whereas PDF-negative LNs are required for the evening activity. In constant darkness, several lines of evidence indicate that the LN morning oscillator (LN-MO) drives the activity rhythms, whereas the LN evening oscillator (LN-EO) does not. Since mutants devoid of functional CRYPTOCHROME (CRY), as opposed to wild-type flies, are rhythmic in constant light, we analyzed transgenic flies expressing PER or CRY in the LN-MO or LN-EO. We show that, under constant light conditions and reduced CRY function, the LN evening oscillator drives robust activity rhythms, whereas the LN morning oscillator does not. Remarkably, light acts by inhibiting the LN-MO behavioral output and activating the LN-EO behavioral output. Finally, we show that PDF signaling is not required for robust activity rhythms in constant light as opposed to its requirement in constant darkness, further supporting the minor contribution of the morning cells to the behavior in the presence of light. We therefore propose that day–night cycles alternatively activate behavioral outputs of the Drosophila evening and morning lateral neurons. PMID:18044989

  12. Effects of TWIN-OF-EYELESS on Clock Gene Expression and Central-Pacemaker Neuron Development in Drosophila

    PubMed Central

    Glossop, Nicholas Robert John; Gummadova, Jennet Orazmuradovna; Ghangrekar, Indrayani; Hardin, Paul Eric; Coutts, Graham Andrew

    2014-01-01

    Circadian oscillators are autonomous molecular rhythms that reside in cells to align whole organism physiology and behaviour to the 24h day. In flies, as in mammals, the oscillator operates in cells that co-express CLOCK (CLK) and CYCLE (CYC). Recent work in Drosophila has shown that CLK is unique in its ability to generate heterologous oscillators, indicating that Clk-gene-expression defines the circadian-cell-fate. Here, using standard in vitro and in vivo techniques, we show that TWIN-OF-EYELESS (TOY; dPax6) regulates Clk-expression in small ventrolateral neurons (s-LNvs) that coordinate sleep-wake cycles. Crucially, toy binds multiple sites at the Clk locus; is expressed independent of CLK-CYC in LNvs; regulates CLK protein levels under optimal photoperiodic conditions; and, sets clock-speed during endogenous free-run. Furthermore, TOY is necessary for the onset of Clk-expression in LNvs during embryogenesis. We propose that TOY contributes to a transcription complex that functions upstream of the oscillator to promote Clk-expression in s-LNvs. PMID:24916389

  13. Mammalian circadian signaling networks and therapeutic targets.

    PubMed

    Liu, Andrew C; Lewis, Warren G; Kay, Steve A

    2007-10-01

    Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is a key feature of the circadian clock system. In particular, intercellular coupling in the SCN synchronizes neuron oscillators and confers robustness against perturbations. Recent advances in our knowledge of and ability to manipulate circadian rhythms make available cell-based clock models, which lack strong coupling and are ideal for target discovery and chemical biology.

  14. Transmedulla Neurons in the Sky Compass Network of the Honeybee (Apis mellifera) Are a Possible Site of Circadian Input

    PubMed Central

    Zeller, Maximilian; Held, Martina; Bender, Julia; Berz, Annuska; Heinloth, Tanja; Hellfritz, Timm; Pfeiffer, Keram

    2015-01-01

    Honeybees are known for their ability to use the sun’s azimuth and the sky’s polarization pattern for spatial orientation. Sky compass orientation in bees has been extensively studied at the behavioral level but our knowledge about the underlying neuronal systems and mechanisms is very limited. Electrophysiological studies in other insect species suggest that neurons of the sky compass system integrate information about the polarization pattern of the sky, its chromatic gradient, and the azimuth of the sun. In order to obtain a stable directional signal throughout the day, circadian changes between the sky polarization pattern and the solar azimuth must be compensated. Likewise, the system must be modulated in a context specific way to compensate for changes in intensity, polarization and chromatic properties of light caused by clouds, vegetation and landscape. The goal of this study was to identify neurons of the sky compass pathway in the honeybee brain and to find potential sites of circadian and neuromodulatory input into this pathway. To this end we first traced the sky compass pathway from the polarization-sensitive dorsal rim area of the compound eye via the medulla and the anterior optic tubercle to the lateral complex using dye injections. Neurons forming this pathway strongly resembled neurons of the sky compass pathway in other insect species. Next we combined tracer injections with immunocytochemistry against the circadian neuropeptide pigment dispersing factor and the neuromodulators serotonin, and γ-aminobutyric acid. We identified neurons, connecting the dorsal rim area of the medulla to the anterior optic tubercle, as a possible site of neuromodulation and interaction with the circadian system. These neurons have conspicuous spines in close proximity to pigment dispersing factor-, serotonin-, and GABA-immunoreactive neurons. Our data therefore show for the first time a potential interaction site between the sky compass pathway and the circadian

  15. Transmedulla Neurons in the Sky Compass Network of the Honeybee (Apis mellifera) Are a Possible Site of Circadian Input.

    PubMed

    Zeller, Maximilian; Held, Martina; Bender, Julia; Berz, Annuska; Heinloth, Tanja; Hellfritz, Timm; Pfeiffer, Keram

    2015-01-01

    Honeybees are known for their ability to use the sun's azimuth and the sky's polarization pattern for spatial orientation. Sky compass orientation in bees has been extensively studied at the behavioral level but our knowledge about the underlying neuronal systems and mechanisms is very limited. Electrophysiological studies in other insect species suggest that neurons of the sky compass system integrate information about the polarization pattern of the sky, its chromatic gradient, and the azimuth of the sun. In order to obtain a stable directional signal throughout the day, circadian changes between the sky polarization pattern and the solar azimuth must be compensated. Likewise, the system must be modulated in a context specific way to compensate for changes in intensity, polarization and chromatic properties of light caused by clouds, vegetation and landscape. The goal of this study was to identify neurons of the sky compass pathway in the honeybee brain and to find potential sites of circadian and neuromodulatory input into this pathway. To this end we first traced the sky compass pathway from the polarization-sensitive dorsal rim area of the compound eye via the medulla and the anterior optic tubercle to the lateral complex using dye injections. Neurons forming this pathway strongly resembled neurons of the sky compass pathway in other insect species. Next we combined tracer injections with immunocytochemistry against the circadian neuropeptide pigment dispersing factor and the neuromodulators serotonin, and γ-aminobutyric acid. We identified neurons, connecting the dorsal rim area of the medulla to the anterior optic tubercle, as a possible site of neuromodulation and interaction with the circadian system. These neurons have conspicuous spines in close proximity to pigment dispersing factor-, serotonin-, and GABA-immunoreactive neurons. Our data therefore show for the first time a potential interaction site between the sky compass pathway and the circadian

  16. SIRT1 Relays Nutritional Inputs to the Circadian Clock Through the Sf1 Neurons of the Ventromedial Hypothalamus

    PubMed Central

    Orozco-Solis, Ricardo; Ramadori, Giorgio; Coppari, Roberto

    2015-01-01

    Circadian rhythms govern homeostasis and organism physiology. Nutritional cues act as time givers, contributing to the synchronization between central and peripheral clocks. Neuronal food-synchronized clocks are thought to reside in hypothalamic nuclei such as the ventromedial hypothalamus (VMH) and the dorsomedial hypothalamus or extrahypothalamic brain areas such as nucleus accumbens. Interestingly, the metabolic sensor of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1) is highly expressed in the VMH and was shown to contribute to both control of energy balance and clock function. We used mice with targeted ablation of Sirt1 in the steroidogenic factor 1 neurons of the VMH to gain insight on the role played by this deacetylase in the modulation of the central clock by nutritional inputs. By studying circadian behavior and circadian gene expression, we reveal that SIRT1 operates as a metabolic sensor connecting food intake to circadian behavior. Indeed, under food restriction and absence of light, SIRT1 in the VMH contributes to activity behavior and circadian gene expression in the suprachiasmatic nucleus. Thus, under specific physiological conditions, SIRT1 contributes to the modulation of the circadian clock by nutrients. PMID:25763637

  17. 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. PMID:26097465

  18. Circadian Rhythm of Neuron R15 of Aplysia californica: In Vivo Photoentrainment.

    PubMed

    Audesirk, G; Strumwasser, F

    1975-06-01

    (1) The neuron R15 in the parietovisceral ganglion of Aplysia has a circadian rhythm of spiking activity when recorded in the isolated ganglion. The rhythm is entrained in vivo by light-dark cycles. (2) The phase of the R15 rhythm is a function not only of the entraining light schedule, but also of the time of dissection. Changes in the dissection time during the light portion of the light-dark cycle yield little change in the subsequent R15 peak time. Dissections during the dark portion produce peak times that vary with dissection time with a slope that is approximately one. (3) The circadian rhythm of R15 can be phase-shifted in vivo by changes in the phase of the entraining light-dark cycle in one to two weeks. R15 neurons of blinded Aplysia, however, show little or no phase shift in this time. (4) It is concluded that the eyes are important as receptors for the photoentrainment of the R15 rhythm in vivo, but that neural connections from the eyes to R15 are not required.

  19. Circadian Rhythm of Neuron R15 of Aplysia californica: In Vivo Photoentrainment

    PubMed Central

    Audesirk, Gerald; Strumwasser, Felix

    1975-01-01

    (1) The neuron R15 in the parietovisceral ganglion of Aplysia has a circadian rhythm of spiking activity when recorded in the isolated ganglion. The rhythm is entrained in vivo by light-dark cycles. (2) The phase of the R15 rhythm is a function not only of the entraining light schedule, but also of the time of dissection. Changes in the dissection time during the light portion of the light-dark cycle yield little change in the subsequent R15 peak time. Dissections during the dark portion produce peak times that vary with dissection time with a slope that is approximately one. (3) The circadian rhythm of R15 can be phase-shifted in vivo by changes in the phase of the entraining light-dark cycle in one to two weeks. R15 neurons of blinded Aplysia, however, show little or no phase shift in this time. (4) It is concluded that the eyes are important as receptors for the photoentrainment of the R15 rhythm in vivo, but that neural connections from the eyes to R15 are not required. PMID:16592252

  20. 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.

  1. Fast Delayed Rectifier Potassium Current Required for Circadian Neural Activity

    PubMed Central

    JN, Itri; S, Michel; MJ, Vansteensel; JH, Meijer; CS, 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 underlying these rhythms are largely unknown. Using the mouse brain slice preparation, we demonstrate that the magnitude of fast delayed rectifier potassium currents exhibits a diurnal rhythm that peaks during the day. Importantly, 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 found to be widely distributed within the SCN with higher expression during the day. We conclude that the fast delayed rectifier 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

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

    PubMed Central

    Jones, Jeff R.

    2016-01-01

    The brain’s biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. PMID:27602274

  3. 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 α and KV β2 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.

  4. 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 α and KVβ2 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

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

    PubMed Central

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

    2009-01-01

    Background In mammals, the synchronized activity of cell autonomous clocks in the suprachiasmatic nuclei (SCN) enables this structure to function as the master circadian clock, coordinating daily rhythms in physiology and behavior. However, the dominance of this clock has been challenged by the observations that metabolic duress can over-ride SCN controlled rhythms, and that clock genes are expressed in many brain areas, including those implicated in the regulation of appetite and feeding. The recent development of mice in which clock gene/protein activity is reported by bioluminescent constructs (luciferase or luc) now enables us to track molecular oscillations in numerous tissues ex vivo. Consequently we determined both clock activities and responsiveness to metabolic perturbations of cells and tissues within the mediobasal hypothalamus (MBH), a site pivotal for optimal internal homeostatic regulation. Results Here we demonstrate endogenous circadian rhythms of PER2::LUC expression in discrete subdivisions of the arcuate (Arc) and dorsomedial nuclei (DMH). Rhythms resolved to single cells did not maintain long-term synchrony with one-another, leading to a damping of oscillations at both cell and tissue levels. Complementary electrophysiology recordings revealed rhythms in neuronal activity in the Arc and DMH. Further, PER2::LUC rhythms were detected in the ependymal layer of the third ventricle and in the median eminence/pars tuberalis (ME/PT). A high-fat diet had no effect on the molecular oscillations in the MBH, whereas food deprivation resulted in an altered phase in the ME/PT. Conclusion Our results provide the first single cell resolution of endogenous circadian rhythms in clock gene expression in any intact tissue outside the SCN, reveal the cellular basis for tissue level damping in extra-SCN oscillators and demonstrate that an oscillator in the ME/PT is responsive to changes in metabolism. PMID:19712475

  6. The neuroarchitecture of the circadian clock in the brain of Drosophila melanogaster.

    PubMed

    Helfrich-Förster, Charlotte

    2003-10-01

    Neuroethologists try to assign behavioral functions to certain brain centers, if possible down to individual neurons and to the expression of specific genes. This approach has been successfully applied for the control of circadian rhythmic behavior in the fruit fly Drosophila melanogaster. Several so-called "clock genes" are expressed in specific neurons in the lateral and dorsal brain where they generate cell-autonomous molecular circadian oscillations. These clusters are connected with each other and contribute differentially to the control of behavioral rhythmicity. This report reviews the latest work on characterizing individual circadian pacemaker neurons in the fruit fly's brain that control activity and pupal eclosion, leading to the questions by which neuronal pathways they are synchronized to the external light-dark cycle, and how they impose periodicity on behavior.

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

    PubMed Central

    Mordel, Jérôme; Karnas, Diana; Inyushkin, Alexey; Challet, Etienne; Pévet, Paul; Meissl, Hilmar

    2011-01-01

    Abstract In mammals, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is composed of numerous synchronized oscillating cells that drive daily behavioural and physiological processes. Several entrainment pathways, afferent inputs to the SCN with their neurotransmitter and neuromodulator systems, can reset the circadian system regularly and also modulate neuronal activity within the SCN. In the present study, we investigated the function of the inhibitory neurotransmitter glycine on neuronal activity in the mouse SCN and on resetting of the circadian clock. The effects of glycine on the electrical activity of SCN cells from C57Bl/6 mice were studied either by patch-clamp recordings from acute brain slices or by long-term recordings from organotypic brain slices using multi-microelectrode arrays (MEA). Voltage-clamp recordings confirmed the existence of glycine-induced, chloride-selective currents in SCN neurons. These currents were reversibly suppressed by strychnine, phenylbenzene ω-phosphono-α-amino acid (PMBA) or ginkgolide B, selective blockers of glycine receptors (GlyRs). Long-term recordings of the spontaneous activity of SCN neurons revealed that glycine application induces a phase advance during the subjective day and a phase delay during the early subjective night. Both effects were suppressed by strychnine or by PMBA. These results suggest that glycine is able to modulate circadian activity by acting directly on its specific receptors in SCN neurons. PMID:21486797

  8. Single-Cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes and Interaction Networks Involved in the Central Circadian Clock

    PubMed Central

    Park, James; Zhu, Haisun; O'Sullivan, Sean; Ogunnaike, Babatunde A.; Weaver, David R.; Schwaber, James S.; Vadigepalli, Rajanikanth

    2016-01-01

    Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN). Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular phenotypes, we characterized the transcriptional, spatial, and functional organization of 352 SCN neurons from mice experiencing phase-shifts in their circadian cycle. Using the community structure detection method and multivariate analytical techniques, we identified previously undescribed neuronal phenotypes that are likely to participate in regulatory networks with known SCN cell types. Based on the newly discovered neuronal phenotypes, we developed a data-driven neuronal network structure in which multiple cell types interact through known synaptic and paracrine signaling mechanisms. These results provide a basis from which to interpret the functional variability of SCN neurons and describe methodologies toward understanding how a population of heterogeneous single cells organizes into cellular networks that underlie tissue-level function. PMID:27826225

  9. Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey.

    PubMed

    Landgraf, Dominic; Long, Jaimie E; Welsh, David K

    2016-05-01

    An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined.

  10. Cellular circadian clocks in mood disorders.

    PubMed

    McCarthy, Michael J; Welsh, David K

    2012-10-01

    Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks

  11. Heart pacemaker

    MedlinePlus

    ... PA: Elsevier Saunders; 2015:chap 37. Swerdlow CD, Wang PJ, Zipes DP. Pacemakers and implantable cardioverter-defibrillators. ... and lifestyle Controlling your high blood pressure Dietary fats explained Fast food tips Heart attack - discharge Heart ...

  12. 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.

  13. How coupling determines the entrainment of circadian clocks

    NASA Astrophysics Data System (ADS)

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

    2011-08-01

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

  14. Programmable Pacemaker

    NASA Technical Reports Server (NTRS)

    1996-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2011-11-01

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

  17. Respiratory-like rhythmic activity can be produced by an excitatory network of non-pacemaker neuron models.

    PubMed

    Kosmidis, Efstratios K; Pierrefiche, Olivier; Vibert, Jean-François

    2004-08-01

    It is still unclear whether the respiratory-like rhythm observed in slice preparations containing the pre-Bötzinger complex is of pacemaker or network origin. The rhythm persists in the absence of inhibition, but blocking pacemaker activity did not always result in rhythm abolition. We developed a computational model of the slice to show that respiratory-like rhythm can emerge as a network property without pacemakers or synaptic inhibition. The key currents of our model cell are the low- and high-threshold calcium currents and the calcium-dependent potassium current. Depolarization of a single unit by current steps or by raising the external potassium concentration can induce periodic bursting activity. Gaussian stimulation increased the excitability of the model without evoking oscillatory activity, as indicated by autocorrelation analysis. In response to hyperpolarizing pulses, the model produces prolonged relative refractory periods. At the network level, an increase of external potassium concentration triggers rhythmic activity that can be attributed to cellular periodic bursting, network properties, or both, depending on different parameters. Gaussian stimulation also induces rhythmic activity that depends solely on network properties. In all cases, the calcium-dependent potassium current has a central role in burst termination and interburst duration. However, when periodic inhibition is considered, the activation of this current is responsible for the characteristic amplification ramp of the emerged rhythm. Our results may explain controversial results from studies blocking pacemakers in vitro and show a shift in the role of the calcium-dependent potassium current in the presence of network inhibition.

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

    PubMed Central

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

    2014-01-01

    Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output. DOI: http://dx.doi.org/10.7554/eLife.03781.001 PMID:25217530

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

    PubMed

    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.

  20. Circadian rhythm of temperature preference and its neural control in Drosophila

    PubMed Central

    Kaneko, Haruna; Head, Lauren M.; Ling, Jinli; Tang, Xin; Liu, Yilin; Hardin, Paul E.; Emery, Patrick; Hamada, Fumika N.

    2012-01-01

    A daily body temperature rhythm (BTR) is critical for the maintenance of homeostasis in mammals. While mammals use internal energy to regulate body temperature, ectotherms typically regulate body temperature behaviorally [1]. Some ectotherms maintain homeostasis via a daily temperature preference rhythm (TPR) [2], but the underlying mechanisms are largely unknown. Here, we show that Drosophila exhibit a daily circadian clock dependent TPR that resembles mammalian BTR. Pacemaker neurons critical for locomotor activity are not necessary for TPR; instead, the dorsal neuron 2s (DN2s), whose function was previously unknown, is sufficient. This indicates that TPR, like BTR, is controlled independently from locomotor activity. Therefore, the mechanisms controlling temperature fluctuations in fly TPR and mammalian BTR may share parallel features. Taken together, our results reveal the existence of a novel DN2- based circadian neural circuit that specifically regulates TPR; thus, understanding the mechanisms of TPR will shed new light on the function and neural control of circadian rhythms. PMID:22981774

  1. Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour

    PubMed Central

    Doi, Masao; Murai, Iori; Kunisue, Sumihiro; Setsu, Genzui; Uchio, Naohiro; Tanaka, Rina; Kobayashi, Sakurako; Shimatani, Hiroyuki; Hayashi, Hida; Chao, Hsu-Wen; Nakagawa, Yuuki; Takahashi, Yukari; Hotta, Yunhong; Yasunaga, Jun-ichirou; Matsuoka, Masao; Hastings, Michael H.; Kiyonari, Hiroshi; Okamura, Hitoshi

    2016-01-01

    G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz. PMID:26882873

  2. Photoperiodic modulation of circadian rhythms in the cricket Gryllus bimaculatus.

    PubMed

    Koga, Mika; Ushirogawa, Hiroshi; Tomioka, Kenji

    2005-06-01

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

  3. Differential effects of omega-3 fatty acid docosahexaenoic acid and palmitate on the circadian transcriptional profile of clock genes in immortalized hypothalamic neurons

    PubMed Central

    Greco, James A.; Oosterman, Johanneke E.

    2014-01-01

    Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbα, in a circadian manner. 25 μM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IκBα, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms. PMID:25144192

  4. Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic Nucleus Ex Vivo

    PubMed Central

    Koo, Jinmi; Choe, Han Kyoung; Kim, Hee-Dae; Chun, Sung Kook; Son, Gi Hoon

    2015-01-01

    Background In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. Methods We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. Results Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. Conclusion These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock. PMID:25491783

  5. Mitogen-activated protein kinase is a functional component of the autonomous circadian system in the suprachiasmatic nucleus.

    PubMed

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

    2008-04-30

    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.

  6. Circadian rhythm and menopause.

    PubMed

    Pines, A

    2016-12-01

    Circadian rhythm is an internal biological clock which initiates and monitors various physiological processes with a fixed time-related schedule. The master circadian pacemaker is located in the suprachiasmatic nucleus in the hypothalamus. The circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels. This cyclical physiological process, which is very complex and multifactorial, may be associated with metabolic alterations, atherosclerosis, impaired cognition, mood disturbances and even development of cancer. Sex differences do exist, and the well-known sleep disturbances associated with menopause are a good example. Circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis.

  7. Ontogenetic development of the mammalian circadian system.

    PubMed

    Weinert, Dietmar

    2005-01-01

    This review summarizes the current knowledge about the ontogenetic development of the circadian system in mammals. The developmental changes of overt rhythms are discussed, although the main focus of the review is the underlying neuronal and molecular mechanisms. In addition, the review describes ontogenetic development, not only as a process of morpho-functional maturation. The need of repeated adaptations and readaptations due to changing developmental stage and environmental conditions is also considered. The review analyzes mainly rodent data, obtained from the literature and from the author's own studies. Results from other species, including humans, are presented to demonstrate common features and species-dependent differences. The review first describes the development of the suprachiasmatic nuclei as the central pacemaker system and shows that intrinsic circadian rhythms are already generated in the mammalian fetus. As in adult organisms, the period length is different from 24 h and needs continuous correction by environmental periodicities, or zeitgebers. The investigation of the ontogenetic development of the mechanisms of entrainment reveals that, at prenatal and early postnatal stages, non-photic cues deriving from the mother are effective. Light-dark entrainment develops later. At a certain age, both photic and non-photic zeitgebers may act in parallel, even though the respective time information is 12 h out of phase. That leads to a temporary internal desynchronization. Because rhythmic information needs to be transferred to effector organs, the corresponding neural and humoral signalling pathways are also briefly described. Finally, to be able to transform a rhythmic signal into an overt rhythm, the corresponding effector organs must be functionally mature. As many of these organs are able to generate their own intrinsic rhythms, another aspect of the review is dedicated to the development of peripheral oscillators and mechanisms of their entrainment

  8. Neurobiology of Circadian Rhythm Regulation.

    PubMed

    Rosenwasser, Alan M; Turek, Fred W

    2015-12-01

    Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes. The maintenance of proper coordination within this network of cellular- and tissue-level clocks is essential for health and well-being.

  9. A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

    PubMed Central

    Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L.; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L.; White, Kevin P.; Dinner, Aaron R.; Lear, Bridget C.; Ren, Dejian; Diekman, Casey O.; Raman, Indira M.; Allada, Ravi

    2015-01-01

    Summary Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

  11. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila

    PubMed Central

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-01-01

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. PMID:27577611

  12. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila.

    PubMed

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-08-31

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species.

  13. Heart pacemaker - discharge

    MedlinePlus

    ... please enable JavaScript. A pacemaker is a small, battery-operated device that senses when your heart is ... pacemaker is placed under your skin. These include: Battery powered cordless tools (such as screwdrivers and drills) ...

  14. Calretinin Neurons in the Rat Suprachiasmatic Nucleus.

    PubMed

    Moore, Robert Y

    2016-08-01

    The hypothalamic suprachiasmatic nucleus (SCN), a circadian pacemaker, is present in all mammalian brains. It has a complex organization of peptide-containing neurons that is similar among species, but calcium-binding proteins are expressed variably. Neurons containing calretinin have been described in the SCN in a number of species but not with association to circadian function. The objective of the present study is to characterize a calretinin neuron (CAR) group in the rat anterior hypothalamus anatomically and functionally with a detailed description of its location and a quantitative analysis of neuronal calretinin immunoreactivity at 3 times of day, 0600, 1400, and 1900 h, from animals in either light-dark or constant dark conditions. CAR neurons occupy a region in the dorsal and lateral SCN with a circadian rhythm in CAR immunoreactivity with a peak at 0600 h and a rhythm in cytoplasmic CAR distribution with a peak at 1400 h. CAR neurons should be viewed as an anatomical and functional component of the rat SCN that expands the definition from observations with cell stains. CAR neurons are likely to modulate temporal regulation of calcium in synaptic transmission.

  15. GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

    PubMed Central

    Myung, Jihwan; Hong, Sungho; DeWoskin, Daniel; De Schutter, Erik; Forger, Daniel B.; Takumi, Toru

    2015-01-01

    The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input. We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAA signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation–inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN. PMID:26130804

  16. Vasoactive Intestinal Polypeptide (VIP)-Expressing Neurons in the Suprachiasmatic Nucleus Provide Sparse GABAergic Outputs to Local Neurons with Circadian Regulation Occurring Distal to the Opening of Postsynaptic GABAA Ionotropic Receptors

    PubMed Central

    Fan, Junmei; Zeng, Hongkui; Olson, David P.; Huber, Kimberly M.

    2015-01-01

    GABAergic synaptic transmission plays an important role in resetting and synchronizing circadian rhythms in the suprachiasmatic nucleus (SCN). Although the circadian modulation of intrinsic membrane currents and biochemical signaling have been examined in the SCN, the modulation of specific synaptic pathways within the SCN is unexplored. In addition, little is known about the functional properties of these pathways, including which ones involve GABAA receptors (GABAA-Rs). In brain slices obtained from mice, we examined synaptic responses originating from the SCN neurons expressing vasoactive intestinal peptide (VIP+ neurons). Focusing on the local projection within the ventromedial SCN, we found that VIP+ afferents provided input onto 49% of neurons with a preference for VIP-negative (VIP−) neurons. Responses were mediated by GABAA-Rs. The projection was sparsely connected and preferentially targeted a subset of SCN neurons unrelated to postsynaptic VIP expression. For most aspects of VIP+ network output, there was no circadian regulation. Excitability and spontaneous firing of the presynaptic VIP+ neurons were unchanged between day and night, and their network connectivity and synaptic function up through the evoked synaptic conductance were also unchanged. On the other hand, VIP+ input onto VIP− neurons became less inhibitory at night suggesting a postsynaptic alteration in the coupling of GABAA-R conductances to action potential firing. These data suggest that components of the VIP network and its synaptic output up through GABAA-R opening are invariant during the circadian cycle, but the effect on action potential firing is modulated by postsynaptic processes occurring after GABAA-R channel opening. PMID:25653351

  17. Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss

    PubMed Central

    Tinarelli, Federico; Garcia-Garcia, Celina; Nicassio, Francesco; Tucci, Valter

    2014-01-01

    Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects. PMID:24446504

  18. Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss.

    PubMed

    Tinarelli, Federico; Garcia-Garcia, Celina; Nicassio, Francesco; Tucci, Valter

    2014-03-05

    Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects.

  19. Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats

    PubMed Central

    Sikkema, Carl

    2016-01-01

    In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned “internal synchronization,” but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression. PMID:28090585

  20. 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.

  1. Adaptation of Circadian Neuronal Network to Photoperiod in High-Latitude European Drosophilids.

    PubMed

    Menegazzi, Pamela; Dalla Benetta, Elena; Beauchamp, Marta; Schlichting, Matthias; Steffan-Dewenter, Ingolf; Helfrich-Förster, Charlotte

    2017-03-20

    The genus Drosophila contains over 2,000 species that, stemming from a common ancestor in the Old World Tropics, populate today very different environments [1, 2] (reviewed in [3]). We found significant differences in the activity pattern of Drosophila species belonging to the holarctic virilis group, i.e., D. ezoana and D. littoralis, collected in Northern Europe, compared to that of the cosmopolitan D. melanogaster, collected close to the equator. These behavioral differences might have been of adaptive significance for colonizing high-latitude habitats and hence adjust to long photoperiods. Most interestingly, the flies' locomotor activity correlates with the neurochemistry of their circadian clock network, which differs between low and high latitude for the expression pattern of the blue light photopigment cryptochrome (CRY) and the neuropeptide Pigment-dispersing factor (PDF) [4-6]. In D. melanogaster, CRY and PDF are known to modulate the timing of activity and to maintain robust rhythmicity under constant conditions [7-11]. We could partly simulate the rhythmic behavior of the high-latitude virilis group species by mimicking their CRY/PDF expression patterns in a laboratory strain of D. melanogaster. We therefore suggest that these alterations in the CRY/PDF clock neurochemistry might have allowed the virilis group species to colonize high-latitude environments.

  2. Photopic transduction implicated in human circadian entrainment

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  3. A dual-color luciferase assay system reveals circadian resetting of cultured fibroblasts by co-cultured adrenal glands.

    PubMed

    Noguchi, Takako; Ikeda, Masaaki; Ohmiya, Yoshihiro; Nakajima, Yoshihiro

    2012-01-01

    In mammals, circadian rhythms of various organs and tissues are synchronized by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. Glucocorticoids released from the adrenal glands can synchronize circadian rhythms in other tissues. Many hormones show circadian rhythms in their plasma concentrations; however, whether organs outside the SCN can serve as master synchronizers to entrain circadian rhythms in target tissues is not well understood. To further delineate the function of the adrenal glands and the interactions of circadian rhythms in putative master synchronizing organs and their target tissues, here we report a simple co-culture system using a dual-color luciferase assay to monitor circadian rhythms separately in various explanted tissues and fibroblasts. In this system, circadian rhythms of organs and target cells were simultaneously tracked by the green-emitting beetle luciferase from Pyrearinus termitilluminans (ELuc) and the red-emitting beetle luciferase from Phrixothrix hirtus (SLR), respectively. We obtained tissues from the adrenal glands, thyroid glands, and lungs of transgenic mice that expressed ELuc under control of the promoter from a canonical clock gene, mBmal1. The tissues were co-cultured with Rat-1 fibroblasts as representative target cells expressing SLR under control of the mBmal1 promoter. Amplitudes of the circadian rhythms of Rat-1 fibroblasts were potentiated when the fibroblasts were co-cultured with adrenal gland tissue, but not when co-cultured with thyroid gland or lung tissue. The phases of Rat-1 fibroblasts were reset by application of adrenal gland tissue, whereas the phases of adrenal gland tissue were not influenced by Rat-1 fibroblasts. Furthermore, the effect of the adrenal gland tissue on the fibroblasts was blocked by application of a glucocorticoid receptor (GR) antagonist. These results demonstrate that glucocorticoids are strong circadian synchronizers for fibroblasts and that this co

  4. Folate deprivation modulates the expression of autophagy- and circadian-related genes in HT-22 hippocampal neuron cells through GR-mediated pathway.

    PubMed

    Sun, Qinwei; Yang, Yang; Li, Xi; He, Bin; Jia, Yimin; Zhang, Nana; Zhao, Ruqian

    2016-08-01

    Folic acid (FA) is an extremely important nutrient for brain formation and development. FA deficiency is highly linked to brain degeneration and age-related diseases, which are also associated with autophagic activities and circadian rhythm in hippocampal neurons. However, little is known how autophagy- and circadian-related genes in hippocampal neurons are regulated under FA deficiency. Here, hippocampal neuroncells (HT-22) were employed to determine the effect of FA deprivation (FD) on the expression of relevant genes and to reveal the potential role of glucocorticoid receptor (GR). FD increased autophagic activities in HT-22 cells, associated with significantly (P<0.05) enhanced GR activation indicated by higher ratio of GR phosphorylation. Out of 17 autophagy-related genes determined, 8 was significantly (P<0.05) up-regulated in FD group, which includes ATG2b, ATG3, ATG4c, ATG5, ATG10, ATG12, ATG13 and ATG14. Meanwhile, 4 out of 7 circadian-related genes detected, Clock, Cry1, Cry2 and Per2, were significantly (P<0.05) up-regulated. The protein content of autophagy markers, LC3A and LC3B, was also increased significantly (P<0.05). ChIP assay showed that FD promoted (P<0.05) GR binding to the promoter sequence of ATG3 and Per2. Moreover, MeDIP analysis demonstrated significant (P<0.05) hypomethylation in the promoter sequence of ATG12, ATG13 and Per2 genes. Together, we speculate that FD increases the transcription of autophagy- and circadian-related genes through, at least partly, GR-mediated pathway. Our results provide a basis for future investigations into the intracellular regulatory network in response to folate deficiency.

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

    PubMed

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

    1998-11-01

    Codings involving spike trains at synapses with inhibitory postsynaptic potentials on pacemakers were examined in crayfish stretch receptor organs by modulating presynaptic instantaneous rates periodically (triangles or sines; frequencies, slopes and depths under, respectively, 5.0 Hz, 40.0/s/s and 25.0/s). Timings were described by interspike and cross-intervals ("phases"); patterns (dispersions, sequences) and forms (timing classes) were identified using pooled graphs (instant along the cycle when a spike occurs vs preceding interval) and return maps (plots of successive intervals). A remarkable heterogeneity of postsynaptic intervals and phases characterizes each modulation. All cycles separate into the same portions: each contains a particular form and switches abruptly to the next. Forms differ in irregularity and predictability: they are (see text) "p:q alternations", "intermittent", "phase walk-throughs", "messy erratic" and "messy stammering". Postsynaptic cycles are asymmetric (hysteresis). This contrasts with the presynaptic homogeneity, smoothness and symmetry. All control parameters are, individually and jointly, strongly influential. Presynaptic slopes, say, act through a postsynaptic sensitivity to their magnitude and sign; when increasing, hysteresis augments and forms change or disappear. Appropriate noise attenuates between-train contrasts, providing modulations are under 0.5 Hz. Postsynaptic natural intervals impose critical time bases, separating presynaptic intervals (around, above or below them) with dissimilar consequences. Coding rules are numerous and have restricted domains; generalizations are misleading. Modulation-driven forms are trendy pacemaker-driven forms. However, dissimilarities, slight when patterns are almost pacemaker, increase as inhibition departs from pacemaker and incorporate unpredictable features. Physiological significance-(1) Pacemaker-driven forms, simple and ubiquitous, appear to be elementary building blocks of

  6. Pacemaker-neuron–dependent disturbance of the molecular clockwork by a Drosophila CLOCK mutant homologous to the mouse Clock mutation

    PubMed Central

    Lee, Euna; Cho, Eunjoo; Kang, Doo Hyun; Jeong, Eun Hee; Chen, Zheng; Yoo, Seung-Hee; Kim, Eun Young

    2016-01-01

    Circadian clocks are composed of transcriptional/translational feedback loops (TTFLs) at the cellular level. In Drosophila TTFLs, the transcription factor dCLOCK (dCLK)/CYCLE (CYC) activates clock target gene expression, which is repressed by the physical interaction with PERIOD (PER). Here, we show that amino acids (AA) 657–707 of dCLK, a region that is homologous to the mouse Clock exon 19-encoded region, is crucial for PER binding and E-box–dependent transactivation in S2 cells. Consistently, in transgenic flies expressing dCLK with an AA657–707 deletion in the Clock (Clkout) genetic background (p{dClk-Δ};Clkout), oscillation of core clock genes’ mRNAs displayed diminished amplitude compared with control flies, and the highly abundant dCLKΔ657–707 showed significantly decreased binding to PER. Behaviorally, the p{dClk-Δ};Clkout flies exhibited arrhythmic locomotor behavior in the photic entrainment condition but showed anticipatory activities of temperature transition and improved free-running rhythms in the temperature entrainment condition. Surprisingly, p{dClk-Δ};Clkout flies showed pacemaker-neuron–dependent alterations in molecular rhythms; the abundance of dCLK target clock proteins was reduced in ventral lateral neurons (LNvs) but not in dorsal neurons (DNs) in both entrainment conditions. In p{dClk-Δ};Clkout flies, however, strong but delayed molecular oscillations in temperature cycle-sensitive pacemaker neurons, such as DN1s and DN2s, were correlated with delayed anticipatory activities of temperature transition. Taken together, our study reveals that the LNv molecular clockwork is more sensitive than the clockwork of DNs to dysregulation of dCLK by AA657–707 deletion. Therefore, we propose that the dCLK/CYC-controlled TTFL operates differently in subsets of pacemaker neurons, which may contribute to their specific functions. PMID:27489346

  7. Circadian Rhythms

    MedlinePlus

    ... chronobiology. Are circadian rhythms the same thing as biological clocks? No, but they are related. Our biological clocks drive our circadian rhythms. What are biological clocks? The biological clocks that control circadian rhythms ...

  8. What Is a Pacemaker?

    MedlinePlus

    ... your pacemaker. • If you work around industrial microwaves, electricity, cars or other large motors, ask your doctor about possible effects. Can I use a cell phone or microwave oven if I have a pacemaker? Microwave ovens, electric blankets, remote controls for TV and other common ...

  9. A migrating pacemaker.

    PubMed

    Gale, C P; Mulley, G P

    2005-03-01

    A deceased 79 year old man with a permanent cardiac pacemaker was due to be cremated, but the pacemaker generator was not detectable by palpation. A hand held metal detector to locate the device so that it could be extracted before cremation.

  10. Vasoactive intestinal polypeptide entrains circadian rhythms in astrocytes

    PubMed Central

    Marpegan, Luciano; Krall, Thomas J.; Herzog, Erik D.

    2009-01-01

    Many mammalian cell types show daily rhythms in gene expression driven by a circadian pacemaker. For example, cultured astrocytes display circadian rhythms in Period1 and Period2 expression. It is not known, however, how or which intercellular factors synchronize and sustain rhythmicity in astrocytes. Because astrocytes are highly sensitive to vasoactive intestinal polypeptide (VIP), a neuropeptide released by neurons and important for the coordination of daily cycling, we hypothesized that VIP entrains circadian rhythms in astrocytes. We used astrocyte cultures derived from knock-in mice containing a bioluminescent reporter of PERIOD2 (PER2) protein, to assess the effects of VIP on the rhythmic properties of astrocytes. VIP induced a dose-dependent increase in the peak-to-trough amplitude of the ensemble rhythms of PER2 expression with maximal effects near 100nM VIP and threshold values between 0.1 and 1 nM. VIP also induced dose- and phase-dependent shifts in PER2 rhythms and daily VIP administration entrained bioluminescence rhythms of astrocytes to a predicted phase angle. This is the first demonstration that a neuropeptide can entrain glial cells to a phase predicted by a phase response curve. We conclude that VIP potently entrains astrocytes in vitro and is a candidate for coordinating daily rhythms among glia in the brain. PMID:19346450

  11. Comparative Analysis of Pdf-Mediated Circadian Behaviors Between Drosophila melanogaster and D. virilis

    PubMed Central

    Bahn, Jae Hoon; Lee, Gyunghee; Park, Jae H.

    2009-01-01

    A group of small ventrolateral neurons (s-LNv's) are the principal pacemaker for circadian locomotor rhythmicity of Drosophila melanogaster, and the pigment-dispersing factor (Pdf) neuropeptide plays an essential role as a clock messenger within these neurons. In our comparative studies on Pdf-associated circadian rhythms, we found that daily locomotor activity patterns of D. virilis were significantly different from those of D. melanogaster. Activities of D. virilis adults were mainly restricted to the photophase under light:dark cycles and subsequently became arrhythmic or weakly rhythmic in constant conditions. Such activity patterns resemble those of Pdf01 mutant of D. melanogaster. Intriguingly, endogenous D. virilis Pdf (DvPdf) expression was not detected in the s-LNv-like neurons in the adult brains, implying that the Pdf01-like behavioral phenotypes of D. virilis are attributed in part to the lack of DvPdf in the s-LNv-like neurons. Heterologous transgenic analysis showed that cis-regulatory elements of the DvPdf transgene are capable of directing their expression in all endogenous Pdf neurons including s-LNv's, as well as in non-Pdf clock neurons (LNd's and fifth s-LNv) in a D. melanogaster host. Together these findings suggest a significant difference in the regulatory mechanisms of Pdf transcription between the two species and such a difference is causally associated with species-specific establishment of daily locomotor activity patterns. PMID:19153257

  12. Effect of light during lactation on the phasic and tonic responses of the rat pacemaker.

    PubMed

    Canal-Corretger, M M; Cambras, T; Díez-Noguera, A

    2003-01-01

    The circadian system in mammals generates endogenous circadian rhythms and entrains them to external cycles. Here, we examine whether the lighting conditions under which rats are reared affect the properties of the circadian pacemaker. We maintained three groups of rats under constant darkness (DD-rats), constant bright light (LL-rats) or light-dark cycles of 24 hours (LD-rats) during lactation. We then studied motor activity rhythm under constant light of four intensities, and under seven light-dark cycles with periods ranging between 22 and 27 hours. Results show that neither the tau nor the phase angle to the external cycle differed between groups. Differences were found in the amplitude of the circadian rhythm and in the number of rats that became arrhythmic under LL. We conclude that the light received during lactation affects the strength of the circadian pacemaker and its sensitivity to light.

  13. 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

  14. Endogenous circadian rhythm in human motor activity uncoupled from circadian influences on cardiac dynamics.

    PubMed

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

    2007-12-26

    The endogenous circadian pacemaker influences key physiologic functions, such as body temperature and heart rate, and is normally synchronized with the sleep/wake cycle. Epidemiological studies demonstrate a 24-h pattern in adverse cardiovascular events with a peak at approximately 10 a.m. It is unknown whether this pattern in cardiac risk is caused by a day/night pattern of behaviors, including activity level and/or influences from the internal circadian pacemaker. We recently found that a scaling index of cardiac vulnerability has an endogenous circadian peak at the circadian phase corresponding to approximately 10 a.m., which conceivably could contribute to the morning peak in cardiac risk. Here, we test whether this endogenous circadian influence on cardiac dynamics is caused by circadian-mediated changes in motor activity or whether activity and heart rate dynamics are decoupled across the circadian cycle. We analyze high-frequency recordings of motion from young healthy subjects during two complementary protocols that decouple the sleep/wake cycle from the circadian cycle while controlling scheduled behaviors. We find that static activity properties (mean and standard deviation) exhibit significant circadian rhythms with a peak at the circadian phase corresponding to 5-9 p.m. ( approximately 9 h later than the peak in the scale-invariant index of heartbeat fluctuations). In contrast, dynamic characteristics of the temporal scale-invariant organization of activity fluctuations (long-range correlations) do not exhibit a circadian rhythm. These findings suggest that endogenous circadian-mediated activity variations are not responsible for the endogenous circadian rhythm in the scale-invariant structure of heartbeat fluctuations and likely do not contribute to the increase in cardiac risk at approximately 10 a.m.

  15. Thrombus on pacemaker lead.

    PubMed

    Raut, Monish S; Maheshwari, Arun; Dubey, Sumir

    2015-12-01

    A 58-year-old male was admitted with history of shortness of breath and recurrent fever since two months. He had undergone permanent pacemaker implantation six years back for complete heart block. The patient was persistently having thrombocytopenia. Echocardiographic examination revealed mass (size 4.28 cm(2)) attached to pacemaker lead in right atrium. The patient was scheduled for open-heart surgery for removal of right atrial mass. During surgery, pacemaker leads and pulse generator were also removed along with mass considering the possible source of infection.

  16. Circadian Periods of Sensitivity for Ramelteon on the onset of Running-wheel Activity and the Peak of Suprachiasmatic Nucleus Neuronal Firing Rhythms in C3H/HeN Mice

    PubMed Central

    Rawashdeh, Oliver; Hudson, Randall L.; Stepien, Iwona; Dubocovich, Margarita L.

    2016-01-01

    Ramelteon, an MT1/MT2 melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H/ HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90 μg/mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H/HeN mice. The PRC for ramelteon resembles that for melatonin in C3H/ HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8–CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6 ± 0.29 h, n = 3) and at CT2 phase delays (−3.2 ± 0.12 h, n = 6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7 ± 0.15 h, n = 4, p < .05; CT2: −1.13 ± 0.08 h, n = 6, p < .001, respectively). The phase shifts induced by both melatonin and ramelteon in the SCN brain slice at either CT10 or CT2 corresponded with the period of sensitivity observed in vivo. In conclusion, melatonin and ramelteon showed identical periods of circadian sensitivity at CT10 (advance) and CT2 (delay) to shift the onset of circadian activity rhythms in vivo and the peak of SCN neuronal firing rhythms in vitro

  17. Anatomy and physiology of neurons with processes in the accessory medulla of the cockroach Leucophaea maderae.

    PubMed

    Loesel, R; Homberg, U

    2001-10-15

    The accessory medulla (AMe), a small neuropil in the insect optic lobe, has been proposed to serve a circadian pacemaker function analogous to the role of the suprachiasmatic nucleus in mammals. Building upon considerable knowledge of the circadian system of the cockroach Leucophaea maderae, we investigated the properties of AMe neurons in this insect with intracellular recordings combined with dye injections. Responses of neurons with processes in the AMe to visual stimuli, including stationary white light, moving objects, and polarized light were compared with the responses of adjacent medulla tangential neurons. Neurons with processes in the AMe and additional ramifications in the medulla strongly responded to stationary light stimuli and might, therefore, be part of photic entrainment pathways to the clock. Accessory medulla neurons lacking significant processes in the medulla but with projections to the midbrain or to the contralateral optic lobe, in contrast, responded weakly or not at all to light and, thus, seem to be part of the clock's output pathway. Two types of commissural neurons with tangential arborizations in both medullae were sensitive to polarized light, suggesting a role of these neurons in celestial navigation. Sidebranches in the AMae of one of the two cell types are discussed with respect to a possible involvement of the AMe in polarization vision. Finally, neurons responding to movement stimuli did not arborize in the AMe. The results show that the AMe receives photic input and support a role of this neuropil in circadian timekeeping functions.

  18. Peripheral circadian oscillators and their rhythmic regulation.

    PubMed

    Fukuhara, Chiaki; Tosini, Gianluca

    2003-05-01

    Most of the organisms living on earth show 24 hour (circadian) rhythms that are endogenously controlled by biological clocks. In mammals, these rhythms are generated by the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. However, recent studies have demonstrated that circadian oscillators can be found in many organs and tissues, and it appears that the circadian oscillators in the periphery are not self-sustained, since, in vitro, the oscillation disappears after a few cycles. Although analysis of the clockwork mechanism indicates that the molecular composition of the clock in the SCN and in the peripheral tissues is very similar, the mechanism responsible for the damping of the circadian oscillation in the periphery is unknown. Recent studies have also indicated that the mammalian circadian system is hierarchically organized in that the SCN (i.e., the master circadian pacemaker) controls the peripheral oscillators in order to coordinate the physiological events in an entire body. The mechanisms by which the SCN controls peripheral oscillators are just starting to be elucidated. The aim of this review is to summarize the most recent findings on functioning of these extra-SCN oscillators and the mechanisms the SCN controls peripheral oscillators.

  19. 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

  20. Time keeping by the quail's eye: circadian regulation of melatonin production.

    PubMed

    Steele, Christopher T; Tosini, Gianluca; Siopes, Thomas; Underwood, Herbert

    2006-02-01

    Previous studies have shown that eye removal disrupts the circadian body temperature and activity rhythms of Japanese quail supporting the hypothesis that the eyes act as pacemakers within the quail circadian system. Furthermore, the putative ocular pacemakers are coupled to the rest of the circadian system via neural and hormonal outputs. Although the neural pathway has yet to be identified, experiments suggest that the daily rhythm of ocular melatonin synthesis and release is the hormonal output. We sought to strengthen the hypothesis that the eyes are the loci of circadian pacemakers, and that melatonin output is involved, by examining melatonin secretion in cultured quail retinas. Using an in vitro flow-through system we demonstrated that (1) isolated retinal tissue could exhibit a rhythm of melatonin release, (2) the rhythm of melatonin synthesis is directly entrainable by 24-h light-dark cycles, and (3) supplementation of the culture medium with serotonin is necessary for robust, rhythmic production of melatonin in constant darkness. These results show definitively that the eyes are the loci of a biological clock and, in light of previous studies showing the disruptive effects of blinding on the circadian system, strengthen the hypothesis that the ocular clock is a circadian pacemaker that can affect the rest of the circadian system via the cyclic synthesis and release of melatonin. The quail retina is proving to be a valuable in vitro model for investigating properties of circadian pacemakers.

  1. Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks.

    PubMed

    Tataroglu, Ozgur; Zhao, Xiaohu; Busza, Ania; Ling, Jinli; O'Neill, John S; Emery, Patrick

    2015-11-19

    Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles.

  2. Circadian rhythms and fractal fluctuations in forearm motion

    NASA Astrophysics Data System (ADS)

    Hu, Kun; Hilton, Michael F.

    2005-03-01

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

  3. 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

  4. Circadian Plasticity of Mammalian Inhibitory Interneurons

    PubMed Central

    2017-01-01

    Inhibitory interneurons participate in all neuronal circuits in the mammalian brain, including the circadian clock system, and are indispensable for their effective function. Although the clock neurons have different molecular and electrical properties, their main function is the generation of circadian oscillations. Here we review the circadian plasticity of GABAergic interneurons in several areas of the mammalian brain, suprachiasmatic nucleus, neocortex, hippocampus, olfactory bulb, cerebellum, striatum, and in the retina. PMID:28367335

  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. Radiation effect on implanted pacemakers

    SciTech Connect

    Pourhamidi, A.H.

    1983-10-01

    It was previously thought that diagnostic or therapeutic ionizing radiation did not have an adverse effect on the function of cardiac pacemakers. Recently, however, some authors have reported damaging effect of therapeutic radiation on cardiac pulse generators. An analysis of a recently-extracted pacemaker documented the effect of radiation on the pacemaker pulse generator.

  7. Circadian rhythms of women with fibromyalgia

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.

    2001-01-01

    Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.

  8. Ageing and Circadian rhythms

    PubMed Central

    Giebultowicz, Jadwiga M.; Long, Dani M.

    2015-01-01

    Circadian clocks are cell-autonomous molecular feedback loops that generate daily rhythms in gene expression, cellular functions, physiological processes and behavior. The mechanisms of circadian clocks are well understood in young fruit flies Drosophila melanogaster, but less is known about how circadian system changes during organismal aging. Similar as in humans, rest/activity rhythms tend to weaken with age in fruit flies, suggesting conservation of aging-related changes in the circadian system. It has been shown that aging is associated with reduced expression of core clock genes in peripheral head clocks while similar reduction may not occur in central clock neurons regulating behavioral rhythms. Arrhythmic flies with mutations in core clock genes display accelerated aging and shortened lifespan suggesting that weakened circadian rhythms may contribute to aging phenotypes. To understand whether strong circadian clocks support organism’s healthspan and lifespan, future research needs to focus on age-related changes in clock genes as well as clock-controlled genes in specific organs and tissues. PMID:26000238

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

    Wiater, Michael F; Li, Ai-Jun; Dinh, Thu T; Jansen, Heiko T; Ritter, Sue

    2013-10-15

    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.

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

    PubMed

    Liu, Fang; Chang, Hung-Chun

    2017-01-20

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

  13. The role of circadian rhythm in breast cancer.

    PubMed

    Li, Shujing; Ao, Xiang; Wu, Huijian

    2013-08-01

    The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer.

  14. Impact of nutrients on circadian rhythmicity.

    PubMed

    Oosterman, Johanneke E; Kalsbeek, Andries; la Fleur, Susanne E; Belsham, Denise D

    2015-03-01

    The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.

  15. Impact of nutrients on circadian rhythmicity

    PubMed Central

    Oosterman, Johanneke E.; Kalsbeek, Andries; la Fleur, Susanne E.

    2014-01-01

    The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock. PMID:25519730

  16. Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists.

    PubMed

    Edgar, D M; Miller, J D; Prosser, R A; Dean, R R; Dement, W C

    1993-01-01

    The suprachiasmatic nuclei (SCN) receive primary afferents from the median and dorsal raphe, but the role of these projections in circadian timekeeping is poorly understood. Studies of the SCN in vitro suggest that quipazine, a general serotonin (5-HT) receptor agonist, can produce circadian time-dependent phase advances and phase delays in circadian rhythms of neuronal activity. The present study addresses whether quipazine and the selective 5-HT1A receptor agonist 8-OH-DPAT are similarly effective in vivo. Drinking and wheel-running patterns of male Wistar rats individually housed in constant darkness were monitored before and after subcutaneous administration of quipazine (5-10 mg/kg) at either circadian time (CT) 6 or CT 18, with and without running wheels available. Dose-dependent phase advances (20-180 min) were produced at CT 6. Significant phase shifts were not observed at CT 18. CT 6 quipazine-treated animals also showed a sustained and significant shortening of rhythm period (tau) following treatment (-0.28 hr; p < 0.002). tau shortening was inconsistently observed in CT 18 quipazine-treated rats. Neither quipazine-induced phase shifts nor tau effects were dependent on wheel-running activity per se. 8-OH-DPAT delivered via intracerebral ventricular treatment into the third ventricle (5 microliters at 100 microM in saline) produced slightly smaller phase advances (20-90 min) at CT 6, but did not produce phase delays at CT 18 or changes in tau. These findings support in vitro evidence that 5-HT-ergic agonists can phase-shift the circadian pacemaker.

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

    PubMed

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

    2012-03-15

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

  18. Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals.

    PubMed

    Schibler, Ueli; Gotic, Ivana; Saini, Camille; Gos, Pascal; Curie, Thomas; Emmenegger, Yann; Sinturel, Flore; Gosselin, Pauline; Gerber, Alan; Fleury-Olela, Fabienne; Rando, Gianpaolo; Demarque, Maud; Franken, Paul

    2015-01-01

    In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs.

  19. 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.

  20. Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms.

    PubMed

    Herzog, Erik D; Hermanstyne, Tracey; Smyllie, Nicola J; Hastings, Michael H

    2017-01-03

    The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcription-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Na(+) drive and nighttime K(+) drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep-wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness.

  1. Circadian regulation of lipid metabolism.

    PubMed

    Gooley, Joshua J

    2016-11-01

    The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.

  2. What Are the Risks of Pacemaker Surgery?

    MedlinePlus

    ... NHLBI on Twitter. What Are the Risks of Pacemaker Surgery? Pacemaker surgery generally is safe. If problems do occur, ... bruising, or infection in the area where the pacemaker was placed Blood vessel or nerve damage A ...

  3. Pacemaker leads and cardiac perforation

    PubMed Central

    Prasad, Rachana; Andrews, Richard

    2017-01-01

    This case series highlights the rare but potentially life threatening complication of ventricular perforation caused by pacemaker leads and discusses appropriate investigations and management strategies. PMID:28321317

  4. Pacemaker Use Following Heart Transplantation

    PubMed Central

    Mallidi, Hari R.; Bates, Michael

    2017-01-01

    Background: The incidence of permanent pacemaker implantation after orthotopic heart transplantation has been reported to be 2%-24%. Transplanted hearts usually exhibit sinus rhythm in the operating room following reperfusion, and most patients do not exhibit significant arrhythmias during the postoperative period. However, among the patients who do exhibit abnormalities, pacemakers may be implanted for early sinus node dysfunction but are rarely used after 6 months. Permanent pacing is often required for atrioventricular block. A different cohort of transplant patients presents later with bradycardia requiring pacemaker implantation, reported to occur in approximately 1.5% of patients. The objectives of this study were to investigate the indications for pacemaker implantation, compare the need for pacemakers following bicaval vs biatrial anastomosis, and examine the long-term outcomes of heart transplant patients who received pacemakers. Methods: For this retrospective, case-cohort, single-institution study, patients were identified from clinical research and administrative transplant databases. Information was supplemented with review of the medical records. Standard statistical techniques were used, with chi-square testing for categorical variables and the 2-tailed t test for continuous variables. Survival was compared with the use of log-rank methods. Results: Between January 1968 and February 2008, 1,450 heart transplants were performed at Stanford University. Eighty-four patients (5.8%) were identified as having had a pacemaker implanted. Of these patients, 65.5% (55) had the device implanted within 30 days of transplantation, and 34.5% (29) had late implantation. The mean survival of patients who had an early pacemaker implant was 6.4 years compared to 7.7 years for those with a late pacemaker implant (P<0.05). Sinus node dysfunction and heart block were the most common indications for pacemaker implantation. Starting in 1997, a bicaval technique was used

  5. 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

  6. Trends in cardiac pacemaker batteries.

    PubMed

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

    2004-10-01

    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.

  7. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

    PubMed Central

    Morris, Christopher J.; Yang, Jessica N.; Garcia, Joanna I.; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M.; Shea, Steven A.; Scheer, Frank A. J. L.

    2015-01-01

    Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers. PMID:25870289

  8. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans.

    PubMed

    Morris, Christopher J; Yang, Jessica N; Garcia, Joanna I; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M; Shea, Steven A; Scheer, Frank A J L

    2015-04-28

    Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.

  9. Cremation of Leadless Pacemaker.

    PubMed

    Cheung, Lily; Chan, Gary C P; Chan, Joseph Y S; Lau, Chu-Pak

    2017-03-11

    Cremation of implanted cardiac electronic devices can be associated with explosion from rapid gas formation causing potential hazard to the crematoria staffs and facilities. We present four patients who had undergone cremation with a leadless pacemaker (Micra(TM) , Medtronic Inc., MN) left inside their bodies. There was neither reported explosion nor damage to the cremation chamber during the cremation process. In this small series, cremation of Micra(TM) is not associated with noticeable explosion. This article is protected by copyright. All rights reserved.

  10. 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.

  11. A role for the circadian genes in drug addiction

    PubMed Central

    Falcón, Edgardo; McClung, Colleen A.

    2009-01-01

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

  12. Circadian rhythms: mechanisms and therapeutic implications.

    PubMed

    Levi, Francis; Schibler, Ueli

    2007-01-01

    The mammalian circadian system is organized in a hierarchical manner in that a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain's hypothalamus synchronizes cellular circadian oscillators in most peripheral body cells. Fasting-feeding cycles accompanying rest-activity rhythms are the major timing cues in the synchronization of many, if not most, peripheral clocks, suggesting that the temporal coordination of metabolism and proliferation is a major task of the mammalian timing system. The inactivation of noxious food components by hepatic, intestinal, and renal detoxification systems is among the metabolic processes regulated in a circadian manner, with the understanding of the involved clock output pathways emerging. The rhythmic control of xenobiotic detoxification provides the molecular basis for the dosing time-dependence of drug toxicities and efficacy. This knowledge can in turn be used in improving or designing chronotherapeutics for the patients who suffer from many of the major human diseases.

  13. Defibrillator/monitor/pacemakers.

    PubMed

    1998-02-01

    This study updates our May-June 1993 Evaluation of defibrillator/monitor/pacemakers, published in Health Devices 22(5-6), in which we tested eight units from six suppliers. For this Update Evaluation, we tested three additional units, each from a different supplier. We also present update information, including some new ratings, for most of the previously evaluated units. We judged the new units against the same basic criteria and rated and ranked them using the same scheme--with some minor revisions--as in our original Evaluation. We judged the suitability of these units for three primary clinical applications: (1) general crash-cart use, (2) prehospital (emergency medical service [EMS]) use, and (3) in-hospital transport use. Because our criteria have changed slightly since the original study, we have repeated them in this issue. The test methods have not changed significantly and can be found in the original 1993 Evaluation. For more detailed information about this technology, the environments in which these units are used, and the factors to consider when selecting this type of device, we encourage readers to refer to the following sections in the original Evaluation: the Clinical Perspective "The Importance of Early Defibrillation"; the Clinical and Technical Overview; and the Selection and Use Guide for Defibrillator/Monitor/Pacemakers.

  14. 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.

  15. 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.

  16. Histamine-immunoreactive neurons in the brain of the cockroach Leucophaea maderae.

    PubMed

    Loesel, R; Homberg, U

    1999-09-25

    Histamine is the neurotransmitter of insect photoreceptor cells but has also been found in a small number of interneurons in the insect brain. In order to investigate whether the accessory medulla (AMe), the putative circadian pacemaker of the cockroach Leucophaea maderae receives direct visual input from histaminergic photoreceptors, we analyzed the distribution of histamine-like immunoreactivity in the optic lobe and midbrain of the cockroach. Intense immunostaining was detected in photoreceptor cells of the compound eye, which terminated in the first optic neuropil, the lamina, and in a distal layer of the medulla, the second optic neuropil. Histamine immunostaining in parts of the AMe, however, originated from a centrifugal neuron of the midbrain. Within the midbrain 21-23 bilaterally symmetric pairs of cell bodies were stained. Most areas of the brain were innervated by one or more of these neurons, but the protocerebral bridge and the mushroom bodies were devoid of histamine immunoreactivity. The branching patterns of most histamine-immunoreactive neurons could be reconstructed individually. While the majority of identified neurons arborized in both brain hemispheres, five cells were local neurons of the antennal lobe. A comparison with other insect species shows striking similarities in the position of certain histamine-immunoreactive neurons, but considerable variations in the presence and branching patterns of others. The data suggest a role for histamine in a non-photic input to the circadian system of the cockroach.

  17. Effect of network architecture on synchronization and entrainment properties of the circadian oscillations in the suprachiasmatic nucleus.

    PubMed

    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

  18. Behavioral and molecular analyses suggest that circadian output is disrupted by disconnected mutants in D. melanogaster.

    PubMed Central

    Hardin, P E; Hall, J C; Rosbash, M

    1992-01-01

    Mutations in the disconnected (disco) gene act to disrupt neural cell patterning in the Drosophila visual system. These mutations also affect adult locomotor activity rhythms, as disco flies are arrhythmic under conditions of constant darkness (DD). To determine the state of the circadian pacemaker in disco mutants, we constructed with pers double mutants (a short period allele of the period gene) and assayed their behavioral rhythms in light-dark cycles (LD), and their biochemical rhythms of period gene expression under both LD and DD conditions. The results demonstrate that disco flies are rhythmic, indicating that they have an active circadian pacemaker that can be entrained by light. They also suggest that disco mutants block or interfere with elements of the circadian system located between the central pacemaker and its outputs that mediate overt rhythms. Images PMID:1740100

  19. Programming of sensor driven pacemakers.

    PubMed

    Strobel, J S; Kay, G N

    2000-02-01

    The chronotropic response is the most important means by which cardiac output is increased and oxygen delivery is maintained in response to increased oxygen consumption during exercise or stress. When the chronotropic response is suboptimal or absent, exercise intolerance results. This condition, called chronotropic incompetence can be treated effectively with a sensor-driven rate-responsive pacemaker. The effectiveness of this therapy assumes that the pacemaker is programmed appropriately. This article focuses on the programming of sensor-driven pacemakers and provides additional suggestions for follow-up testing to ensure maximal benefit from these devices.

  20. 1978 Pacemaker Newspaper Awards: What Makes a Pacemaker?

    ERIC Educational Resources Information Center

    Brasler, Wayne

    1979-01-01

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

  1. Development of pacemaker properties and rhythmogenic mechanisms in the mouse embryonic respiratory network

    PubMed Central

    Chevalier, Marc; Toporikova, Natalia; Simmers, John; Thoby-Brisson, Muriel

    2016-01-01

    Breathing is a vital rhythmic behavior generated by hindbrain neuronal circuitry, including the preBötzinger complex network (preBötC) that controls inspiration. The emergence of preBötC network activity during prenatal development has been described, but little is known regarding inspiratory neurons expressing pacemaker properties at embryonic stages. Here, we combined calcium imaging and electrophysiological recordings in mouse embryo brainstem slices together with computational modeling to reveal the existence of heterogeneous pacemaker oscillatory properties relying on distinct combinations of burst-generating INaP and ICAN conductances. The respective proportion of the different inspiratory pacemaker subtypes changes during prenatal development. Concomitantly, network rhythmogenesis switches from a purely INaP/ICAN-dependent mechanism at E16.5 to a combined pacemaker/network-driven process at E18.5. Our results provide the first description of pacemaker bursting properties in embryonic preBötC neurons and indicate that network rhythmogenesis undergoes important changes during prenatal development through alterations in both circuit properties and the biophysical characteristics of pacemaker neurons. DOI: http://dx.doi.org/10.7554/eLife.16125.001 PMID:27434668

  2. 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

  3. Circadian rhythms and addiction: mechanistic insights and future directions.

    PubMed

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

    2014-06-01

    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.

  4. Fibroblast PER2 Circadian Rhythmicity Depends on Cell Density

    PubMed Central

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

    2013-01-01

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

  5. The Effects of Spaceflight on the Rat Circadian Timing System

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

    Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than

  6. How Does a Pacemaker Work?

    MedlinePlus

    ... consists of a battery, a computerized generator, and wires with sensors at their tips. (The sensors are ... are surrounded by a thin metal box. The wires connect the generator to the heart. A pacemaker ...

  7. Neurobiology of food anticipatory circadian rhythms.

    PubMed

    Mistlberger, Ralph E

    2011-09-26

    Circadian rhythms in mammals can be entrained by daily schedules of light or food availability. A master light-entrainable circadian pacemaker located in the suprachiasmatic nucleus (SCN) is comprised of a population of cell autonomous, transcriptionally based circadian oscillators with defined retinal inputs, circadian clock genes and neural outputs. By contrast, the neurobiology of food-entrainable circadian rhythmicity remains poorly understood at the systems and cellular levels. Induction of food-anticipatory activity rhythms by daily feeding schedules does not require the SCN, but these rhythms do exhibit defining properties of circadian clock control. Clock gene rhythms expressed in other brain regions and in peripheral organs are preferentially reset by mealtime, but lesions of specific hypothalamic, corticolimbic and brainstem structures do not eliminate all food anticipatory rhythms, suggesting control by a distributed, decentralized system of oscillators, or the existence of a critical oscillator at an unknown location. The melanocortin system and dorsomedial hypothalamus may play modulatory roles setting the level of anticipatory activity. The metabolic hormones ghrelin and leptin are not required to induce behavioral food anticipatory rhythms, but may also participate in gain setting. Clock gene mutations that disrupt light-entrainable rhythms generally do not eliminate food anticipatory rhythms, suggesting a novel timing mechanism. Recent evidence for non-transcriptional and network based circadian rhythmicity provides precedence, but any such mechanisms are likely to interact closely with known circadian clock genes, and some important double and triple clock gene knockouts remain to be phenotyped for food entrainment. Given the dominant role of food as an entraining stimulus for metabolic rhythms, the timing of daily food intake and the fidelity of food entrainment mechanisms are likely to have clinical relevance.

  8. Development of PDF-immunoreactive cells, possible clock neurons, in the housefly Musca domestica.

    PubMed

    Pyza, Elzbieta; Siuta, Tomasz; Tanimura, Teiichi

    2003-10-01

    Even though the housefly Musca domestica shows clear circadian rhythms in its behavioural and physiological processes, a circadian pacemaker system controlling these rhythms has not yet been described morphologically in this species. In M. domestica, neurons immunoreactive to pigment-dispersing factor (PDF), a neurotransmitter/neuromodulator of circadian information arising from a circadian clock and transmitted to target cells, are similar in their number and distribution to the PDF neurons of Drosophila melanogaster. In D. melanogaster these neurons co-localize PER protein and have been identified as clock neurons in that species. Here we report PDF-immunoreactive cells in the housefly's brain during postembryonic development in the larval and pupal stages, as well as in the adult fly soon after eclosion. In the housefly's brain, there are three groups of PDF-immunoreactive neurons: two groups with small (sPDFMe) and large (lPDFMe) cell bodies in the proximal medulla of the optic lobe; and one group in the dorsal protocerebrum (PDFD). Three out of four sPDFMe can be detected during the first hour of larval development, but the fourth sPDFMe is observed in the larva only from 48 hours after hatching, along with five lPDFMe neurons, seen first as two subgroups, and three out of four PDFD neurons. During postembryonic development these neurons show changes in their structure and immunoreactivity. New PDF neurons are observed during pupal development but these neurons mostly do not survive into adulthood. In the adult fly's brain, the PDF neurons have also been examined in double-labelled preparations made with a second antibody directed against the product of one of several clock genes: period (per), timeless (tim), or cryptochrome (cry). Among them, only immunoreactivity to CRY-like protein has been detected in the brain of M. domestica and has shown a daily rhythm in its concentration, as examined immunocytochemically. CRY was co-localized with PDF in the s

  9. Modeling the Physiology of Circadian Timekeeping

    DTIC Science & Technology

    2011-08-31

    neurons can be achieved. Although it is basic research, it could have many potential future applications, including better devices for deep brain ... stimulation and cardiac pacemakers. With my Young Investigator Award, I finished a collaboration with the Division of Sleep Medicine at Harvard

  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. Introduction: circadian rhythm and its disruption: impact on reproductive function.

    PubMed

    Casper, Robert F; Gladanac, Bojana

    2014-08-01

    Almost all forms of life have predictable daily or circadian rhythms in molecular, endocrine, and behavioral functions. In mammals, a central pacemaker located in the suprachiasmatic nuclei coordinates the timing of these rhythms. Daily light exposure that affects the retina of the eye directly influences this area, which is required to align endogenous processes to the appropriate time of day. The present "Views and Reviews" articles discuss the influence of circadian rhythms, especially nightly secretion of melatonin, on reproductive function and parturition. In addition, an examination is made of problems that arise from recurrent circadian rhythm disruption associated with changes in light exposure patterns common to modern day society. Finally, a possible solution to prevent disruptions in circadian phase markers by filtering out short wavelengths from nocturnal light is reviewed.

  12. 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

  13. Clinical experience with nuclear pacemakers.

    PubMed

    Parsonnet, V; Myers, G H; Gilbert, L; Zucker, I R

    1975-12-01

    Approximately 1,400 nuclear pacemakers have been implanted in patients since April, 1970, without a single battery failure; 64 of these have been implanted at the Newark Beth Israel Medical Center. All except four of the 64 pulse generators were attached to transvenous electrodes, 39 to pacing wires already in place. Fifty-nine of the 64 units are in service and continue to function normally in a follow-up period of up to 2 years. In the total worldwide experience, 70 pacemakers are out of service, approximately half because of the patient's death, and the rest for infection or lead problems, and only three or four because of difficulties with components. The first 15 ARCO pacemakers implanted 2 years ago continue to function well. Of the 15 control pacemakers implanted at the same time, one unit has failed. We have concluded that a nuclear pacemaker should not be used in a patient with limited life expectancy or in an infant, but for the otherwise healthy young or middle-age individual, it should be the unit of choice.

  14. A statistical model of the human core-temperature circadian rhythm

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

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

    PubMed

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

    2016-07-15

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

  16. Pacemaker-associated Bacillus cereus endocarditis.

    PubMed

    Barraud, Olivier; Hidri, Nadia; Ly, Kim; Pichon, Nicolas; Manea, Petrus; Ploy, Marie-Cécile; Garnier, Fabien

    2012-11-01

    We report the case of a pacemaker-associated Bacillus cereus endocarditis in a nonimmunocompromised patient. Antibiotic treatment was ineffective, and the pacemaker had to be removed. B. cereus was cultured from several blood samples and from the pacemaker electrodes. This case underlines the contribution of the rpoB gene for Bacillus species determination.

  17. 21 CFR 870.3670 - Pacemaker charger.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker charger. 870.3670 Section 870.3670 Food... DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a...

  18. 21 CFR 870.3670 - Pacemaker charger.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker charger. 870.3670 Section 870.3670 Food... DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a...

  19. 21 CFR 870.3670 - Pacemaker charger.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker charger. 870.3670 Section 870.3670 Food... DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a...

  20. 21 CFR 870.3700 - Pacemaker programmers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker programmers. 870.3700 Section 870.3700...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A pacemaker programmer is a device used to change noninvasively one or more...

  1. 21 CFR 870.3670 - Pacemaker charger.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker charger. 870.3670 Section 870.3670 Food... DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a...

  2. 21 CFR 870.3700 - Pacemaker programmers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker programmers. 870.3700 Section 870.3700...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A pacemaker programmer is a device used to change noninvasively one or more...

  3. 21 CFR 870.3700 - Pacemaker programmers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker programmers. 870.3700 Section 870.3700...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A pacemaker programmer is a device used to change noninvasively one or more...

  4. 21 CFR 870.3700 - Pacemaker programmers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker programmers. 870.3700 Section 870.3700...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A pacemaker programmer is a device used to noninvasively change one or more...

  5. 21 CFR 870.3670 - Pacemaker charger.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker charger. 870.3670 Section 870.3670 Food... DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used transcutaneously to recharge the batteries of a...

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

    NASA Astrophysics Data System (ADS)

    Ivanov, Plamen Ch.

    2005-03-01

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

  7. Phenotyping Circadian Rhythms in Mice

    PubMed Central

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    Circadian rhythms take place with a periodicity of twenty-four hours, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the “central pacemaker” of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hours as manifest when an animal is placed into constant dark- or “free running”- conditions. Simple measurements of an organism's activity in free running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their home cage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are outlined here including the process of entrainment, determination of tau (period length) in free running conditions, determination of circadian periodicity in response to light disruption (i.e. jet lag studies), and evaluation of clock plasticity in non-twenty-four hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of one's environmental surroundings. PMID:26331760

  8. Lithium pacemaker batteries - an overview

    SciTech Connect

    Liang, C.C.; Holmes, C.F.

    1980-01-01

    Batteries used as power sources in cardiac pacemakers are expected to have high energy density, long storage and operating life and high reliability. They must be nonhazardous under normal operating as well as abusive conditions. Intensive research activities on the past 10-15 years have resulted in the development of a variety of high energy density batteries using Li as the anode material (Li-batteries). At least six different chemical systems with Li anodes are in use as power sources for cardiac pacemakers. Some basic characteristics of these systems are discussed. 11 refs.

  9. Inadvertent transarterial pacemaker lead placement.

    PubMed

    Bajaj, Ravi R; Fam, Neil; Singh, Sheldon M

    2015-01-01

    We present a case of a 73-year-old patient with acute left-sided hemiparesis four months after right ventricular pacemaker insertion. Post-procedural electrocardiogram revealed a paced RBBB complex and an abnormal lead path on chest X-ray. Subsequent echocardiography and computed tomography showed left ventricular pacemaker malposition with retrograde passage to the punctured subclavian artery. We also discuss the utility of routine cardiac investigations post-insertion to identify signal lead malposition as well as management strategies once identified.

  10. 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

  11. Avian circadian organization: a chorus of clocks.

    PubMed

    Cassone, Vincent M

    2014-01-01

    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.

  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. Development and morphology of the clock-gene-expressing lateral neurons of Drosophila melanogaster.

    PubMed

    Helfrich-Förster, Charlotte; Shafer, Orie T; Wülbeck, Corinna; Grieshaber, Eva; Rieger, Dirk; Taghert, Paul

    2007-01-01

    The clock-gene-expressing lateral neurons are essential for the locomotor activity rhythm of Drosophila melanogaster. Traditionally, these neurons are divided into three groups: the dorsal lateral neurons (LN(d)), the large ventral lateral neurons (l-LN(v)), and the small ventral lateral neurons (s-LN(v)), whereby the latter group consists of four neurons that express the neuropeptide pigment-dispersing factor (PDF) and a fifth PDF-negative neuron. So far, only the l-LN(v) and the PDF-positive s-LN(v) have been shown to project into the accessory medulla, a small neuropil that contains the circadian pacemaker center in several insects. We show here that the other lateral neurons also arborize in the accessory medulla, predominantly forming postsynaptic sites. Both the l-LN(v) and LN(d) are anatomically well suited to connect the accessory medullae. Whereas the l-LN(v) may receive ipsilateral photic input from the Hofbauer-Buchner eyelet, the LN(d) invade mainly the contralateral accessory medulla and thus may receive photic input from the contralateral side. Both the LN(d) and the l-LN(v) differentiate during midmetamorphosis. They do so in close proximity to one another and the fifth PDF-negative s-LN(v), suggesting that these cell groups may derive from common precursors.

  14. Circadian regulation of cortisol release in behaviorally split golden hamsters.

    PubMed

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

    2012-02-01

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

  15. A New Perspective for Parkinson's Disease: Circadian Rhythm.

    PubMed

    Li, Siyue; Wang, Yali; Wang, Fen; Hu, Li-Fang; Liu, Chun-Feng

    2017-02-01

    Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.

  16. Interplay between the endocrine and circadian systems in fishes.

    PubMed

    Isorna, Esther; de Pedro, Nuria; Valenciano, Ana I; Alonso-Gómez, Ángel L; Delgado, María J

    2017-03-01

    The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs.

  17. Electrical interference in non-competitive pacemakers.

    PubMed

    Sowton, E; Gray, K; Preston, T

    1970-09-01

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

  18. [Wide QRS tachycardia preceded by pacemaker spikes].

    PubMed

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

    2014-04-01

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

  19. Rapid Adjustment of Circadian Clocks to Simulated Travel to Time Zones across the Globe.

    PubMed

    Harrison, Elizabeth M; Gorman, Michael R

    2015-12-01

    Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure-based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules.

  20. Entrainment of circadian clocks in mammals by arousal and food.

    PubMed

    Mistlberger, Ralph E; Antle, Michael C

    2011-06-30

    Circadian rhythms in mammals are regulated by a system of endogenous circadian oscillators (clock cells) in the brain and in most peripheral organs and tissues. One group of clock cells in the hypothalamic SCN (suprachiasmatic nuclei) functions as a pacemaker for co-ordinating the timing of oscillators elsewhere in the brain and body. This master clock can be reset and entrained by daily LD (light-dark) cycles and thereby also serves to interface internal with external time, ensuring an appropriate alignment of behavioural and physiological rhythms with the solar day. Two features of the mammalian circadian system provide flexibility in circadian programming to exploit temporal regularities of social stimuli or food availability. One feature is the sensitivity of the SCN pacemaker to behavioural arousal stimulated during the usual sleep period, which can reset its phase and modulate its response to LD stimuli. Neural pathways from the brainstem and thalamus mediate these effects by releasing neurochemicals that inhibit retinal inputs to the SCN clock or that alter clock-gene expression in SCN clock cells. A second feature is the sensitivity of circadian oscillators outside of the SCN to stimuli associated with food intake, which enables animals to uncouple rhythms of behaviour and physiology from LD cycles and align these with predictable daily mealtimes. The location of oscillators necessary for food-entrained behavioural rhythms is not yet certain. Persistence of these rhythms in mice with clock-gene mutations that disable the SCN pacemaker suggests diversity in the molecular basis of light- and food-entrainable clocks.

  1. 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.

  2. Interruption of pacemaker signals by a diencephalic nucleus in the African electric fish, Gymnarchus niloticus.

    PubMed

    Zhang, Ying; Kawasaki, Masashi

    2006-05-01

    The African electric fish Gymnarchus niloticus rhythmically emits electric organ discharges (EODs) for communication and navigation. The EODs are generated by the electric organ in the tail in response to the command signals from the medullary pacemaker complex, which consists of a pacemaker nucleus (PN), two lateral relay nuclei (LRN) and a medial relay nucleus (MRN). The premotor structure and its modulatory influences on the pacemaker complex have been investigated in this paper. A bilateral prepacemaker nucleus (PPn) was found in the area of the dorsal posterior nucleus (DP) of the thalamus by retrograde labeling from the PN. No retrogradely labeled neurons outside the pacemaker complex were found after tracer injection into the LRN or MRN. Accordingly, anterogradely labeled terminal fibers from PPn neurons were found only in the PN. Iontophoresis of L-glutamate into the region of the PPn induced EOD interruptions. Despite the exclusive projection of the PPn neurons to the PN, extracellular and intracellular recordings showed that PN neurons continue their firing while MRN neurons ceased their firing during EOD interruption. This mode of EOD interruption differs from those found in any other weakly electric fishes in which EOD cessation mechanisms have been known.

  3. Circadian clock function in the mammalian ovary.

    PubMed

    Sellix, Michael T

    2015-02-01

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

  4. [Future cardiac pacemakers – technical visions].

    PubMed

    Haeberlin, Andreas; Zurbuchen, Adrian; Pfenniger, Aloïs; Fuhrer, Jürg; Vogel, Rolf

    2015-08-01

    Cardiac pacemakers are routinely used for the treatment of bradyarrhythmias. Contemporary pacemakers are reliable and allow for a patient specific programming. However, pacemaker replacements due to battery depletion are common (~25 % of all implantation procedures) and bear the risk of complications. Batteryless pacemakers may allow overcoming this limitation. To power a batteryless pacemaker, a mechanism for intracorporeal energy harvesting is required. Such a generator may consist out of subcutaneously implanted solar cells, transforming the small amount of transcutaneously available light into electrical energy. Alternatively, intravascular turbines may harvest energy from the blood flow. Energy may also be harvested from the ventricular wall motion by a dedicated mechanical clockwork converting motion into electrical energy. All these approaches have successfully been tested in vivo. Pacemaker leads constitute another Achilles heel of contemporary pacemakers. Thus, leadless devices are desired. Miniaturized pacemaker circuits and suitable energy harvesting mechanisms (incorporated in a single device) may allow catheter-based implantation of the pacemaker in the heart. Such miniaturized battery- and leadless pacemakers would combine the advantages of both approaches and overcome major limitations of today’s systems.

  5. The effect of lens aging and cataract surgery on circadian rhythm

    PubMed Central

    Yan, Shen-Shen; Wang, Wei

    2016-01-01

    Many organisms have evolved an approximately 24-hour circadian rhythm that allows them to achieve internal physiological homeostasis with external environment. Suprachiasmatic nucleus (SCN) is the central pacemaker of circadian rhythm, and its activity is entrained to the external light-dark cycle. The SCN controls circadian rhythm through regulating the synthesis of melatonin by pineal gland via a multisynaptic pathway. Light, especially short-wavelength blue light, is the most potent environmental time cue in circadian photoentrainment. Recently, the discovery of a novel type of retinal photoreceptors, intrinsically photosensitive retinal ganglion cells, sheds light on the mechanism of circadian photoentrainment and raises concerns about the effect of ocular diseases on circadian system. With age, light transmittance is significantly decreased due to the aging of crystalline lens, thus possibly resulting in progressive loss of circadian photoreception. In the current review, we summarize the circadian physiology, highlight the important role of light in circadian rhythm regulation, discuss about the correlation between age-related cataract and sleep disorders, and compare the effect of blue light- filtering intraocular lenses (IOLs) and ultraviolet only filtering IOLs on circadian rhythm. PMID:27500118

  6. The effect of lens aging and cataract surgery on circadian rhythm.

    PubMed

    Yan, Shen-Shen; Wang, Wei

    2016-01-01

    Many organisms have evolved an approximately 24-hour circadian rhythm that allows them to achieve internal physiological homeostasis with external environment. Suprachiasmatic nucleus (SCN) is the central pacemaker of circadian rhythm, and its activity is entrained to the external light-dark cycle. The SCN controls circadian rhythm through regulating the synthesis of melatonin by pineal gland via a multisynaptic pathway. Light, especially short-wavelength blue light, is the most potent environmental time cue in circadian photoentrainment. Recently, the discovery of a novel type of retinal photoreceptors, intrinsically photosensitive retinal ganglion cells, sheds light on the mechanism of circadian photoentrainment and raises concerns about the effect of ocular diseases on circadian system. With age, light transmittance is significantly decreased due to the aging of crystalline lens, thus possibly resulting in progressive loss of circadian photoreception. In the current review, we summarize the circadian physiology, highlight the important role of light in circadian rhythm regulation, discuss about the correlation between age-related cataract and sleep disorders, and compare the effect of blue light- filtering intraocular lenses (IOLs) and ultraviolet only filtering IOLs on circadian rhythm.

  7. Circadian regulation of bird song, call, and locomotor behavior by pineal melatonin in the zebra finch.

    PubMed

    Wang, Gang; Harpole, Clifford E; Trivedi, Amit K; Cassone, Vincent M

    2012-04-01

    As both a photoreceptor and pacemaker in the avian circadian clock system, the pineal gland is crucial for maintaining and synchronizing overt circadian rhythms in processes such as locomotor activity and body temperature through its circadian secretion of the pineal hormone melatonin. In addition to receptor presence in circadian and visual system structures, high-affinity melatonin binding and receptor mRNA are present in the song control system of male oscine passeriform birds. The present study explores the role of pineal melatonin in circadian organization of singing and calling behavior in comparison to locomotor activity under different lighting conditions. Similar to locomotor activity, both singing and calling behavior were regulated on a circadian basis by the central clock system through pineal melatonin, since these behaviors free-ran with a circadian period and since pinealectomy abolished them in constant environmental conditions. Further, rhythmic melatonin administration restored their rhythmicity. However, the rates by which these behaviors became arrhythmic and the rates of their entrainment to rhythmic melatonin administration differed among locomotor activity, singing and calling under constant dim light and constant bright light. Overall, the study demonstrates a role for pineal melatonin in regulating circadian oscillations of avian vocalizations in addition to locomotor activity. It is suggested that these behaviors might be controlled by separable circadian clockworks and that pineal melatonin entrains them all through a circadian clock.

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

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    Nelson, D E; Takahashi, J S

    1991-01-01

    1. Light-induced phase shifts of the circadian rhythm of wheel-running activity were used to measure the photic sensitivity of a circadian pacemaker and the visual pathway that conveys light information to it in the golden hamster (Mesocricetus auratus). The sensitivity to stimulus irradiance and duration was assessed by measuring the magnitude of phase-shift responses to photic stimuli of different irradiance and duration. The visual sensitivity was also measured at three different phases of the circadian rhythm. 2. The stimulus-response curves measured at different circadian phases suggest that the maximum phase-shift is the only aspect of visual responsivity to change as a function of the circadian day. The half-saturation constants (sigma) for the stimulus-response curves are not significantly different over the three circadian phases tested. The photic sensitivity to irradiance (1/sigma) appears to remain constant over the circadian day. 3. The hamster circadian pacemaker and the photoreceptive system that subserves it are more sensitive to the irradiance of longer-duration stimuli than to irradiance of briefer stimuli. The system is maximally sensitive to the irradiance of stimuli of 300 s and longer in duration. A quantitative model is presented to explain the changes that occur in the stimulus-response curves as a function of photic stimulus duration. 4. The threshold for photic stimulation of the hamster circadian pacemaker is also quite high. The threshold irradiance (the minimum irradiance necessary to induce statistically significant responses) is approximately 10(11) photons cm-2 s-1 for optimal stimulus durations. This threshold is equivalent to a luminance at the cornea of 0.1 cd m-2. 5. We also measured the sensitivity of this visual pathway to the total number of photons in a stimulus. This system is maximally sensitive to photons in stimuli between 30 and 3600 s in duration. The maximum quantum efficiency of photic integration occurs in 300 s

  11. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality.

    PubMed

    Souêtre, E; Salvati, E; Belugou, J L; Pringuey, D; Candito, M; Krebs, B; Ardisson, J L; Darcourt, G

    1989-06-01

    Circadian rhythms of body temperature, plasma cortisol, norepinephrine (NE), thyroid stimulating hormone (TSH), and melatonin were compared in 16 endogenously depressed, 15 recovered (after 3 weeks of anti-depressant treatment), and 16 normal subjects. The depressed patients showed clear circadian rhythm abnormalities, consisting mainly in amplitude reduction. This amplitude reduction was significantly correlated with the patients' Hamilton depression scores. Normal circadian profiles were restored after recovery when amplitude, in particular, was increased. Features of the circadian rhythms observed in remission may be associated with antidepressant drug effects, whereas those observed in depression resemble the circadian rhythms observed in normal subjects living under conditions of temporal isolation and those of blind subjects. Our findings suggest that depression may be related both to a weakening of the coupling processes between internal pacemakers and to an abnormal sensitivity to environmental information.

  12. 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.

  13. Circadian Dysfunction Induces Leptin Resistance in Mice.

    PubMed

    Kettner, Nicole M; Mayo, Sara A; Hua, Jack; Lee, Choogon; Moore, David D; Fu, Loning

    2015-09-01

    Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per and Cry mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.

  14. Lithium-iodine pacemaker cell

    SciTech Connect

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

    1980-01-01

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

  15. 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

  16. Ethanol consumption in mice: relationships with circadian period and entrainment

    PubMed Central

    Trujillo, Jennifer L.; Do, David T.; Grahame, Nicholas J.; Roberts, Amanda J.; Gorman, Michael R.

    2011-01-01

    A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep and body temperature, and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred High- (HAP) and Low- (LAP) Alcohol Preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 h or 22 h or remained in a standard 24 h cycle. Upon discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake. PMID:20880659

  17. Circadian Role in Daily Pattern of Cardiovascular Risk

    NASA Astrophysics Data System (ADS)

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

    2004-03-01

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

  18. CROSS-DISCIPLINARY PHYSICS AND RELATED AREAS OF SCIENCE AND TECHNOLOGY: Modelling of intercellular synchronization in the Drosophila circadian clock

    NASA Astrophysics Data System (ADS)

    Wang, Jun-Wei; Chen, Ai-Min; Zhang, Jia-Jun; Yuan, Zhan-Jiang; Zhou, Tian-Shou

    2009-03-01

    In circadian rhythm generation, intercellular signaling factors are shown to play a crucial role in both sustaining intrinsic cellular rhythmicity and acquiring collective behaviours across a population of circadian neurons. However, the physical mechanism behind their role remains to be fully understood. In this paper, we propose an indirectly coupled multicellular model for the synchronization of Drosophila circadian oscillators combining both intracellular and intercellular dynamics. By simulating different experimental conditions, we find that such an indirect coupling way can synchronize both heterogeneous self-sustained circadian neurons and heterogeneous mutational damped circadian neurons. Moreover, they can also be entrained to ambient light-dark (LD) cycles depending on intercellular signaling.

  19. Extraordinary behavioral entrainment following circadian rhythm bifurcation in mice

    PubMed Central

    Harrison, Elizabeth M.; Walbeek, Thijs J.; Sun, Jonathan; Johnson, Jeremy; Poonawala, Qays; Gorman, Michael R.

    2016-01-01

    The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (<0.1 lux), rather than completely dark nights, permits expression of an altered circadian waveform wherein mice in light/dark/light/dark (LDLD) cycles “bifurcate” their rhythms into two rest and activity intervals per 24 h. Secondly, this bifurcated state enables mice to adopt stable activity rhythms under 15 or 30 h days (LDLD T15/T30), well beyond conventional limits of entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions. PMID:27929128

  20. Dynamical Analysis of bantam-Regulated Drosophila Circadian Rhythm Model

    NASA Astrophysics Data System (ADS)

    Li, Ying; Liu, Zengrong

    MicroRNAs (miRNAs) interact with 3‧untranslated region (UTR) elements of target genes to regulate mRNA stability or translation, and play a crucial role in regulating many different biological processes. bantam, a conserved miRNA, is involved in several functions, such as regulating Drosophila growth and circadian rhythm. Recently, it has been discovered that bantam plays a crucial role in the core circadian pacemaker. In this paper, based on experimental observations, a detailed dynamical model of bantam-regulated circadian clock system is developed to show the post-transcriptional behaviors in the modulation of Drosophila circadian rhythm, in which the regulation of bantam is incorporated into a classical model. The dynamical behaviors of the model are consistent with the experimental observations, which shows that bantam is an important regulator of Drosophila circadian rhythm. The sensitivity analysis of parameters demonstrates that with the regulation of bantam the system is more sensitive to perturbations, indicating that bantam regulation makes it easier for the organism to modulate its period against the environmental perturbations. The effectiveness in rescuing locomotor activity rhythms of mutated flies shows that bantam is necessary for strong and sustained rhythms. In addition, the biological mechanisms of bantam regulation are analyzed, which may help us more clearly understand Drosophila circadian rhythm regulated by other miRNAs.

  1. Extraordinary behavioral entrainment following circadian rhythm bifurcation in mice.

    PubMed

    Harrison, Elizabeth M; Walbeek, Thijs J; Sun, Jonathan; Johnson, Jeremy; Poonawala, Qays; Gorman, Michael R

    2016-12-08

    The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (<0.1 lux), rather than completely dark nights, permits expression of an altered circadian waveform wherein mice in light/dark/light/dark (LDLD) cycles "bifurcate" their rhythms into two rest and activity intervals per 24 h. Secondly, this bifurcated state enables mice to adopt stable activity rhythms under 15 or 30 h days (LDLD T15/T30), well beyond conventional limits of entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.

  2. 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

  3. 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.

  4. The nuclear pacemaker: Is renewed interest warranted

    SciTech Connect

    Parsonnet, V.; Berstein, A.D.; Perry, G.Y. )

    1990-10-01

    From 1973 through 1987, 155 radioisotope-powered nuclear pacemakers were implanted in 132 patients at the Newark Beth Israel Medical Center. The longevity of the first 15 devices, all of which were fixed-rate (VOO) pacemakers, was significantly better than that of 15 lithium-chemistry demand (VVI) pacemakers used as control devices (p = 0.0002). Of the entire cohort of 155 nuclear pacemakers, 136 were VVI devices and 19 were VOO units. The patients with VOO pacemakers needed reoperations more often than did those with VVI pacemakers, chiefly for mode change (p less than 0.001). Power-source failure was observed in only 1 case, but 47 nuclear pacemakers were removed for other reasons, including component malfunction (15 units), mode change (12 units), high pacing thresholds (8 units) and lead or connector problems (5 units). The actuarial survival at 15 years was 99% for power sources and 82% for the entire pacing systems (pulse generators plus leads). The frequency of malignancy was similar to that of the population at large and primary tumor sites were randomly distributed. Deaths most commonly were due to cardiac causes (68%). Thus, nuclear pacemakers are safe and reliable and their greater initial cost appears to be offset by their longevity and the resulting decrease in the frequency of reoperations. It is reasonable to suggest that further use be made of long-lasting nuclear power sources for modern pacemakers and other implantable rhythm-management devices.

  5. 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

    2012-02-07

    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 α-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.

  6. Circadian Rhythm Sleep Disorders

    PubMed Central

    Zhu, Lirong; Zee, Phyllis C.

    2012-01-01

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

  7. The differential effects of ionizing radiation on the circadian oscillator and other functions in the eye of Aplysia.

    PubMed Central

    Woolum, J C; Strumwasser, F

    1980-01-01

    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 otpic nerve, whereas irradiation with a 40-krad dose abolishes the rhythm without affecting any of the four other functions of this eye (1 rad = 0.01 J/kg = 0.01/Gy). We estimate a 50% survival of the oscillator function at doses of about 6 krad. The oscillators of irradiated eyes are not merely desynchronized when the rhythm is abolished, because in vitro light-dark entrainment does not restore free-running rhythmicity. 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 approximately equal to 10(8) A3, which is somewhat larger than the target size for viral infectivity function, as one example. There are reservations about estimating target size in a complex organ such as the eye. 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. Images PMID:6933570

  8. 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

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

    NASA Astrophysics Data System (ADS)

    Borek, Bartłomiej; 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.

  10. Pacemaker failure resulting from radiation damage

    SciTech Connect

    Quertermous, T.; Megahy, M.S.; Das Gupta, D.S.; Griem, M.L.

    1983-07-01

    The authors present a case of radiation-induced pacemaker failure. After 2000 rad (20 Gy) of photon irradiation for metastatic bronchogenic carcinoma, the pulse generator circuitry failed, producing a runaway rhythm. This suggests that present pacemaker circuitry may be more susceptible to irradiation than previously believed, and that even modest radiation doses can induce life-threatening arrhythmias.

  11. A Percutaneously Implantable Fetal Pacemaker

    PubMed Central

    Zhou, Li; Vest, Adriana N.; Chmait, Ramen H.; Bar-Cohen, Yaniv; Pruetz, Jay; Silka, Michael; Zheng, Kaihui; Peck, Ray; Loeb, Gerald E.

    2015-01-01

    A miniaturized, self-contained pacemaker that could be implanted with a minimally invasive technique would dramatically improve the survival rate for fetuses that develop hydrops fetalis as a result of congenital heart block. We are currently validating a device that we developed to address this bradyarrhythmia. Preclinical studies in a fetal sheep model are underway to demonstrate that the device can be implanted via a minimally invasive approach, can mechanically withstand the harsh bodily environment, can induce effective contractions of the heart muscle with an adequate safety factor, and can successfully operate for the required device lifetime of three months using the previously-developed closed loop transcutaneous recharging system. PMID:25570982

  12. Biofilm on artificial pacemaker: fiction or reality?

    PubMed

    Santos, Ana Paula Azevedo; Watanabe, Evandro; Andrade, Denise de

    2011-11-01

    Cardiac pacing through cardiac pacemaker is one of the most promising alternatives in the treatment of arrhythmias, but it can cause reactions natural or complex reactions, either early or late. This study aimed to describe the scientific evidence on the risk of infection and biofilm formation associated with cardiac pacemaker. This is a study of integrative literature review. It included 14 publications classified into three thematic categories: diagnosis (microbiological and/or clinical), complications and therapy of infections. Staphylococcus epidermidis and Staphylococcus aureus were the microorganisms most frequently isolated. It was not possible to determine the incidence of infection associated with pacemakers, since the studies were generally of prevalence. In terms of therapy, the complete removal of pacemakers stood out, especially in cases of suspected biofilm. Still controversial is the use of systemic antibiotic prophylaxis in reducing the incidence of infection associated with implantation of a pacemaker.

  13. Modulation of light-driven arousal by LIM-homeodomain transcription factor Apterous in large PDF-positive lateral neurons of the Drosophila brain

    PubMed Central

    Shimada, Naoto; Inami, Show; Sato, Shoma; Kitamoto, Toshihiro; Sakai, Takaomi

    2016-01-01

    Apterous (Ap), the best studied LIM-homeodomain transcription factor in Drosophila, cooperates with the cofactor Chip (Chi) to regulate transcription of specific target genes. Although Ap regulates various developmental processes, its function in the adult brain remains unclear. Here, we report that Ap and Chi in the neurons expressing PDF, a neuropeptide, play important roles in proper sleep/wake regulation in adult flies. PDF-expressing neurons consist of two neuronal clusters: small ventral-lateral neurons (s-LNvs) acting as the circadian pacemaker and large ventral-lateral neurons (l-LNvs) regulating light-driven arousal. We identified that Ap localizes to the nuclei of s-LNvs and l-LNvs. In light-dark (LD) cycles, RNAi knockdown or the targeted expression of dominant-negative forms of Ap or Chi in PDF-expressing neurons or l-LNvs promoted arousal. In contrast, in constant darkness, knockdown of Ap in PDF-expressing neurons did not promote arousal, indicating that a reduced Ap function in PDF-expressing neurons promotes light-driven arousal. Furthermore, Ap expression in l-LNvs showed daily rhythms (peaking at midnight), which are generated by a direct light-dependent mechanism rather than by the endogenous clock. These results raise the possibility that the daily oscillation of Ap expression in l-LNvs may contribute to the buffering of light-driven arousal in wild-type flies. PMID:27853240

  14. Changing the waveform of circadian rhythms: considerations for shift-work.

    PubMed

    Harrison, Elizabeth M; Gorman, Michael R

    2012-01-01

    Circadian disruption in shift-work is common and has deleterious effects on health and performance. Current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker, which unfortunately in humans, shifts slowly and often incompletely. Temporal reorganization of rhythmic waveform (i.e., the shape of its 24 h oscillation), rather than phase, however, may better match performance demands of shift-workers and can be quickly and feasibly implemented in animals. In fact, a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep/wake rhythm promoting alertness in both night and daylight hours. Although bifurcation has yet to be formally assessed in humans, evidence of conserved properties of circadian organization and plasticity predict its occurrence: humans respond to conventional manipulations of waveform (e.g., photoperiodism); behaviorally, the sleep/wake rhythm is adaptable; and finally, the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker. In short, investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified.

  15. 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.

  16. 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

  17. 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.

  18. Sensing properties of pacemaker leads.

    PubMed

    Irnich, W

    1986-11-01

    It is already general practice to attribute sensing properties to geometry and surface structure of pacemaker leads. We have to analyze critically whether claims of having found leads with high sensitivity are in accordance with experimental and theoretical findings. From a model can be derived what kind of typical signal structure will originate from an electrode when an excitation wave crosses it, and what of this signal is influenced by electrode parameters. With decreasing surface area, the frequency content of the signal, the impedance, and, theoretically, the amplitude, increases. If the pacemaker characteristics are not matched to the lead properties, this inverse relationship becomes a direct one: If the input impedance is too low or the upper cut-off frequency of the bandpass is not high enough, the effective heart signal seems to be diminished with decreasing size. This, however, is more a pulse generator than a lead problem. If all pacers would possess an input impedance of greater than or equal to 100 K omega and an upper cut-off frequency of greater than or equal to 350 Hz, an attenuation of the heart signal would be less than or equal to 10% and thus, the results with different leads would be very similar and of equally high sensitivity.

  19. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker lead adaptor. 870.3620 Section 870.3620...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to adapt a pacemaker lead so that...

  20. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker lead adaptor. 870.3620 Section 870.3620...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to adapt a pacemaker lead so that...

  1. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker lead adaptor. 870.3620 Section 870.3620...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to adapt a pacemaker lead so that...

  2. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker lead adaptor. 870.3620 Section 870.3620...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to adapt a pacemaker lead so that...

  3. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED..., used to repair a pacemaker lead or to reconnect a pacemaker lead to a pacemaker generator....

  4. 21 CFR 870.3610 - Implantable pacemaker pulse generator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Implantable pacemaker pulse generator. 870.3610... pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that has... implantable pacemaker pulse generator device that was in commercial distribution before May 28, 1976, or...

  5. 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.

  6. Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior.

    PubMed

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

    2016-11-01

    The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.

  7. Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms

    PubMed Central

    Atger, Florian; Mauvoisin, Daniel; Weger, Benjamin; Gobet, Cédric; Gachon, Frédéric

    2017-01-01

    Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases. PMID:28337174

  8. Blood transcriptome based biomarkers for human circadian phase.

    PubMed

    Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan

    2017-02-20

    Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain's circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R(2) of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R(2) was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.

  9. Blood transcriptome based biomarkers for human circadian phase

    PubMed Central

    Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan

    2017-01-01

    Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples. DOI: http://dx.doi.org/10.7554/eLife.20214.001 PMID:28218891

  10. Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

    PubMed Central

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

    2016-01-01

    The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior. PMID:27870848

  11. DsRNA as a stimulator of cell pacemaker activity

    SciTech Connect

    Airapetyan, S.N.; Zakharyan, R.A.; Rychkov, G.E.; Dadalyan, S.S.; Bakunts, I.S.; Agabalyan, A.S.

    1986-03-01

    The authors study the action of double-stranded RNAs (dsRNA) on the characteristics of neuron pacemaker activity which permits prediction of the character of action of dsRNA on the pacemaker activity of cells and organs, and takes the investigators closer to an understanding of the membrane mechanisms underlying the action of dsRNA on the cell. The methods for isolating and fractionating dsRNA from yeasts and the intracellular recording of the electrical activity of the snail giant neuron have been described by the authors earlier. The authors determined the dependence of Ca/sup 2 +/ entry upon dsRNA concentration using the isotope /sup 45/Ca. Preweighed ganglia were incubated five each for an hour in 2 ml Ringer's solution containing dsRNA and 5 microliters /sup 45/CaCl/sub 2/ of 12.5 mCi activity. After incubation, the ganglia were rinsed three times for 8 min each time in normal Ringers solution. The washed ganglia were dissolved for one day in KOH. The amount of isotope entering was counted using Brav's scintillator and an RGT counter tuned to the /sup 45/Ca isotope. The physiological saline used for the isolated ganglion contained 85 mmole NaCl, 4 mmole KCl, 8 mmole CaCl/sub 2/, 10 mmole MgCl/sub 2/, 10 mmole Tris-HCl, and 5 mmole glucose.

  12. 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.

  13. 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

  14. 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.

  15. Circadian organization in hemimetabolous insects.

    PubMed

    Tomioka, Kenji; Abdelsalam, Salaheldin

    2004-12-01

    The circadian system of hemimetabolous insects is reviewed in respect to the locus of the circadian clock and multioscillatory organization. Because of relatively easy access to the nervous system, the neuronal organization of the clock system in hemimetabolous insects has been studied, yielding identification of the compound eye as the major photoreceptor for entrainment and the optic lobe for the circadian clock locus. The clock site within the optic lobe is inconsistent among reported species; in cockroaches the lobula was previously thought to be a most likely clock locus but accessory medulla is recently stressed to be a clock center, while more distal part of the optic lobe including the lamina and the outer medulla area for the cricket. Identification of the clock cells needs further critical studies. Although each optic lobe clock seems functionally identical, in respect to photic entrainment and generation of the rhythm, the bilaterally paired clocks form a functional unit. They interact to produce a stable time structure within individual insects by exchanging photic and temporal information through neural pathways, in which serotonin and pigment-dispersing factor (PDF) are involved as chemical messengers. The mutual interaction also plays an important role in seasonal adaptation of the rhythm.

  16. Circadian Behaviour in Neuroglobin Deficient Mice

    PubMed Central

    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

  17. Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities

    PubMed Central

    Altimus, C.M.; Güler, A.D.; Alam, N.M.; Arman, A.C.; Prusky, G.T.; Sampath, A.P.; Hattar, S

    2010-01-01

    In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. We demonstrate in genetic mouse models lacking functional rods, or where rods are the only functional photoreceptors, that rods are solely responsible for photoentrainment at scotopic light intensities. Surprisingly, rods were also capable of driving circadian photoentrainment at photopic intensities where they were incapable of supporting a visually–guided behavior. Using animals in which cone photoreceptors were ablated, we demonstrate that rods signal through cones at high light intensities, but not low light intensities. Thus two distinct retinal circuits drive ipRGC function to support circadian photoentrainment across a wide range of light intensities. PMID:20711184

  18. [Biological role and clinical relevance of central and peripheral circadian clocks].

    PubMed

    Husse, J; Leliavski, A; Oster, H

    2013-03-01

    In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony.

  19. Pacemaker failure associated with therapeutic radiation

    SciTech Connect

    Brooks, C.; Mutter, M.

    1988-11-01

    A 48-year-old white man with a multiprogrammable Intramedics 259-01 pacemaker was treated for inoperable lung cancer with a course of cobalt-60 radiotherapy (total 3500 rad). Several weeks subsequent to his last radiation treatment, the patient presented to the emergency department with chest and abdominal pain, shortness of breath, hypotension, and tachycardia. A paced tachycardia was noted, and application of a magnet over the pacemaker completely inhibited its function, allowing a normal sinus rhythm to ensue and the patient's symptoms to be relieved. Pacemaker failure probably was a complication of radiotherapy.

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

    PubMed Central

    Shafer, Orie T.; Yao, Zepeng

    2014-01-01

    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

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

    PubMed

    Suksaranjit, P; Prasidthrathsint, K

    2014-01-01

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

  2. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms.

    PubMed

    Landgraf, Dominic; Joiner, William J; McCarthy, Michael J; Kiessling, Silke; Barandas, Rita; Young, Jared W; Cermakian, Nicolas; Welsh, David K

    2016-08-01

    Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian

  3. 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.

  4. Communication between circadian clusters: The key to a plastic network.

    PubMed

    Beckwith, Esteban J; Ceriani, M Fernanda

    2015-11-14

    Drosophila melanogaster is a model organism that has been instrumental in understanding the circadian clock at different levels. A range of studies on the anatomical and neurochemical properties of clock neurons in the fly led to a model of interacting neural circuits that control circadian behavior. Here we focus on recent research on the dynamics of the multiple communication pathways between clock neurons, and, particularly, on how the circadian timekeeping system responds to changes in environmental conditions. It is increasingly clear that the fly clock employs multiple signalling cues, such as neuropeptides, fast neurotransmitters, and other signalling molecules, in the dynamic interplay between neuronal clusters. These neuronal groups seem to interact in a plastic fashion, e.g., rearranging their hierarchy in response to changing environmental conditions. A picture is emerging supporting that these dynamic mechanisms are in place to provide an optimal balance between flexibility and an extraordinary accuracy.

  5. Ontogeny of Circadian Organization in the Rat

    PubMed Central

    Yamazaki, Shin; Yoshikawa, Tomoko; Biscoe, Elizabeth W.; Numano, Rika; Gallaspy, Lauren M.; Soulsby, Stacy; Papadimas, Evagelia; Pezuk, Pinar; Doyle, Susan E.; Tei, Hajime; Sakaki, Yoshiyuki; Block, Gene D.; Menaker, Michael

    2009-01-01

    The mammalian circadian system is orchestrated by a master pacemaker in the brain but many peripheral tissues also contain independent or quasi-independent circadian oscillators. The adaptive significance of clocks in these structures must lie, in large part, in the phase relationships between the constituent oscillators and their micro- and macro-environments. To examine the relationship between postnatal development, which is dependent on endogenous programs and maternal/environmental influences, and the phase of circadian oscillators, we assessed the circadian phase of pineal, liver, lung, adrenal, and thyroid tissues cultured from Period 1-luciferase (Per1-luc) rat pups of various postnatal ages. The liver, thyroid, and pineal were rhythmic at birth, but the phases of their Per1-luc expression rhythms shifted remarkably during development. To determine if the timing of the phase shift in each tissue could be the result of changing environmental conditions, we monitored the behavior of pups and their mothers. We found that the circadian phase of the liver shifted from the day to night around postnatal day (P) 22 as the pups nursed less during the light and instead ate solid food during the dark. Furthermore, the phase of Per1-luc expression in liver cultures from nursing neonates could be shifted experimentally from the day to the night by allowing pups access to the dam only during the dark. Peak Per1-luc expression also shifted from mid-day to early night in thyroid cultures at about P20, concurrent with the shift in eating times. The phase of Per1-luc expression in the pineal gland shifted from day to night coincident with its sympathetic innervation at around P5. Per1-luc expression was rhythmic in adrenal cultures and peaked around the time of lights-off throughout development, however, the amplitude of the rhythm increased at P25. Lung cultures were completely arrhythmic until P12 when the pups began to leave the nest. Taken together, our data suggest that

  6. How Will a Pacemaker Affect My Lifestyle?

    MedlinePlus

    ... Household appliances, such as microwave ovens High-tension wires Metal detectors Industrial welders Electrical generators These devices ... could damage your pacemaker or shake loose the wires in your heart. Ask your doctor how much ...

  7. Aspergillus pacemaker endocarditis presenting as pulmonary embolism.

    PubMed

    Mateos-Colino, A; Golpe, R; González-Rodríguez, A; González-Juanatey, C; Legarra, J J; Blanco, M

    2005-06-01

    Pacemaker endocarditis (PME) is a rare but severe complication of endocardial pacemaker implantation. Fungal PME is extremely uncommon. The case of a 66-year-old female patient who was diagnosed as having a pulmonary embolus based upon the patient's clinical presentation and computed tomography angiography findings is presented. Transthoracic echocardiography demonstrated a huge vegetation attached to the pacemaker wire. The pacemaker system was removed surgically during cardiovascular bypass. The vegetation was cultured, the results of which were positive for Aspergillus spp. No risk factors for Aspergillus infection were found in the patient. She was treated with liposomal amphotericin B for 3 weeks, followed by itraconazole for 40 weeks. At 1 year later, the patient remains asymptomatic.

  8. Mangalith: a new lithium pacemaker battery

    SciTech Connect

    Gerbier, G.; Lehmann, G.

    1980-01-01

    An original lithium battery system is being developed for pacemaker application. The material used, lithium-manganese dioxide, industrially available at the present time for a variety of electronic applications, has been modified and adapted for pacemaker power requirements. The utilization of a different modification of manganese dioxide offers performance advantages. The cell technology is described and performance comparisons between this new cathode material and the industrial counterpart are reported. 7 refs.

  9. Aging and Circadian Rhythms

    PubMed Central

    Duffy, Jeanne F.; Zitting, Kirsi-Marja; Chinoy, Evan D.

    2015-01-01

    Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. Here, we review key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. PMID:26568120

  10. Mathematical Models of Cardiac Pacemaking Function

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

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

  11. p38 MAP kinase regulates circadian rhythms in Drosophila.

    PubMed

    Vrailas-Mortimer, Alysia D; Ryan, Sarah M; Avey, Matthew J; Mortimer, Nathan T; Dowse, Harold; Sanyal, Subhabrata

    2014-12-01

    The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways.

  12. Brain Circadian Oscillators and Redox Regulation in Mammals

    PubMed Central

    Wang, Tongfei A.

    2014-01-01

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

  13. Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study.

    PubMed

    Dougalis, Antonios G; Matthews, Gillian A C; Liss, Birgit; Ungless, Mark A

    2017-04-03

    Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patterns in vitro but a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicity in silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (IH), a transient, A-type, potassium current (IA), a background, 'persistent' (INaP) sodium current and a transient, low voltage activated (LVA) calcium current (ICaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of IH, IA or calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initially via the deactivation of the delayed rectifier potassium current, while a sodium background 'persistent' current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold.

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

    PubMed Central

    1976-01-01

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

  15. Redox regulation and pro-oxidant reactions in the physiology of circadian systems.

    PubMed

    Méndez, Isabel; Vázquez-Martínez, Olivia; Hernández-Muñoz, Rolando; Valente-Godínez, Héctor; Díaz-Muñoz, Mauricio

    2016-05-01

    Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes.

  16. 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.

  17. Individual differences in circadian waveform of Siberian hamsters under multiple lighting conditions.

    PubMed

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

    2012-10-01

    Because the circadian clock in the mammalian brain derives from a network of interacting cellular oscillators, characterizing the nature and bases of circadian coupling is fundamental to understanding how the pacemaker operates. Various phenomena involving plasticity in circadian waveform have been theorized to reflect changes in oscillator coupling; however, it remains unclear whether these different behavioral paradigms reference a unitary underlying process. To test whether disparate coupling assays index a common mechanism, we examined whether there is covariation among behavioral responses to various lighting conditions that produce changes in circadian waveform. Siberian hamsters, Phodopus sungorus, were transferred from long to short photoperiods to distinguish short photoperiod responders (SP-R) from nonresponders (SP-NR). Short photoperiod chronotyped hamsters were subsequently transferred, along with unselected controls, to 24-h light:dark:light: dark cycles (LDLD) with dim nighttime illumination, a procedure that induces bifurcated entrainment. Under LDLD, SP-R hamsters were more likely to bifurcate their rhythms than were SP-NR hamsters or unselected controls. After transfer from LDLD to constant dim light, SP-R hamsters were also more likely to become arrhythmic compared to SP-NR hamsters and unselected controls. In contrast, short photoperiod chronotype did not influence more transient changes in circadian waveform. The present data reveal a clear relationship in the plasticity of circadian waveform across 3 distinct lighting conditions, suggesting a common mechanism wherein individual differences reflect variation in circadian coupling.

  18. Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators.

    PubMed

    Malloy, Jaclyn N; Paulose, Jiffin K; Li, Ye; Cassone, Vincent M

    2012-08-15

    Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the β-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system.

  19. Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators

    PubMed Central

    Malloy, Jaclyn N.; Paulose, Jiffin K.; Li, Ye

    2012-01-01

    Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the β-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system. PMID:22723262

  20. The role of the circadian system in fractal neurophysiological control

    PubMed Central

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

    2013-01-01

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

  1. The role of the circadian system in fractal neurophysiological control.

    PubMed

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

    2013-11-01

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

  2. Later endogenous circadian temperature nadir relative to an earlier wake time in older people

    NASA Technical Reports Server (NTRS)

    Duffy, J. F.; Dijk, D. J.; Klerman, E. B.; Czeisler, C. A.

    1998-01-01

    The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.

  3. The Arabidopsis Circadian System

    PubMed Central

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

    2002-01-01

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

  4. Circadian physiology of metabolism.

    PubMed

    Panda, Satchidananda

    2016-11-25

    A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

  5. [Circadian rhythm and stroke].

    PubMed

    Terayama, Yasuo

    2013-12-01

    Studies on the relationship between stroke incidence and alterations of circadian rhythm are scarce, while pathologically reduced or abolished circadian variation has been described to cause stroke since a long time ago. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulation balance including platelet function, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, autonomic function, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important.

  6. Relationship between Human Pupillary Light Reflex and Circadian System Status

    PubMed Central

    Bonmati-Carrion, Maria Angeles; Hild, Konstanze; Isherwood, Cheryl; Sweeney, Stephen J.; Revell, Victoria L.; Skene, Debra J.; Rol, Maria Angeles; Madrid, Juan Antonio

    2016-01-01

    Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax ≤ 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne-Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460–490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input. PMID:27636197

  7. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor... entitled “Guidance for the Submission of Research and Marketing Applications for Permanent Pacemaker...

  8. 21 CFR 870.3690 - Pacemaker test magnet.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an inhibited or triggered...

  9. 21 CFR 870.3690 - Pacemaker test magnet.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an inhibited or triggered...

  10. 21 CFR 870.3690 - Pacemaker test magnet.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an inhibited or triggered...

  11. 21 CFR 870.3690 - Pacemaker test magnet.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an inhibited or triggered...

  12. 21 CFR 870.3690 - Pacemaker test magnet.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an inhibited or triggered...

  13. 21 CFR 870.3710 - Pacemaker repair or replacement material.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Section 870.3710 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... adhesive, a sealant, a screw, a crimp, or any other material used to repair a pacemaker lead or to reconnect a pacemaker lead to a pacemaker pulse generator. (b) Classification. Class III (premarket...

  14. 21 CFR 870.3650 - Pacemaker polymeric mesh bag.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold...

  15. 21 CFR 870.3710 - Pacemaker repair or replacement material.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker repair or replacement material. 870.3710... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material is...

  16. 21 CFR 870.3650 - Pacemaker polymeric mesh bag.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold...

  17. 21 CFR 870.3720 - Pacemaker electrode function tester.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker electrode function tester. 870.3720... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3720 Pacemaker electrode function tester. (a) Identification. A pacemaker electrode function tester is a device which...

  18. 21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false External transcutaneous cardiac pacemaker... § 870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a device used to supply a periodic electrical pulse intended...

  19. 21 CFR 870.3720 - Pacemaker electrode function tester.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker electrode function tester. 870.3720... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3720 Pacemaker electrode function tester. (a) Identification. A pacemaker electrode function tester is a device which...

  20. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker service tools. 870.3730 Section 870.3730...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and Allen...

  1. 21 CFR 870.3650 - Pacemaker polymeric mesh bag.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold...

  2. 21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false External transcutaneous cardiac pacemaker... § 870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a device used to supply a periodic electrical pulse intended...

  3. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker service tools. 870.3730 Section 870.3730...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3730 Pacemaker service tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and Allen...

  4. 21 CFR 870.3710 - Pacemaker repair or replacement material.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker repair or replacement material. 870.3710... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material is...

  5. 21 CFR 870.3720 - Pacemaker electrode function tester.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker electrode function tester. 870.3720... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3720 Pacemaker electrode function tester. (a) Identification. A pacemaker electrode function tester is a device which...

  6. 21 CFR 870.3710 - Pacemaker repair or replacement material.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker repair or replacement material. 870.3710... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material is...

  7. 21 CFR 870.3650 - Pacemaker polymeric mesh bag.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold...

  8. 21 CFR 870.5550 - External transcutaneous cardiac pacemaker (noninvasive).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false External transcutaneous cardiac pacemaker... § 870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a device used to supply a periodic electrical pulse intended...

  9. 21 CFR 870.3650 - Pacemaker polymeric mesh bag.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker polymeric mesh bag. 870.3650 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted device used to hold...

  10. 21 CFR 870.1750 - External programmable pacemaker pulse generator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false External programmable pacemaker pulse generator... External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be programmed to produce one or more pulses at...

  11. 21 CFR 870.1750 - External programmable pacemaker pulse generator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false External programmable pacemaker pulse generator... External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be programmed to produce one or more pulses at...

  12. 21 CFR 870.3600 - External pacemaker pulse generator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has...

  13. 21 CFR 870.3640 - Indirect pacemaker generator function analyzer.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Indirect pacemaker generator function analyzer. 870.3640 Section 870.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker...

  14. 21 CFR 870.3630 - Pacemaker generator function analyzer.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Pacemaker generator function analyzer. 870.3630... generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device that is connected to a pacemaker pulse generator to test any or all of the generator's parameters, including...

  15. 21 CFR 870.3640 - Indirect pacemaker generator function analyzer.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Indirect pacemaker generator function analyzer. 870.3640 Section 870.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker...

  16. 21 CFR 870.3630 - Pacemaker generator function analyzer.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker generator function analyzer. 870.3630... generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device that is connected to a pacemaker pulse generator to test any or all of the generator's parameters, including...

  17. 21 CFR 870.3630 - Pacemaker generator function analyzer.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Pacemaker generator function analyzer. 870.3630... generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device that is connected to a pacemaker pulse generator to test any or all of the generator's parameters, including...

  18. 21 CFR 870.3610 - Implantable pacemaker pulse generator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Implantable pacemaker pulse generator. 870.3610 Section 870.3610 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that...

  19. 21 CFR 870.1750 - External programmable pacemaker pulse generator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false External programmable pacemaker pulse generator... External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be programmed to produce one or more pulses at...

  20. 21 CFR 870.3630 - Pacemaker generator function analyzer.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker generator function analyzer. 870.3630... generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device that is connected to a pacemaker pulse generator to test any or all of the generator's parameters, including...

  1. 21 CFR 870.3600 - External pacemaker pulse generator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has...

  2. 21 CFR 870.3630 - Pacemaker generator function analyzer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker generator function analyzer. 870.3630... generator function analyzer. (a) Identification. A pacemaker generator function analyzer is a device that is connected to a pacemaker pulse generator to test any or all of the generator's parameters, including...

  3. 21 CFR 870.1750 - External programmable pacemaker pulse generator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false External programmable pacemaker pulse generator... External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be programmed to produce one or more pulses at...

  4. 21 CFR 870.3600 - External pacemaker pulse generator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has...

  5. 21 CFR 870.3640 - Indirect pacemaker generator function analyzer.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Indirect pacemaker generator function analyzer. 870.3640 Section 870.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker...

  6. 21 CFR 870.3640 - Indirect pacemaker generator function analyzer.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Indirect pacemaker generator function analyzer. 870.3640 Section 870.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker...

  7. 21 CFR 870.3610 - Implantable pacemaker pulse generator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implantable pacemaker pulse generator. 870.3610 Section 870.3610 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that...

  8. 21 CFR 870.3600 - External pacemaker pulse generator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has...

  9. 21 CFR 870.3600 - External pacemaker pulse generator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false External pacemaker pulse generator. 870.3600 Section 870.3600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... pacemaker pulse generator. (a) Identification. An external pacemaker pulse generator is a device that has...

  10. 21 CFR 870.3640 - Indirect pacemaker generator function analyzer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Indirect pacemaker generator function analyzer. 870.3640 Section 870.3640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker...

  11. 21 CFR 870.1750 - External programmable pacemaker pulse generator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false External programmable pacemaker pulse generator... External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can be programmed to produce one or more pulses at...

  12. Synchronization of the mammalian circadian timing system: Light can control peripheral clocks independently of the SCN clock: alternate routes of entrainment optimize the alignment of the body's circadian clock network with external time.

    PubMed

    Husse, Jana; Eichele, Gregor; Oster, Henrik

    2015-10-01

    A vast network of cellular circadian clocks regulates 24-hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light-reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more "federated" and tissue-specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions.

  13. Circadian and ultradian rhythms of clock gene expression in the suprachiasmatic nucleus of freely moving mice

    PubMed Central

    Ono, Daisuke; Honma, Ken-ichi; Honma, Sato

    2015-01-01

    In mammals, the temporal order of physiology and behavior is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Rhythms are generated in cells by an auto-regulatory transcription/translation feedback loop, composed of several clock genes and their protein products. Taking advantage of bioluminescence reporters, we have succeeded in continuously monitoring the expression of clock gene reporters Per1-luc, PER2::LUC and Bmal1-ELuc in the SCN of freely moving mice for up to 3 weeks in constant darkness. Bioluminescence emitted from the SCN was collected with an implanted plastic optical fiber which was connected to a cooled photomultiplier tube. We found robust circadian rhythms in the clock gene expression, the phase-relation of which were the same as those observed ex vivo. The circadian rhythms were superimposed by episodic bursts which had ultradian periods of approximately 3.0 h. Episodic bursts often accompanied activity bouts, but stoichiometric as well as temporal analyses revealed no causality between them. Clock gene expression in the SCN in vivo is regulated by the circadian pacemaker and ultradian rhythms of unknown origin. PMID:26194231

  14. Photic and circadian regulation of melatonin production in the Mozambique tilapia Oreochromis mossambicus.

    PubMed

    Nikaido, Yoshiaki; Ueda, Satomi; Takemura, Akihiro

    2009-01-01

    Diverse circadian systems related to phylogeny and ecological adaptive strategies are proposed in teleosts. Recently, retinal photoreception was reported to be important for the circadian pacemaking activities of the Nile tilapia Oreochromis niloticus. We aimed to confirm the photic and circadian responsiveness of its close relative-the Mozambique tilapia O. mossambicus. Melatonin production in cannulated or ophthalmectomized fish and its secretion from cultured pineal glands were examined under several light regimes. Melatonin production in the cannulated tilapias was measured at 3-h intervals; it fluctuated daily, with a nocturnal increase and a diurnal decrease. Exposing the cannulated fish to several light intensities (1500-0.1 lx) and to natural light (0.1 and 0.3 lx) suppressed melatonin levels within 30 min. Static pineal gland culture under light-dark and reverse light-dark cycles revealed that melatonin synthesis increased during the dark periods. Rhythmic melatonin synthesis disappeared on pineal gland culture under constant dark and light conditions. After ophthalmectomy, plasma melatonin levels did not vary with light-dark cycles. These results suggest that (1) Mozambique tilapias possess strong photic responsiveness, (2) their pineal glands are sensitive to light but lack circadian pacemaker activity, and (3) they require lateral eyes for rhythmic melatonin secretion from the pineal gland.

  15. Circadian and ultradian rhythms of clock gene expression in the suprachiasmatic nucleus of freely moving mice.

    PubMed

    Ono, Daisuke; Honma, Ken-ichi; Honma, Sato

    2015-07-21

    In mammals, the temporal order of physiology and behavior is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Rhythms are generated in cells by an auto-regulatory transcription/translation feedback loop, composed of several clock genes and their protein products. Taking advantage of bioluminescence reporters, we have succeeded in continuously monitoring the expression of clock gene reporters Per1-luc, PER2::LUC and Bmal1-ELuc in the SCN of freely moving mice for up to 3 weeks in constant darkness. Bioluminescence emitted from the SCN was collected with an implanted plastic optical fiber which was connected to a cooled photomultiplier tube. We found robust circadian rhythms in the clock gene expression, the phase-relation of which were the same as those observed ex vivo. The circadian rhythms were superimposed by episodic bursts which had ultradian periods of approximately 3.0 h. Episodic bursts often accompanied activity bouts, but stoichiometric as well as temporal analyses revealed no causality between them. Clock gene expression in the SCN in vivo is regulated by the circadian pacemaker and ultradian rhythms of unknown origin.

  16. Synchronization of the mammalian circadian timing system: Light can control peripheral clocks independently of the SCN clock

    PubMed Central

    Husse, Jana; Eichele, Gregor

    2015-01-01

    A vast network of cellular circadian clocks regulates 24‐hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light‐reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more “federated” and tissue‐specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions. PMID:26252253

  17. Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT.

    PubMed

    Li, Quan; Loh, Dawn H; Kudo, Takashi; Truong, Danny; Derakhshesh, Matthew; Kaswan, Zoë MacDowell; Ghiani, Cristina A; Tsoa, Rosemarie; Cheng, Yin; Sun, Yi E; Colwell, Christopher S

    2015-05-01

    Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2(-/y) mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our finds suggest an integral role of MeCP2 in the circadian timing system and provides a possible mechanistic explanation for the sleep/wake distrubances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.

  18. Circadian Rhythms and Sleep in Drosophila melanogaster.

    PubMed

    Dubowy, Christine; Sehgal, Amita

    2017-04-01

    The advantages of the model organism Drosophila melanogaster, including low genetic redundancy, functional simplicity, and the ability to conduct large-scale genetic screens, have been essential for understanding the molecular nature of circadian (∼24 hr) rhythms, and continue to be valuable in discovering novel regulators of circadian rhythms and sleep. In this review, we discuss the current understanding of these interrelated biological processes in Drosophila and the wider implications of this research. Clock genes period and timeless were first discovered in large-scale Drosophila genetic screens developed in the 1970s. Feedback of period and timeless on their own transcription forms the core of the molecular clock, and accurately timed expression, localization, post-transcriptional modification, and function of these genes is thought to be critical for maintaining the circadian cycle. Regulators, including several phosphatases and kinases, act on different steps of this feedback loop to ensure strong and accurately timed rhythms. Approximately 150 neurons in the fly brain that contain the core components of the molecular clock act together to translate this intracellular cycling into rhythmic behavior. We discuss how different groups of clock neurons serve different functions in allowing clocks to entrain to environmental cues, driving behavioral outputs at different times of day, and allowing flexible behavioral responses in different environmental conditions. The neuropeptide PDF provides an important signal thought to synchronize clock neurons, although the details of how PDF accomplishes this function are still being explored. Secreted signals from clock neurons also influence rhythms in other tissues. SLEEP is, in part, regulated by the circadian clock, which ensures appropriate timing of sleep, but the amount and quality of sleep are also determined by other mechanisms that ensure a homeostatic balance between sleep and wake. Flies have been useful

  19. The social zeitgeber theory, circadian rhythms, and mood disorders: review and evaluation.

    PubMed

    Grandin, Louisa D; Alloy, Lauren B; Abramson, Lyn Y

    2006-10-01

    The social zeitgeber theory [Ehlers, C. L., Frank, E., & Kupfer, D. J. (1988). Social zeitgebers and biological rhythms. Archives of General Psychiatry, 45, 948-952] offers an explanation of how life events trigger depressive episodes. According to this theory, life stress leads to mood episodes by causing disruptions in individuals' social routines and, in turn, their biological circadian rhythms. In this article, we review the literature pertaining to the social zeitgeber theory, as well as evidence that this theory may be applied to (hypo)manic episodes. Given the limited data supporting the social zeitgeber theory to date, we also evaluate whether circadian rhythm disruptions are triggered by an internal mechanism, such as an abnormality in one's pacemaker (the suprachiasmatic nucleus; SCN). We review these two theories in an attempt to understand the potential causes of circadian rhythm disruptions and affective episodes in individuals with unipolar and bipolar disorders. We also propose several areas of future research.

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

    NASA Astrophysics Data System (ADS)

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

    2005-08-01

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

  2. Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus slices from Cry knockout mice.

    PubMed

    Noguchi, Takako; Lo, Kevin; Diemer, Tanja; Welsh, David K

    2016-04-21

    Lithium is widely used as a treatment of bipolar disorder, a neuropsychiatric disorder associated with disrupted circadian rhythms. Lithium is known to lengthen period and increase amplitude of circadian rhythms. One possible pathway for these effects involves inhibition of glycogen synthase kinase-3β (GSK-3β), which regulates degradation of CRY2, a canonical clock protein determining circadian period. CRY1 is also known to play important roles in regulating circadian period and phase, although there is no evidence that it is similarly phosphorylated by GSK-3β. In this paper, we tested the hypothesis that lithium affects circadian rhythms through CRYs. We cultured fibroblasts and slices of the suprachiasmatic nucleus (SCN), the master circadian pacemaker of the brain, from Cry1-/-, Cry2-/-, or wild-type (WT) mice bearing the PER2:LUC circadian reporter. Lithium was applied in the culture medium, and circadian rhythms of PER2 expression were measured. In WT and Cry2-/- fibroblasts, 10mM lithium increased PER2 expression and rhythm amplitude but not period, and 1mM lithium did not affect either period or amplitude. In non-rhythmic Cry1-/- fibroblasts, 10mM lithium increased PER2 expression. In SCN slices, 1mM lithium lengthened period ∼1h in all genotypes, but did not affect amplitude except in Cry2-/- SCN. Thus, the amplitude-enhancing effect of lithium in WT fibroblasts was unaffected by Cry2 knockout and occurred in the absence of period-lengthening, whereas the period-lengthening effect of lithium in WT SCN was unaffected by Cry1 or Cry2 knockout and occurred in the absence of rhythm amplification, suggesting that these two effects of lithium on circadian rhythms are independent of CRYs and of each other.

  3. Alertness, mood and performance rhythm disturbances associated with circadian sleep disorders in the blind.

    PubMed

    Lockley, Steven W; Dijk, Derk-Jan; Kosti, Ourania; Skene, Debra J; Arendt, Josephine

    2008-06-01

    Blind people report disturbances in alertness, mood and performance. In laboratory studies, these waking functions can only be maintained when the wake-dependent deterioration is opposed by appropriately-timed endogenous circadian rhythms. We aimed to quantify whether variations in waking function experienced by blind people living in society were dependent on the phase relationship between the sleep-wake cycle and the circadian pacemaker. The time course of alertness, mood and performance was assessed in 52 blind subjects with and without circadian rhythm disorders every 2 h for 2 days per week for 4 weeks. Sleep-wake timing and circadian phase were assessed from diaries and weekly measurements of urinary 6-sulphatoxymelatonin rhythms, respectively. In those subjects who woke at either a normal circadian phase (n = 26) or abnormally early (n = 5), alertness, mood and performance deteriorated significantly with increased time awake (P < 0.05). In 17 non-entrained ('free-running') subjects, waking function varied significantly with circadian phase such that subjects rated themselves most sleepy (P = 0.03) and most miserable (P = 0.02) when they were awake during the time of peak melatonin production. The internal phase relationship between sleep-wake behaviour and the circadian melatonin rhythm in entrained subjects contributed to predictable differences in the daily profile of alertness, mood and performance. Disruption of this phase relationship in non-entrained blind individuals with circadian rhythm sleep disorders resulted in impaired waking function during the day equivalent to that usually only experienced when awake during the night. Treatment for circadian rhythm disorders should be targeted in normalizing these phase relationships.

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

    PubMed Central

    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

  5. Quantifying the robustness of circadian oscillations at the single-cell level

    NASA Astrophysics Data System (ADS)

    Lambert, Guillaume; Rust, Michael

    2014-03-01

    Cyanobacteria are light-harvesting microorganisms that contribute to 30% of the photosynthetic activity on Earth and contain one of the simplest circadian systems in the animal kingdom. In Synechococcus elongatus , a species of freshwater cyanobacterium, circadian oscillations are regulated by the KaiABC system, a trio of interacting proteins that act as a biomolecular pacemaker of the circadian system. While the core oscillator precisely anticipates Earth's 24h light/dark cycle, it is unclear how much individual cells benefit from the expression and maintenance of a circadian clock. By studying the growth dynamics of individual S . elongatus cells under sudden light variations, we show that several aspects of cellular growth, such as a cell's division probability and its elongation rate, are tightly coupled to the circadian clock. We propose that the evolution and maintenance of a circadian clock increases the fitness of cells by allowing them to take advantage of cyclical light/dark environments by alternating between two phenotypes: expansionary, where cells grow and divide at a fast pace during the first part of the day, and conservative, where cells enter a more quiescent state to better prepare to the stresses associated with the night's prolonged darkness.

  6. Assignment of an essential role for the Neurospora frequency gene in circadian entrainment to temperature cycles.

    PubMed

    Pregueiro, Antonio M; Price-Lloyd, Nathan; Bell-Pedersen, Deborah; Heintzen, Christian; Loros, Jennifer J; Dunlap, Jay C

    2005-02-08

    Circadian systems include slave oscillators and central pacemakers, and the cores of eukaryotic circadian clocks described to date are composed of transcription and translation feedback loops (TTFLs). In the model system Neurospora, normal circadian rhythmicity requires a TTFL in which a White Collar complex (WCC) activates expression of the frequency (frq) gene, and the FRQ protein feeds back to attenuate that activation. To further test the centrality of this TTFL to the circadian mechanism in Neurospora, we used low-amplitude temperature cycles to compare WT and frq-null strains under conditions in which a banding rhythm was elicited. WT cultures were entrained to these temperature cycles. Unlike those normal strains, however, frq-null mutants did not truly entrain to the same cycles. Their peaks and troughs always occurred in the cold and warm periods, respectively, strongly suggesting that the rhythm in Neurospora lacking frq function simply is driven by the temperature cycles. Previous reports suggested that a FRQ-less oscillator (FLO) could be entrained to temperature cycles, rather than being driven, and speculated that the FLO was the underlying circadian-rhythm generator. These inferences appear to derive from the use of a phase reference point affected by both the changing waveform and the phase of the oscillation. Examination of several other phase markers as well as results of additional experimental tests indicate that the FLO is, at best, a slave oscillator to the TTFL, which underlies circadian rhythm generation in Neurospora.

  7. Is metabolic rate a universal 'pacemaker' for biological processes?

    PubMed

    Glazier, Douglas S

    2015-05-01

    A common, long-held belief is that metabolic rate drives the rates of various biological, ecological and evolutionary processes. Although this metabolic pacemaker view (as assumed by the recent, influential 'metabolic theory of ecology') may be true in at least some situations (e.g. those involving moderate temperature effects or physiological processes closely linked to metabolism, such as heartbeat and breathing rate), it suffers from several major limitations, including: (i) it is supported chiefly by indirect, correlational evidence (e.g. similarities between the body-size and temperature scaling of metabolic rate and that of other biological processes, which are not always observed) - direct, mechanistic or experimental support is scarce and much needed; (ii) it is contradicted by abundant evidence showing that various intrinsic and extrinsic factors (e.g. hormonal action and temperature changes) can dissociate the rates of metabolism, growth, development and other biological processes; (iii) there are many examples where metabolic rate appears to respond to, rather than drive the rates of various other biological processes (e.g. ontogenetic growth, food intake and locomotor activity); (iv) there are additional examples where metabolic rate appears to be unrelated to the rate of a biological process (e.g. ageing, circadian rhythms, and molecular evolution); and (v) the theoretical foundation for the metabolic pacemaker view focuses only on the energetic control of biological processes, while ignoring the importance of informational control, as mediated by various genetic, cellular, and neuroendocrine regulatory systems. I argue that a comprehensive understanding of the pace of life must include how biological activities depend on both energy and information and their environmentally sensitive interaction. This conclusion is supported by extensive evidence showing that hormones and other regulatory factors and signalling systems coordinate the processes of

  8. [Cardiac Pacemakers, implantable defibrillators and IRM].

    PubMed

    Frank, R; Hidden-Lucet, F; Himbert, C; Petitot, J C; Fontaine, G

    2003-04-01

    The IRM is formally contraindicated to the pacemaker and cardiac defibrillator wearers because of the risk of inhibition or inappropriate stimulations during the examination. However if the examination is essential, suitable programming of the apparatus and a constant monitoring of the heartbeat rate by a qualified doctor in cardiac stimulation must make it possible to avoid any accident.

  9. 21 CFR 870.3700 - Pacemaker programmers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker programmers. 870.3700 Section 870.3700 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... is required to be filed with the Food and Drug Administration on or before September 20, 2012,...

  10. Clinical assessment of pacemaker power sources

    SciTech Connect

    Bilitch, M.; Parsonnet, V.; Furman, S.

    1980-01-01

    The development of power sources for cardiac pacemakers has progressed from a 15-year usage of mercury-zinc batteries to widely used and accepted lithium cells. At present, there are about 6 different types of lithium cells incorporated into commercially distributed pacemakers. The authors reviewed experience over a 5-year period with 1711 mercury-zinc, 130 nuclear (P238) and 1912 lithium powered pacemakers. The lithium units have included 698 lithium-iodide, 270 lithium-silver chromate, 135 lithium-thionyl chloride, 31 lithium-lead and 353 lithium-cupric sulfide batteries. 57 of the lithium units have failed (91.2% component failure and 5.3% battery failure). 459 mercury-zinc units failed (25% component failure and 68% battery depletion). The data show that lithium powered pacemaker failures are primarily component, while mercury-zinc failures are primarily battery related. It is concluded that mercury-zinc powered pulse generators are obsolete and that lithium and nuclear (P238) power sources are highly reliable over the 5 years for which data are available. 3 refs.

  11. Cardiomyocyte Circadian Oscillations Are Cell-Autonomous, Amplified by β-Adrenergic Signaling, and Synchronized in Cardiac Ventricle Tissue

    PubMed Central

    Welsh, David K.

    2016-01-01

    Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a β-adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell-autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+. PMID:27459195

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

    PubMed

    Taguchi, Takahiro; Maeba, Satoru; Sueda, Taijiro

    2014-09-01

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

  13. Generation of cardiac pacemaker cells by programming and differentiation.

    PubMed

    Husse, Britta; Franz, Wolfgang-Michael

    2016-07-01

    A number of diseases are caused by faulty function of the cardiac pacemaker and described as "sick sinus syndrome". The medical treatment of sick sinus syndrome with electrical pacemaker implants in the diseased heart includes risks. These problems may be overcome via "biological pacemaker" derived from different adult cardiac cells or pluripotent stem cells. The generation of cardiac pacemaker cells requires the understanding of the pacing automaticity. Two characteristic phenomena the "membrane-clock" and the "Ca(2+)-clock" are responsible for the modulation of the pacemaker activity. Processes in the "membrane-clock" generating the spontaneous pacemaker firing are based on the voltage-sensitive membrane ion channel activity starting with slow diastolic depolarization and discharging in the action potential. The influence of the intracellular Ca(2+) modulating the pacemaker activity is characterized by the "Ca(2+)-clock". The generation of pacemaker cells started with the reprogramming of adult cardiac cells by targeted induction of one pacemaker function like HCN1-4 overexpression and enclosed in an activation of single pacemaker specific transcription factors. Reprogramming of adult cardiac cells with the transcription factor Tbx18 created cardiac cells with characteristic features of cardiac pacemaker cells. Another key transcription factor is Tbx3 specifically expressed in the cardiac conduction system including the sinoatrial node and sufficient for the induction of the cardiac pacemaker gene program. For a successful cell therapeutic practice, the generated cells should have all regulating mechanisms of cardiac pacemaker cells. Otherwise, the generated pacemaker cells serve only as investigating model for the fundamental research or as drug testing model for new antiarrhythmics. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  14. Circadian rhythms and memory: not so simple as cogs and gears.

    PubMed

    Eckel-Mahan, Kristin L; Storm, Daniel R

    2009-06-01

    The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

  15. Two steady-entrainment phases and graded masking effects by light generate different circadian chronotypes in Octodon degus.

    PubMed

    Vivanco, Pablo; Rol, Maria Angeles; Madrid, Juan Antonio

    2009-02-01

    Processes involved in the operation of the circadian pacemaker are well characterized; however; little is known about what mechanisms drive the overt diurnal, nocturnal, or crepuscular behavior in a species. In this context, dual-phasing rodents, such as Octodon degus, emerge as a useful model to decipher these keys. Two main chronotypes, nocturnal and diurnal, have been traditionally described in laboratory-housed degus based on the percentage of activity displayed by the animals during the scotophase or photophase. However, if one considers also the entrainment phase angle during the first days following a change from LD to DD conditions, a third chronotype (intermediate)-or more properly, a continuous grading of circadian expressions between diurnal and nocturnal chronotype-can be observed. Our experiments suggest the pacemaker of the diurnal animal is entrained to the photophase, and light does not exert a negative masking effect. The pacemaker of the nocturnal degus, on the other hand, is entrained to the scotophase, and light exerts a strong negative masking effect. Finally, the intermediate chronotype is characterized by variable negative masking effect of light overlapping a pacemaker entrained to the photophase. The phase shift inversion from diurnal to nocturnal chronotype is related to the availability of a wheel in the cage, and the effect may be located downstream from the clock. However, body temperature rhythm recordings, less affected by masking effects, point to an involvement of the circadian pacemaker in chronotype differentiation, as transient entrainment cycles, and not an abrupt phase shift, were detected after providing access to the wheel. The diurnality of degus seems to be the result of a variety of mechanisms, which may explain how different processes can lead to similar chronotypes.

  16. Measuring pacemaker dose: A clinical perspective

    SciTech Connect

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

    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.

  17. Delay-induced multiple stochastic resonances on scale-free neuronal networks.

    PubMed

    Wang, Qingyun; Perc, Matjaz; Duan, Zhisheng; Chen, Guanrong

    2009-06-01

    We study the effects of periodic subthreshold pacemaker activity and time-delayed coupling on stochastic resonance over scale-free neuronal networks. As the two extreme options, we introduce the pacemaker, respectively, to the neuron with the highest degree and to one of the neurons with the lowest degree within the network, but we also consider the case when all neurons are exposed to the periodic forcing. In the absence of delay, we show that an intermediate intensity of noise is able to optimally assist the pacemaker in imposing its rhythm on the whole ensemble, irrespective to its placing, thus providing evidences for stochastic resonance on the scale-free neuronal networks. Interestingly thereby, if the forcing in form of a periodic pulse train is introduced to all neurons forming the network, the stochastic resonance decreases as compared to the case when only a single neuron is paced. Moreover, we show that finite delays in coupling can significantly affect the stochastic resonance on scale-free neuronal networks. In particular, appropriately tuned delays can induce multiple stochastic resonances independently of the placing of the pacemaker, but they can also altogether destroy stochastic resonance. Delay-induced multiple stochastic resonances manifest as well-expressed maxima of the correlation measure, appearing at every multiple of the pacemaker period. We argue that fine-tuned delays and locally active pacemakers are vital for assuring optimal conditions for stochastic resonance on complex neuronal networks.

  18. Circadian clock signals in the adrenal cortex.

    PubMed

    Ota, Takumi; Fustin, Jean-Michel; Yamada, Hiroyuki; Doi, Masao; Okamura, Hitoshi

    2012-02-05

    Circadian secretion of steroid hormones by the adrenal cortex is required to maintain whole body homeostasis and to adequately respond to or anticipate environmental changes. The richly vascularized zona glomerulosa (ZG) cells in the pericapsular region regulate osmotic balance of body fluid by secreting mineralocorticoids responding to circulating bioactive substances, and more medially located zona fasciculata (ZF) cells regulate energy supply and consumption by secreting glucocorticoids under neuronal and hormonal regulation. The circadian clock regulates both steroidogenic pathways: the clock within the ZG regulates mineralocorticoid production via controlling rate-limiting synthetic enzymes, and the ZF secretes glucocorticoid hormones into the systemic circulation under the control of central clock in the suprachiasmatic nucleus. A functional biological clock at the systemic and cellular levels is therefore necessary for steroid synthesis and secretion.

  19. Metabolic regulation of circadian clocks.

    PubMed

    Haydon, Michael J; Hearn, Timothy J; Bell, Laura J; Hannah, Matthew A; Webb, Alex A R

    2013-05-01

    Circadian clocks are 24-h timekeeping mechanisms, which have evolved in plants, animals, fungi and bacteria to anticipate changes in light and temperature associated with the rotation of the Earth. The current paradigm to explain how biological clocks provide timing information is based on multiple interlocking transcription-translation negative feedback loops (TTFL), which drive rhythmic gene expression and circadian behaviour of growth and physiology. Metabolism is an important circadian output, which in plants includes photosynthesis, starch metabolism, nutrient assimilation and redox homeostasis. There is increasing evidence in a range of organisms that these metabolic outputs can also contribute to circadian timing and might also comprise independent circadian oscillators. In this review, we summarise the mechanisms of circadian regulation of metabolism by TTFL and consider increasing evidence that rhythmic metabolism contributes to the circadian network. We highlight how this might be relevant to plant circadian clock function.

  20. Pacemaker deactivation: withdrawal of support or active ending of life?

    PubMed

    Huddle, Thomas S; Amos Bailey, F

    2012-12-01

    In spite of ethical analyses assimilating the palliative deactivation of pacemakers to commonly accepted withdrawings of life-sustaining therapy, many clinicians remain ethically uncomfortable with pacemaker deactivation at the end of life. Various reasons have been posited for this discomfort. Some cardiologists have suggested that reluctance to deactivate pacemakers may stem from a sense that the pacemaker has become part of the patient's "self." The authors suggest that Daniel Sulmasy is correct to contend that any such identification of the pacemaker is misguided. The authors argue that clinicians uncomfortable with pacemaker deactivation are nevertheless correct to see it as incompatible with the traditional medical ethics of withdrawal of support. Traditional medical ethics is presently taken by many to sanction pacemaker deactivation when such deactivation honors the patient's right to refuse treatment. The authors suggest that the right to refuse treatment applies to treatments involving ongoing physician agency. This right cannot underwrite patient demands that physicians reverse the effects of treatments previously administered, in which ongoing physician agency is no longer implicated. The permanently indwelling pacemaker is best seen as such a treatment. As such, its deactivation in the pacemaker-dependent patient is best seen not as withdrawal of support but as active ending of life. That being the case, clinicians adhering to the usual ethical analysis of withdrawal of support are correct to be uncomfortable with pacemaker deactivation at the end of life.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. A Neural Network Underlying Circadian Entrainment and Photoperiodic Adjustment of Sleep and Activity in Drosophila

    PubMed Central

    Schlichting, Matthias; Menegazzi, Pamela; Lelito, Katharine R.; Yao, Zepeng; Buhl, Edgar; Dalla Benetta, Elena; Bahle, Andrew; Denike, Jennifer; Hodge, James John

    2016-01-01

    A sensitivity of the circadian clock to light/dark cycles ensures that biological rhythms maintain optimal phase relationships with the external day. In animals, the circadian clock neuron network (CCNN) driving sleep/activity rhythms receives light input from multiple photoreceptors, but how these photoreceptors modulate CCNN components is not well understood. Here we show that the Hofbauer-Buchner eyelets differentially modulate two classes of ventral lateral neurons (LNvs) within the Drosophila CCNN. The eyelets antagonize Cryptochrome (CRY)- and compound-eye-based photoreception in the large LNvs while synergizing CRY-mediated photoreception in the small LNvs. Furthermore, we show that the large LNvs interact with subsets of “evening cells” to adjust the timing of the evening peak of activity in a day length-dependent manner. Our work identifies a peptidergic connection between the large LNvs and a group of evening cells that is critical for the seasonal adjustment of circadian rhythms. SIGNIFICANCE STATEMENT In animals, circadian clocks have evolved to orchestrate the timing of behavior and metabolism. Consistent timing requires the entrainment these clocks to the solar day, a process that is critical for an organism's health. Light cycles are the most important external cue for the entrainment of circadian clocks, and the circadian system uses multiple photoreceptors to link timekeeping to the light/dark cycle. How light information from these photorecptors is integrated into the circadian clock neuron network to support entrainment is not understood. Our results establish that input from the HB eyelets differentially impacts the physiology of neuronal subgroups. This input pathway, together with input from the compound eyes, precisely times the activity of flies under long summer days. Our results provide a mechanistic model of light transduction and integration into the circadian system, identifying new and unexpected network motifs within the circadian

  6. Around the Fungal Clock: Recent Advances in the Molecular Study of Circadian Clocks in Neurospora and Other Fungi.

    PubMed

    Montenegro-Montero, Alejandro; Canessa, Paulo; Larrondo, Luis F

    2015-01-01

    Night follows day and as a consequence, organisms have evolved molecular machineries that allow them to anticipate and respond to the many changes that accompany these transitions. Circadian clocks are precise yet plastic pacemakers that allow the temporal organization of a plethora of biological process. Circadian clocks are widespread across the tree of life and while their exact molecular components differ among phyla, they tend to share common design principles. In this review, we discuss the circadian system of the filamentous fungus Neurospora crassa. Historically, this fungus has served a key role in the genetic and molecular dissection of circadian clocks, aiding in their detailed mechanistic understanding. Recent studies have provided new insights into the daily molecular dynamics that constitute the Neurospora circadian oscillator, some of which have questioned traditional paradigms describing timekeeping mechanisms in eukaryotes. In addition, recent reports support the idea of a dynamic network of transcription factors underlying the rhythmicity of thousands of genes in Neurospora, many of which oscillate only under specific conditions. Besides Neurospora, which harbors the best characterized circadian system among filamentous fungi, the recent characterization of the circadian system of the plant-pathogenic fungus Botrytis cinerea has provided additional insights into the physiological impact of the clock and potential additional functions of clock proteins in fungi. Finally, we speculate on the presence of FRQ or FRQ-like proteins in diverse fungal lineages.

  7. 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

  8. Circadian Rhythms in Cyanobacteria

    PubMed Central

    Golden, Susan S.

    2015-01-01

    SUMMARY Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718

  9. Socially synchronized circadian oscillators.

    PubMed

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

    2013-08-22

    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.

  10. Phase precession of grid cells in a network model without external pacemaker.

    PubMed

    Thurley, Kay; Hellmundt, Franziska; Leibold, Christian

    2013-09-01

    Rodent brains encode space in both the firing rate and the spike timing of neurons in the medial entorhinal cortex. The rate code is realized by grid fields, that is, the neurons fire at multiple places that are arranged on a hexagonal lattice. Such activity is accompanied by theta oscillations of the local field potential. The phase of spikes thereby encodes space as well, since it decreases with the distance traveled in the field-a phenomenon called phase precession. A likely candidate for grid cells are entorhinal cortex stellate cells, which are type II oscillators and have been suggested to act as pacemakers. It is unclear how spiking of such putative pacemaker neurons would be able to precess in phase relative to a self-generated oscillation. This article presents a computational model of how this paradox can be resolved although the periodicity of the grid fields interferes with the periodic firing of the neurons. Our simulations show that the connections between stellate cells synchronize small cell groups, which allows a population oscillation during grid field activity that is accompanied by theta phase precession. Direct excitatory coupling between the stellate cells, indirect inhibitory coupling via a gamma-oscillating network of interneurons, or both could mediate this phase coordination. Our model further suggests modulation of h-currents to be a feasible mechanism to adjust phase precession to running-speed. The coexistence of rate and timing code for space hence follows as a natural consequence of the self-organization in a recurrent network.

  11. 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

  12. 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.

  13. Circadian clocks and inflammation: reciprocal regulation and shared mediators.

    PubMed

    Cermakian, Nicolas; Westfall, Susan; Kiessling, Silke

    2014-08-01

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

  14. 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 τ 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 (τ 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 < 0.0001) but did not decrease the occurrence of daytime naps compared with placebo. Conclusions Although caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep–Wake Disorder in the blind appropriately. PMID:25891543

  15. 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

  16. [Magnets, pacemaker and defibrillator: fatal attraction?].

    PubMed

    Bergamin, C; Graf, D

    2015-05-27

    This article aims at clarifying the effects of a clinical magnet on pacemakers and Implantable Cardioverter Defibrillators. The effects of electromagnetic interferences on such devices, including interferences linked to electrosurgery and magnetic resonance imaging are also discussed. In general, a magnet provokes a distinctive effect on a pacemaker by converting it into an asynchronous mode of pacing, and on an Implantable Cardioverter Defibrillator by suspending its own antitachyarythmia therapies without affecting the pacing. In the operating room, the magnet has to be used cautiously with precisely defined protocols which respect the type of the device used, the type of intervention planned, the presence or absence of EMI and the pacing-dependency of the patient.

  17. Circadian Rhythm Sleep Disorders

    PubMed Central

    Kim, Min Ju; Lee, Jung Hie; Duffy, Jeanne F.

    2014-01-01

    Objective To review circadian rhythm sleep disorders, including underlying causes, diagnostic considerations, and typical treatments. Methods Literature review and discussion of specific cases. Results Survey studies 1,2 suggest that up to 3% of the adult population suffers from a circadian rhythm sleep disorder (CRSD). However, these sleep disorders are often confused with insomnia, and an estimated 10% of adult and 16% of adolescent sleep disorders patients may have a CRSD 3-6. While some CRSD (such as jet lag) can be self-limiting, others when untreated can lead to adverse medical, psychological, and social consequences. The International Classification of Sleep Disorders classifies CRSD as dyssomnias, with six subtypes: Advanced Sleep Phase Type, Delayed Sleep Phase Type, Irregular Sleep Wake Type, Free Running Type, Jet Lag Type, and Shift Work Type. The primary clinical characteristic of all CRSD is an inability to fall asleep and wake at the desired time. It is believed that CRSD arise from a problem with the internal biological clock (circadian timing system) and/or misalignment between the circadian timing system and the external 24-hour environment. This misalignment can be the result of biological and/or behavioral factors. CRSD can be confused with other sleep or medical disorders. Conclusions Circadian rhythm sleep disorders are a distinct class of sleep disorders characterized by a mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep. If untreated, CRSD can lead to insomnia and excessive daytime sleepiness, with negative medical, psychological, and social consequences. It is important for physicians to recognize potential circadian rhythm sleep disorders so that appropriate diagnosis, treatment, and referral can be made. PMID:25368503

  18. Measuring stem cell circadian rhythm.

    PubMed

    Hrushesky, William; Rich, Ivan N

    2015-01-01

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

  19. The effect of metal detector gates on implanted permanent pacemakers.

    PubMed

    Copperman, Y; Zarfati, D; Laniado, S

    1988-10-01

    The effect of metal detector security gates, such as are used in airports, was tested in 103 nonselected pacemaker patients. Various types of single and dual chamber units were examined, using telemetry during the test. Pulse rate and duration were measured immediately before and after the procedure. No ill effect was seen on any of the units tested, pacemaker inhibition was not observed, and programmability was not affected. Metal detector security gates have no effect on implanted permanent pacemakers.

  20. Pacemakers and Implantable Defibrillators - Multiple Languages: MedlinePlus

    MedlinePlus

    ... العربية) Pacemaker (Arabic) العربية Bilingual PDF Health Information Translations Chinese - Simplified (简体中文) Pacemaker 心脏起搏器 - 简体中文 (Chinese - Simplified) Bilingual PDF Health Information Translations Chinese - Traditional (繁體中文) Pacemaker 心臟起搏器 - 繁體中文 (Chinese - Traditional) ...

  1. Effect of light on the development of the circadian rhythm of motor activity in the mouse.

    PubMed

    Canal-Corretger, M M; Vilaplana, J; Cambras, T; Díez-Noguera, A

    2001-07-01

    In previous experiments, we found that rats raised in constant light (LL) manifested a more robust circadian rhythm of motor activity in LL and showed longer phase shifts after a light pulse in constant darkness (DD) than chose raised under constant darkness. In addition, we observed that the effects produced by constant light differed depending on the time of postnatal development in which it was given. These results suggest that both sensitivity to light and the functioning of the circadian pacemaker of the rat could be affected by the environmental conditions experienced during postembryonic development. Thus, the present experiment aimed to study whether postnatal exposure to light could also affect the circadian system of the mouse. Three groups of mice were formed: One group was raised under constant darkness during lactation (DD group), the second under constant light (LL group), and the third under light-dark cycles (LD group). After lactation, the three groups were submitted first to constant light of high intensity, then to LD cycles, and finally to constant darkness. In the DD stage, a light pulse was given. Finally, mice were submitted to constant light of low intensity. We observed that the circadian rhythm of the DD group was more disturbed under constant light than the rhythm of the LL group, and that, when light intensity increased, the period of the rhythm of the DD group lengthened more than that of the LL group. No significant differences among the groups were found in the phase shift induced by the light pulse. Therefore, it appears that DD mice are more sensitive to light than their LL counterparts. However, at present there is no evidence to affirm that the light environment experienced by the mouse during postnatal development affects the circadian pacemaker.

  2. Permanent pacemaker malfunction: diagnostic aspects of temporary pacing.

    PubMed Central

    Berman, N D

    1980-01-01

    A temporary pacing electrode can function as a diagnostic as well as a therapeutic tool. This is illustrated in two patients whose permanent pacemakers unexpectedly failed. In the first patient a demand pacemaker was inhibited by a magnet rather than converting to the asynchronous mode. In the second the pacemaker appeared to be producing low-voltage potentials not detectable on the surface electrocardiogram. The presence of a temporary pacing electrode can be useful for defining the cause of pacemaker failure and the nature of any associated arrhythmias. Images FIG. 1 FIG. 3 PMID:7260759

  3. A Rare Case of Recurrent Pacemaker Allergic Reaction

    PubMed Central

    Shittu, Muhammed; Shah, Pooja; Elkhalili, Walid; Suleiman, Addi; Shaaban, Hamid; Shah, Pradip A.; Shamoon, Fayez

    2015-01-01

    Allergic reactions to pacemaker device components are uncommon. However, when they occur, they usually mimic pacemaker infection, which results in multiple device replacements and increased morbidity burden. Here we present a 40-year-old female with pacemaker insertion due to complete heart block and who had multiple device replacements because of allergic sensitivity to various pacemaker component-encasing materials, confirmed by allergic testing to these materials. She had complete resolution of her symptoms after replacement with gold-plated device, to which she was not allergic. PMID:26240735

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

    PubMed Central

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

    2012-01-01

    In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry)] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity. PMID:22815753

  5. Adrenal clocks and the role of adrenal hormones in the regulation of circadian physiology.

    PubMed

    Leliavski, Alexei; Dumbell, Rebecca; Ott, Volker; Oster, Henrik

    2015-02-01

    The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) and subordinate clocks that disseminate time information to various central and peripheral tissues. While the function of the SCN in circadian rhythm regulation has been extensively studied, we still have limited understanding of how peripheral tissue clock function contributes to the regulation of physiological processes. The adrenal gland plays a special role in this context as adrenal hormones show strong circadian secretion rhythms affecting downstream physiological processes. At the same time, they have been shown to affect clock gene expression in various other tissues, thus mediating systemic entrainment to external zeitgebers and promoting internal circadian alignment. In this review, we discuss the function of circadian clocks in the adrenal gland, how they are reset by the SCN and may further relay time-of-day information to other tissues. Focusing on glucocorticoids, we conclude by outlining the impact of adrenal rhythm disruption on neuropsychiatric, metabolic, immune, and malignant disorders.

  6. 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

  7. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders.

    PubMed

    Hardeland, Rüdiger

    2009-07-01

    Tasimelteon, developed by Vanda Pharmaceuticals Inc under license from Bristol-Myers Squibb Co, is a melatonin receptor agonist. Because of the high density of melatonin receptors in the circadian pacemaker, the suprachiasmatic nucleus, melatonergic actions can phase-shift circadian rhythms and promote sleep. Tasimelteon was effective in reducing sleep onset latency (in phase II and III clinical trials) and in resetting the circadian melatonin rhythm (in phase II trials), which indicated its potential suitability as treatment for jet lag, shift work and circadian rhythm sleep disorders. Statistically significant improvements in sleep maintenance have also been observed with the drug. Tasimelteon has been claimed to be useful in the treatment of depression, and preclinical evidence in this respect is to be confirmed in a phase II clinical trial, which was ready to be initiated at the time of publication. It is plausible that the drug may be effective in the treatment of depressive disorders, at least those that are related to circadian dysfunction, and that it may attenuate sleep problems in depressed patients of different subtypes. A general suitability in mitigating other symptoms of major depressive disorder cannot be deduced from the actions of tasimelteon via the melatonin receptors MT1 and MT2. The drug is well tolerated, does not induce impairment of next-day functioning or dependence, and seems to be safe in short-term treatment; however, toxicological data would be required for assessing its long-term safety.

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

    PubMed Central

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

    2010-01-01

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

  9. RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides.

    PubMed

    Abruzzi, Katharine C; Zadina, Abigail; Luo, Weifei; Wiyanto, Evelyn; Rahman, Reazur; Guo, Fang; Shafer, Orie; Rosbash, Michael

    2017-02-01

    Locomotor activity rhythms are controlled by a network of ~150 circadian neurons within the adult Drosophila brain. They are subdivided based on their anatomical locations and properties. We profiled transcripts "around the clock" from three key groups of circadian neurons with different functions. We also profiled a non-circadian outgroup, dopaminergic (TH) neurons. They have cycling transcripts but fewer than clock neurons as well as low expression and poor cycling of clock gene transcripts. This suggests that TH neurons do not have a canonical circadian clock and that their gene expression cycling is driven by brain systemic cues. The three circadian groups are surprisingly diverse in their cycling transcripts and overall gene expression patterns, which include known and putative novel neuropeptides. Even the overall phase distributions of cycling transcripts are distinct, indicating that different regulatory principles govern transcript oscillations. This surprising cell-type diversity parallels the functional heterogeneity of the different neurons.

  10. RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides

    PubMed Central

    Luo, Weifei; Wiyanto, Evelyn; Rahman, Reazur; Guo, Fang; Shafer, Orie

    2017-01-01

    Locomotor activity rhythms are controlled by a network of ~150 circadian neurons within the adult Drosophila brain. They are subdivided based on their anatomical locations and properties. We profiled transcripts “around the clock” from three key groups of circadian neurons with different functions. We also profiled a non-circadian outgroup, dopaminergic (TH) neurons. They have cycling transcripts but fewer than clock neurons as well as low expression and poor cycling of clock gene transcripts. This suggests that TH neurons do not have a canonical circadian clock and that their gene expression cycling is driven by brain systemic cues. The three circadian groups are surprisingly diverse in their cycling transcripts and overall gene expression patterns, which include known and putative novel neuropeptides. Even the overall phase distributions of cycling transcripts are distinct, indicating that different regulatory principles govern transcript oscillations. This surprising cell-type diversity parallels the functional heterogeneity of the different neurons. PMID:28182648

  11. Light evokes rapid circadian network oscillator desynchrony followed by gradual phase retuning of synchrony.

    PubMed

    Roberts, Logan; Leise, Tanya L; Noguchi, Takako; Galschiodt, Alexis M; Houl, Jerry H; Welsh, David K; Holmes, Todd C

    2015-03-30

    Circadian neural circuits generate near 24-hr physiological rhythms that can be entrained by light to coordinate animal physiology with daily solar cycles. To examine how a circadian circuit reorganizes its activity in response to light, we imaged period (per) clock gene cycling for up to 6 days at single-neuron resolution in whole-brain explant cultures prepared from per-luciferase transgenic flies. We compared cultures subjected to a phase-advancing light pulse (LP) to cultures maintained in darkness (DD). In DD, individual neuronal oscillators in all circadian subgroups are initially well synchronized but then show monotonic decrease in oscillator rhythm amplitude and synchrony with time. The small ventral lateral neurons (s-LNvs) and dorsal lateral neurons (LNds) exhibit this decrease at a slower relative rate. In contrast, the LP evokes a rapid loss of oscillator synchrony between and within most circadian neuronal subgroups, followed by gradual phase retuning of whole-circuit oscillator synchrony. The LNds maintain high rhythmic amplitude and synchrony following the LP along with the most rapid coherent phase advance. Immunocytochemical analysis of PER shows that these dynamics in DD and LP are recapitulated in vivo. Anatomically distinct circadian neuronal subgroups vary in their response to the LP, showing differences in the degree and kinetics of their loss, recovery and/or strengthening of synchrony, and rhythmicity. Transient desynchrony appears to be an integral feature of light response of the Drosophila multicellular circadian clock. Individual oscillators in different neuronal subgroups of the circadian circuit show distinct kinetic signatures of light response and phase retuning.

  12. 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…

  13. Circadian Rhythms in Adipose Tissue Physiology.

    PubMed

    Kiehn, Jana-Thabea; Tsang, Anthony H; Heyde, Isabel; Leinweber, Brinja; Kolbe, Isa; Leliavski, Alexei; Oster, Henrik

    2017-03-16

    The different types of adipose tissues fulfill a wide range of biological functions-from energy storage to hormone secretion and thermogenesis-many of which show pronounced variations over the course of the day. Such 24-h rhythms in physiology and behavior are coordinated by endogenous circadian clocks found in all tissues and cells, including adipocytes. At the molecular level, these clocks are based on interlocked transcriptional-translational feedback loops comprised of a set of clock genes/proteins. Tissue-specific clock-controlled transcriptional programs translate time-of-day information into physiologically relevant signals. In adipose tissues, clock gene control has been documented for adipocyte proliferation and differentiation, lipid metabolism as well as endocrine function and other adipose oscillations are under control of systemic signals tied to endocrine, neuronal, or behavioral rhythms. Circadian rhythm disruption, for example, by night shift work or through genetic alterations, is associated with changes in adipocyte metabolism and hormone secretion. At the same time, adipose metabolic state feeds back to central and peripheral clocks, adjusting behavioral and physiological rhythms. In this overview article, we summarize our current knowledge about the crosstalk between circadian clocks and energy metabolism with a focus on adipose physiology. © 2017 American Physiological Society. Compr Physiol 7:383-427, 2017.

  14. Responses of a bursting pacemaker to excitation reveal spatial segregation between bursting and spiking mechanisms

    PubMed Central

    Maran, Selva K; Sieling, Fred H; Demla, Kavita; Prinz, Astrid A; Canavier, Carmen C

    2011-01-01

    Central pattern generators (CPGs) frequently include bursting neurons that serve as pacemakers for rhythm generation. Phase resetting curves (PRCs) can provide insight into mechanisms underlying phase locking in such circuits. PRCs were constructed for a pacemaker bursting complex in the pyloric circuit in the stomatogastric ganglion of the lobster and crab. This complex is comprised of the Anterior Burster (AB) neuron and two Pyloric Dilator (PD) neurons that are all electrically coupled. Artificial excitatory synaptic conductance pulses of different strengths and durations were injected into one of the AB or PD somata using the Dynamic Clamp. Previously, we characterized the inhibitory PRCs by assuming a single slow process that enabled synaptic inputs to trigger switches between an up state in which spiking occurs and a down state in which it does not. Excitation produced five different PRC shapes, which could not be explained with such a simple model. A separate dendritic compartment was required to separate the mechanism that generates the up and down phases of the bursting envelope (1) from synaptic inputs applied at the soma, (2) from axonal spike generation and (3) from a slow process with a slower time scale than burst generation. This study reveals that due to the nonlinear properties and compartmentalization of ionic channels, the response to excitation is more complex than inhibition. PMID:21360137

  15. Circadian rhythm of wrist temperature in normal-living subjects A candidate of new index of the circadian system.

    PubMed

    Sarabia, J A; Rol, M A; Mendiola, P; Madrid, J A

    2008-11-28

    Most circadian rhythms are under the control of a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. A marker rhythm, (e.g., one used in chronotherapy) has to be periodic and easy to measure over long periods using non-invasive methods. The most frequent reference variables for human chronotherapy include salivary melatonin or cortisol, urinary 6-sulfatoximelatonin, actimetry and core body temperature (CBT). Recent evidence suggests that sleepiness may be more closely linked to increased peripheral skin temperature than to a core temperature drop, and that distal skin temperature seems to be correlated and phase-advanced with respect to CBT, suggesting that heat loss from the extremities may drive the circadian CBT rhythm. The aim of the present study was to evaluate whether the wrist skin temperature rhythm could be used as a possible index of the human circadian system. To this end, wrist skin temperature (WT1), as determined by a wireless data logger in healthy normal living subjects, was correlated with sleep-wake diaries and oral temperature (OT) recordings. WT and sleep habits were studied in 99 university students. Each subject wore a wireless iButton sensor attached to the inner side of a sport wristband. Our results show that the WT rhythm exhibits an inverse phase relationship with OT, and it is phase-advanced by 60 min with respect to OT. WT started to increase in association to bed time and dropped sharply after awakening. A secondary WT increase, independent of feeding, was observed in the early afternoon. In conclusion, WT wireless recording can be considered a reliable procedure to evaluate circadian rhythmicity, and an index to establish and follow the effects of chronotherapy in normal living subjects.

  16. Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health

    PubMed Central

    Ribas-Latre, Aleix; Eckel-Mahan, Kristin

    2016-01-01

    , can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations. Major conclusions Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future. PMID:26977390

  17. Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation.

    PubMed

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

    2014-05-08

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

  18. SCOP/PHLPP1β mediates circadian regulation of long-term recognition memory

    PubMed Central

    Shimizu, Kimiko; Kobayashi, Yodai; Nakatsuji, Erika; Yamazaki, Maya; Shimba, Shigeki; Sakimura, Kenji; Fukada, Yoshitaka

    2016-01-01

    Learning and memory depend on the time of day in various organisms, but it is not clear whether and how the circadian clock regulates memory performance. Here we show that consolidation of long-term recognition memory is a circadian-regulated process, which is blunted by disruption of the hippocampal clock. We focused on SCOP, a key molecule regulating hippocampus-dependent long-term memory for objects. The amounts of SCOP and its binding partner K-Ras in the hippocampal membrane rafts exhibit robust circadian changes, and SCOP knockdown in the hippocampal CA1 impairs long-term memory at night. Circadian changes in stimulus-dependent activation of ERK in the hippocampal neurons are dependent on the SCOP levels in the membrane rafts, while Scop knockout abrogates the activation rhythm. We conclude that long-term memory formation is regulated by the circadian clock through SCOP dynamics in the membrane rafts of the hippocampal CA1. PMID:27686624

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

    PubMed

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

    2014-06-01

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

  20. Effects of systemically applied nAChRα7 agonists and antagonists on light-induced phase shifts of hamster circadian activity rhythms.

    PubMed

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

    2014-06-01

    Many physiological systems in mammals are linked to the body's master circadian rhythm in the sleep/wake cycle and dysfunctions in this rhythm has been associated with neurological diseases such as major depression, Alzheimer's Disease and schizophrenia. There is some evidence that nicotinic cholinergic input to the master circadian pacemaker, the suprachiasmatic nucleus, may modulate circadian activity rhythms, but data employing in vivo preparations is sparse. Therefore we examined the ability of intraperitoneally applied nicotinic agonists and antagonists relatively selective for the α7 nicotinic receptor to modulate light-induced phase shifts of hamster circadian wheel running rhythms. Hamsters were maintained in constant darkness and exposed to light pulses early and late in their active period, mimicking dusk and dawn respectively, which elicited phase delays and advances of their circadian wheel running rhythms. The α7 receptor antagonists bPiDDB (0.03-3mg/kg) and methyllacaconitine (0.1-1mg/kg) inhibited both light- induced phase advances and delays of circadian wheel running rhythms by as much as 75% versus vehicle injections. In contrast, systemic injections of the α7 agonists PHA 543613 and ABT107, both at 0.156-2.5mg/kg, had no effect on light induced phase advances or delays. Further, α7 nicotinic receptors were identified in the hamster suprachiasmatic nucleus using an antibody that recognizes α7 nicotinic receptors. These results clearly identify the ability of α7 nicotinic receptor antagonists to inhibit light-entrainment of the hamster circadian pacemaker. Therefore, nicotinic compounds may be useful for the treatment of circadian dysfunction associated with neurological diseases.

  1. 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

  2. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and Allen...

  3. 21 CFR 870.3730 - Pacemaker service tools.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker service tools. 870.3730 Section 870.3730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... tools. (a) Identification. Pacemaker service tools are devices such as screwdrivers and Allen...

  4. 21 CFR 870.3720 - Pacemaker electrode function tester.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Pacemaker electrode function tester. 870.3720 Section 870.3720 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... connected to an implanted pacemaker lead that supplies an accurately calibrated, variable pacing pulse...

  5. 21 CFR 870.3720 - Pacemaker electrode function tester.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Pacemaker electrode function tester. 870.3720 Section 870.3720 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... connected to an implanted pacemaker lead that supplies an accurately calibrated, variable pacing pulse...

  6. Emergency room and inpatient use after cardiac pacemaker implantation.

    PubMed

    Sloan, Frank Allen; George, Linda Kaufman; Hu, Linyan

    2013-02-15

    Although studies have demonstrated health benefits, there is limited evidence on utilization and cost changes associated with cardiac pacemaker implantation from national community samples. The aim of this study was to quantify changes in emergency room (ER) and hospital inpatient use and in Medicare payments per beneficiary/year after pacemaker implantation. Outcomes for pacemaker recipients after and before implantation and between pacemaker recipients and controls were compared using propensity score matching. Data came from Health and Retirement Study interviews merged with Medicare claims. Sample subjects were aged ≥68 years with diagnosed conduction disorders or cardiac dysrhythmias in the previous 3 years. Outcome measures were (1) ER visits, inpatient admissions and days, and Medicare payments for ER and inpatient care in the after period for the pacemaker versus control groups, defined per beneficiary/year, (2) difference in differences in the same 5 outcome variables, and (3) binary variables for whether or not utilization or payments were lower in the after versus before periods for the pacemaker versus control groups. In conclusion, most pacemaker recipients improved, as measured by reductions in use and payments in the after versus before period, and there were reductions in ER visits and hospital admissions for conditions commonly leading to pacemaker implantation.

  7. A circadian biosignature in the labeled release data from Mars?

    NASA Astrophysics Data System (ADS)

    Van Dongen, Hans P. A.; Miller, Joseph D.; Levin, Gilbert V.; Straat, Patricia A.

    2005-09-01

    Organisms on Earth commonly exhibit a circadian rhythm, which is synchronized to the 24-hour day-night (diurnal) cycle of the planet. However, if isolated from strong environmental time cues (e.g., light-dark, temperature, etc.), many organisms revert to a "free-running" rhythm that is close to, but significantly different from, the diurnal cycle. Such a free-running rhythm is a distinct biological feature, as it requires an endogenous pacemaker that is not just passively driven by rhythms in the environment. On Mars, a free-running rhythm (i.e., significantly different from the Martian diurnal cycle of 24.66 hours) would constitute independent proof of the presence of living organisms. Evidence for such a circadian biosignature from Mars has been sought in the data sent by the 1976 Viking Labeled Release (LR) life detection experiment . In the search for circadian rhythmicity, oscillatory fluctuations in the amount of radiolabeled gas in the headspace of the LR test cell of Viking Lander 2, test cycle 3, were studied. The cycle duration of the LR oscillations examined did not differ significantly from that of the daily cell temperature oscillations controlled ultimately by the Martian diurnal cycle. Thus, these specific LR oscillations produced no independent evidence for an endogenous biological origin. However, it was found that the amplitudes of the oscillations in the gas (presumably CO2) were greater than could be accounted for by the most likely non-biological mechanism (i.e., temperature-induced changes in soil solubility of CO2). The possibility thus remained that biological activity, synchronized to the Martian diurnal cycle, could be responsible for at least part of the oscillatory activity in the LR signals. We now propose to consider all data from the nine active and control cycles of the Martian LR experiment. A comprehensive set of null and alternative hypotheses is proposed for statistical testing using the digitized data. Advanced, statistically

  8. Circadian Rhythms and Psychiatric Illness

    PubMed Central

    Asarnow, Lauren D.; Soehner, Adriane M.; Harvey, Allison G.

    2014-01-01

    Purpose of review The present review provides a conceptual introduction to sleep and circadian research in psychiatric illness, and discusses recent experimental and intervention findings in this area. Recent Findings In this review, studies published since January 2011 on circadian disturbance and psychiatric illness have been summarized. Summary Exciting new results have increasingly utilized objective and validated instruments to measure the circadian system in experimental studies. Since 2011, treatment research has still predominantly utilized self-report measures as outcome variables. However, research in the treatment domain for sleep/circadian disturbances comorbid with psychiatric illness has advanced the field in its work to broaden the validation of existing sleep treatments to additional patient populations with comorbid sleep/circadian disruptions, address how to increase access to and affordability of treatment for sleep and circadian dysfunction for patients with psychiatric disorders, and how to combine psychosocial treatments with psychopharmacology to optimize treatment outcomes. PMID:24060916

  9. Chromatin Dynamics of Circadian Transcription

    PubMed Central

    Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

    2015-01-01

    The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Disruption of this transcriptional program leads to a variety of pathologies, including insomnia, depression and metabolic disorders. Circadian rhythms in gene expression rely on specific chromatin transitions which are ultimately coordinated by the molecular clock. As a consequence, a highly plastic and dynamic circadian epigenome can be delineated across different tissues and cell types. Intriguingly, genome topology appears to coordinate cyclic transcription at circadian interactomes, in which circadian genes are in physical contact within the cell nucleus in a time-specific manner. Moreover, the clock machinery shows functional interplays with key metabolic regulators, thereby connecting the circadian epigenome to cellular metabolism. Unraveling the molecular aspects of such interplays is likely to reveal new therapeutic strategies towards the treatment of metabolic disorders. PMID:27014564

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

    PubMed

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

    2005-10-20

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

  11. Combined Standby Transvenous Defibrillator and Demand Pacemaker.

    DTIC Science & Technology

    1975-12-01

    AD-A097 441 CARDIAC CARE SYSTEMS INC RED BANK NJ F/B 6/5 COM13INED STANDBY TRANSVENOJS DEFIBRILLATOR AND DEMAND PACEMAKER--ETC(U) DEC 75 L RUBIN...Development Command Fort Detrick, Frederick, MD 21701 Contract Number DAMD17-74-C-4108. Cardiac Care Systems, Inc. 80 E. Front Street Red Bank , NJ...8217 Cardiac Care Systems, Inc. 4I 80 E. Front Street 61 3121A1j0.4 Red Bank , NJ 07701 a .0_ e- /i\\ - -__________ I1. CONTROLLING OFFICE NAME AND ADDRESS 1.)42

  12. 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.

  13. Submicrosecond pacemaker precision is behaviorally modulated: the gymnotiform electromotor pathway.

    PubMed

    Moortgat, K T; Keller, C H; Bullock, T H; Sejnowski, T J

    1998-04-14

    What are the limits and modulators of neural precision? We address this question in the most regular biological oscillator known, the electric organ command nucleus in the brainstem of wave-type gymnotiform fish. These fish produce an oscillating electric field, the electric organ discharge (EOD), used in electrolocation and communication. We show here that the EOD precision, measured by the coefficient of variation (CV = SD/mean period) is as low as 2 x 10(-4) in five species representing three families that range widely in species and individual mean EOD frequencies (70-1,250 Hz). Intracellular recording in the pacemaker nucleus (Pn), which commands the EOD cycle by cycle, revealed that individual Pn neurons of the same species also display an extremely low CV (CV = 6 x 10(-4), 0.8 micro sec SD). Although the EOD CV can remain at its minimum for hours, it varies with novel environmental conditions, during communication, and spontaneously. Spontaneous changes occur as abrupt steps (250 ms), oscillations (3-5 Hz), or slow ramps (10-30 s). Several findings suggest that these changes are under active control and depend on behavioral state: mean EOD frequency and CV can change independently; CV often decreases in response to behavioral stimuli; and lesions of one of the two inputs to the Pn had more influence on CV than lesions of the other input.

  14. Network effects of glutamate on neuronal activity in the medial septum/diagonal band complex in vitro.

    PubMed

    Popova, I Yu; Karavaev, E N; Kitchigina, V F

    2011-01-01

    Inter-neuronal interactions within the medial septum/diagonal band complex (MSDB) are of great interest as this region is believed to be the hippocampal theta rhythm pacemaker. However, the role of glutamatergic system in functioning of the septal cells is yet unclear. Here, we demonstrate for the first time the effects of glutamate in physiological concentration (1 microM) on the MSDB neuronal spontaneous and evoked activities in vitro. These effects (activation of 70% and inhibition of 30% of responsive neurons) differed in pacemaker and non-pacemaker cells. Pacemaker cells were always activated under glutamate, whereas non-pacemaker neurons could be either activated or inhibited. Indeed, in the burst pacemakers, glutamate increased the frequency of rhythmic activity. In a total MSDB neuron population, in 30% of neurons glutamate applications modified responses to the electrical stimulation by unifying the temporal parameters of neuron responses. Along with the increase in the theta-burst frequency, this indicates that the glutamatergic system is involved in the process ofintraseptal synchronization. Obtained data shed light on the role ofglutamatergic system in septal neuron interactions and broaden our understanding of theta oscillation mechanisms in the septo-hippocampal system.

  15. 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.

  16. 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

  17. Coupling Circadian Rhythms of Metabolism and Chromatin Remodeling

    PubMed Central

    Masri, Selma; Orozco-Solis, Ricardo; Aguilar-Arnal, Lorena; Cervantes, Marlene; Sassone-Corsi, Paolo

    2015-01-01

    The circadian clock controls a large variety of neuronal, endocrine, behavioral and physiological responses in mammals. This control is exerted in large part at the transcriptional level on genes expressed in a cyclic manner. A highly specialized transcriptional machinery based on clock regulatory factors organized in feedback autoregulatory loops governs a significant portion of the genome. These oscillations in gene expression are paralleled by critical events of chromatin remodeling that appear to provide plasticity to circadian regulation. Specifically, the NAD+-dependent deacetylases SIRT1 and SIRT6 have been linked to circadian control of gene expression. This, and additional accumulating evidence, shows that the circadian epigenome appears to share intimate links with cellular metabolic processes and has remarkable plasticity showing reprogramming in response to nutritional challenges. In addition to SIRT1 and SIRT6, a number of chromatin remodelers have been implicated in clock control, including the histone H3K4 tri-methyltransferase MLL1. Deciphering the molecular mechanisms that link metabolism, epigenetic control and circadian responses will provide valauble insights towards innovative strategies of therapeutic intervention. PMID:26332964

  18. CREB influences timing and entrainment of the SCN circadian clock.

    PubMed

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

    2010-12-01

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

  19. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-07-13

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity.

  20. The Neurobiology of Circadian Rhythms.

    PubMed

    Sollars, Patricia J; Pickard, Gary E

    2015-12-01

    There is a growing recognition that the coordinated timing of behavioral, physiologic, and metabolic circadian rhythms is a requirement for a healthy body and mind. In mammals, the primary circadian oscillator is the hypothalamic suprachiasmatic nucleus (SCN), which is responsible for circadian coordination throughout the organism. Temporal homeostasis is recognized as a complex interplay between rhythmic clock gene expression in brain regions outside the SCN and in peripheral organs. Abnormalities in this intricate circadian orchestration may alter sleep patterns and contribute to the pathophysiology of affective disorders.

  1. Circadian Regulation of Synaptic Plasticity

    PubMed Central

    Frank, Marcos G.

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

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

    PubMed Central

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

    2010-01-01

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

  3. Dual origins of the intracellular circadian calcium rhythm in the suprachiasmatic nucleus

    PubMed Central

    Enoki, Ryosuke; Ono, Daisuke; Kuroda, Shigeru; Honma, Sato; Honma, Ken-ichi

    2017-01-01

    In mammals, the master circadian clock is located in the suprachiasmatic nucleus (SCN), where most neurons show circadian rhythms of intracellular Ca2+ levels. However, the origin of these Ca2+ rhythms remains largely unknown. In this study, we successfully monitored the intracellular circadian Ca2+ rhythms together with the circadian PER2 and firing rhythms in a single SCN slice ex vivo, which enabled us to explore the origins. The phase relation between the circadian PER2 and Ca2+ rhythms, but not between the circadian PER2 and firing rhythms, was significantly altered in Cry1/Cry2 double knockout mice, which display a loss of intercellular synchronization in the SCN. In addition, in Cry1/Cry2 double knockout mice, circadian Ca2+ rhythms were abolished in the dorsolateral SCN, but were maintained in the majority of the ventromedial SCN. These findings indicate that intracellular circadian Ca2+ rhythms are composed of an exogenous and endogenous component involving PER2 expression. PMID:28155916

  4. 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

  5. Unique food-entrained circadian rhythm in cysteine414-alanine mutant mCRY1 transgenic mice.

    PubMed

    Okano, Satoshi; Yasui, Akira; Hayasaka, Kiyoshi; Nakajima, Osamu

    Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Daily scheduled restricted feeding (RF), in which the food available time is restricted for several hours each day, elicits anticipatory activity. This food-anticipatory activity (FAA) is controlled by a food-entrainable oscillator (FEO) that is distinct from the suprachiasmatic nucleus (SCN), the master pacemaker in mammals. In an earlier report, we described generation of transgenic (Tg) mice ubiquitously overexpressing cysteine414-alanine mutant mCRY1. The Tg mice displayed long locomotor free-running periods (approximately 28 h) with rhythm splitting. Furthermore, their locomotor activity immediately re-adjusted to the advance of light-dark cycles (LD), suggesting some disorder in the coupling of SCN neurons. The present study examined the restricted feeding cycle (RF)-induced entrainment of locomotor activity in Tg mice in various light conditions. In LD, wild-type controls showed both FAA and LD-entrained activities. In Tg mice, almost all activity was eventually consolidated to a single bout before the feeding time. The result suggests a possibility that in Tg mice the feeding cycle dominates the LD cycle as an entrainment agent. In constant darkness (DD), wild-type mice exhibited robust free-run activity and FAA during RF. For Tg mice, only the rhythm entrained to RF was observed in DD. Furthermore, after returning to free feeding, the free-run started from the RF-entrained phase. These results suggest that the SCN of Tg mice is entrainable to RF and that the mCRY1 mutation alters the sensitivity of SCN to the cycle of nonphotic zeitgebers.

  6. 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 (τDD) 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 χ(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.

  7. [Circadian rhythm sleep-wake disorder (circadian rhythm sleep disorder)].

    PubMed

    Tagaya, Hirokuni; Murayama, Norio; Fukase, Yuko

    2015-06-01

    The role of the circadian system is forecasting the daily and yearly change of environment. Circadian rhythm sleep-wake disorder (CRSWD) is defined as physical and social impairment caused by misalignment between circadian rhythm and desirable social schedule. CRSWDs are induced by medical or environmental factors as well as dysfunctions of circadian system. Clinicians should be aware that sleep-inducing medications, restless legs syndrome, delirium and less obedience to social schedule are frequent cause of CRSWD among elderly. Bright light therapy and orally administered small dose of melatonin or melatonin agonist at proper circadian phase are recommended treatments. Sleep-inducing medications should not be considered as CRSWD treatments, especially to elderly.

  8. Light Evokes Rapid Circadian Network Oscillator Desynchrony Followed by Gradual Phase Retuning of Synchrony

    PubMed Central

    Roberts, Logan; Leise, Tanya L.; Noguchi, Takako; Galschiodt, Alexis M.; Houl, Jerry H.; Welsh, David K.; Holmes, Todd C.

    2015-01-01

    Summary Background Circadian neural circuits generate near 24 hr physiological rhythms that can be entrained by light to coordinate animal physiology with daily solar cycles. To examine how a circadian circuit reorganizes its activity in response to light, we imaged period (per) clock gene cycling for up to 6 days at single neuron resolution in whole brain explant cultures prepared from per-luciferase transgenic flies. We compared cultures subjected to a phase-advancing light pulse (LP) to cultures maintained in darkness (DD). Results In DD, individual neuronal oscillators in all circadian subgroups are initially well synchronized, then show monotonic decrease in oscillator rhythm amplitude and synchrony with time. The s-LNvs and LNds exhibit this decrease at a slower relative rate. In contrast, the LP evokes a rapid loss of oscillator synchrony between and within most circadian neuronal subgroups followed by gradual phase retuning of whole circuit oscillator synchrony. The LNds maintain high rhythmic amplitude and synchrony following the LP along with the most rapid coherent phase advance. Immunocytochemical analysis of PER show these dynamics in DD and LP are recapitulated in vivo. Anatomically distinct circadian neuronal subgroups vary in their response to the LP, showing differences in the degree and kinetics of their loss, recovery and/or strengthening of synchrony and rhythmicity. Conclusions Transient desynchrony appears to be an integral feature of light response of the Drosophila multicellular circadian clock. Individual oscillators in different neuronal subgroups of the circadian circuit show distinct kinetic signatures of light response and phase retuning. PMID:25754644

  9. Pacemaker potentials for the periodic burst discharge in the heart ganglion of a stomatopod, Squilla oratoria.

    PubMed

    Watanabe, A; Obara, S; Akiyama, T

    1967-03-01

    From somata of the pacemaker neurons in the Squilla heart ganglion, pacemaker potentials for the spontaneous periodic burst discharge are recorded with intracellular electrodes. The electrical activity is composed of slow potentials and superimposed spikes, and is divided into four types, which are: (a) "mammalian heart" type, (b) "slow generator" type, (c) "slow grower" type, and (d) "slow deficient" type. Since axons which are far from the somata do not produce slow potentials, the soma and dendrites must be where the slow potentials are generated. Hyperpolarization impedes generation of the slow potential, showing that it is an electrically excitable response. Membrane impedance increases on depolarization. Brief hyperpolarizing current can abolish the plateau but brief tetanic inhibitory fiber stimulation is more effective for the abolition. A single stimulus to the axon evokes the slow potential when the stimulus is applied some time after a previous burst. Repetitive stimuli to the axon are more effective in eliciting the slow potential, but the depolarization is not maintained on continuous stimulation. Synchronization of the slow potential among neurons is achieved by: (a) the electrotonic connections, with periodic change in resistance of the soma membrane, (b) active spread of the slow potential, and (c) synchronization through spikes.

  10. Pacemaker Potentials for the Periodic Burst Discharge in the Heart Ganglion of a Stomatopod, Squilla oratoria

    PubMed Central

    Watanabe, Akira; Obara, Shosaku; Akiyama, Toyohiro

    1967-01-01

    From somata of the pacemaker neurons in the Squilla heart ganglion, pacemaker potentials for the spontaneous periodic burst discharge are recorded with intracellular electrodes. The electrical activity is composed of slow potentials and superimposed spikes, and is divided into four types, which are: (a) "mammalian heart" type, (b) "slow generator" type, (c) "slow grower" type, and (d) "slow deficient" type. Since axons which are far from the somata do not produce slow potentials, the soma and dendrites must be where the slow potentials are generated. Hyperpolarization impedes generation of the slow potential, showing that it is an electrically excitable response. Membrane impedance increases on depolarization. Brief hyperpolarizing current can abolish the plateau but brief tetanic inhibitory fiber stimulation is more effective for the abolition. A single stimulus to the axon evokes the slow potential when the stimulus is applied some time after a previous burst. Repetitive stimuli to the axon are more effective in eliciting the slow potential, but the depolarization is not maintained on continuous stimulation. Synchronization of the slow potential among neurons is achieved by: (a) the electrotonic connections, with periodic change in resistance of the soma membrane, (b) active spread of the slow potential, and (c) synchronization through spikes. PMID:6034506

  11. Proton Beam Therapy Interference With Implanted Cardiac Pacemakers

    SciTech Connect

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

    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