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1

A mechanism for circadian control of pacemaker neuron excitability.  

PubMed

Although the intracellular molecular clocks that regulate circadian (~24 h) behavioral rhythms are well understood, it remains unclear how molecular clock information is transduced into rhythmic neuronal activity that in turn drives behavioral rhythms. To identify potential clock outputs, the authors generated expression profiles from a homogeneous population of purified pacemaker neurons (LN(v)s) from wild-type and clock mutant Drosophila. They identified a group of genes with enriched expression in LN(v)s and a second group of genes rhythmically expressed in LN(v)s in a clock-dependent manner. Only 10 genes fell into both groups: 4 core clock genes, including period (per) and timeless (tim), and 6 genes previously unstudied in circadian rhythms. The authors focused on one of these 6 genes, Ir, which encodes an inward rectifier K(+) channel likely to regulate resting membrane potential, whose expression peaks around dusk. Reducing Ir expression in LN(v)s increased larval light avoidance and lengthened the period of adult locomotor rhythms, consistent with increased LN(v) excitability. In contrast, increased Ir expression made many adult flies arrhythmic and dampened PER protein oscillations. The authors propose that rhythmic Ir expression contributes to daily rhythms in LN(v) neuronal activity, which in turn feed back to regulate molecular clock oscillations. PMID:23010658

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

2012-10-01

2

Electrical Silencing of Drosophila Pacemaker Neurons Stops the Free-Running Circadian Clock  

Microsoft Academic Search

Electrical silencing of Drosophila circadian pacemaker neurons through targeted expression of K+ channels causes severe deficits in free-running circadian locomotor rhythmicity in complete darkness. Pacemaker electrical silencing also stops the free-running oscillation of PERIOD (PER) and TIMELESS (TIM) proteins that constitutes the core of the cell-autonomous molecular clock. In contrast, electrical silencing fails to abolish PER and TIM oscillation in

Michael N. Nitabach; Justin Blau; Todd C. Holmes

2002-01-01

3

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

PubMed

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. PMID:23456090

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

2013-02-28

4

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

PubMed Central

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

Lee, Youngseok; Montell, Craig

2013-01-01

5

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

PubMed

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

Lee, Youngseok; Montell, Craig

2013-04-17

6

Phase Resetting of the Mammalian Circadian Clock Relies on a Rapid Shift of a Small Population of Pacemaker Neurons  

Microsoft Academic Search

The circadian pacemaker of the suprachiasmatic nuclei (SCN) contains a major pacemaker for 24 h rhythms that is synchronized to the external light-dark cycle. In response to a shift in the external cycle, neurons of the SCN resynchronize with different pace. We performed electrical activity recordings of the SCN of rats in vitro following a 6 hour delay of the

Jos H. T. Rohling; Henk Tjebbe Vanderleest; Stephan Michel; Mariska J. Vansteensel; Johanna H. Meijer; Shin Yamazaki

2011-01-01

7

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

PubMed

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

Duvall, Laura B; Taghert, Paul H

2013-08-01

8

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

PubMed Central

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

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

2011-01-01

9

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

PubMed Central

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 Ca2+ 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-LNvs), to two neurotransmitters implicated in their modulation: acetylcholine (ACh) and ?-aminobutyric acid (GABA). Live imaging of l-LNv cAMP and Ca2+ 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-LNvs, critical neuronal pacemakers whose physiological properties in the adult brain are largely unknown. Our s-LNv 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-LNv modulation and lead to the prediction that cholinergic and GABAergic inputs to s-LNvs will have opposing effects on the phase and/or period of the molecular clock within these critical pacemaker neurons.

Lelito, Katherine R.

2012-01-01

10

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

PubMed Central

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.

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

2008-01-01

11

A Web of Circadian Pacemakers  

Microsoft Academic Search

The mammalian circadian timing system is composed of almost as many individual clocks as there are cells. These countless oscillators have to be synchronized by a central pacemaker to coordinate temporal physiology and behavior. Recently, there has been some progress in understanding the relationship and communication mechanisms between central and peripheral clocks.

Ueli Schibler; Paolo Sassone-Corsi

2002-01-01

12

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

Microsoft Academic Search

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

Charlotte Helfrich-Forster

1995-01-01

13

Pigment-dispersing hormone (PDH)-immunoreactive neurons form a direct coupling pathway between the bilaterally symmetric circadian pacemakers of the cockroach Leucophaea maderae  

Microsoft Academic Search

Circadian locomotor activity rhythms of the cockroach Leucophaea maderae are driven by two bilaterally paired and mutually coupled pacemakers that reside in the optic lobes of the brain. Transplantation studies have shown that this circadian pacemaker is located in the accessory medulla (AMe), a small neuropil of the medulla of the optic lobe. The AMe is densely innervated by about

Thomas Reischig; Bernhard Petri; Monika Stengl

2004-01-01

14

The Circadian Pacemaker in the Ap\\/ysia Eye Sends Axons Throughout the Central Nervous System  

Microsoft Academic Search

Each eye of Aplysia contains a population of electrically coupled pacemaker neurons whose synchronous activity can be recorded from the optic nerve as a compound action potential (CAP). The CAP frequency continues to show a circadian rhythm even when the eye is isolated from the animal and maintained in constant conditions, and thus it contains an autonomous circadian pacemaker, which

LEAH M. OLSON; JON W. JACKLET

15

Stopping the Circadian Pacemaker with Inhibitors of Protein Synthesis  

Microsoft Academic Search

The requirement for protein synthesis in the mechanism of a circadian pacemaker was investigated by using inhibitors of protein synthesis. Continuous treatment of the ocular circadian pacemaker of the molluse Bulla gouldiana with anisomycin or cycloheximide substantially lengthened (up to 39 and 52 hr, respectively) the free-running period of the rhythm. To determine whether high concentrations of inhibitor could stop

Sat Bir S. Khalsa; David Whitmore; Gene D. Block

1992-01-01

16

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

Microsoft Academic Search

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

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

2005-01-01

17

Stopping the circadian pacemaker with inhibitors of protein synthesis.  

PubMed Central

The requirement for protein synthesis in the mechanism of a circadian pacemaker was investigated by using inhibitors of protein synthesis. Continuous treatment of the ocular circadian pacemaker of the mollusc Bulla gouldiana with anisomycin or cycloheximide substantially lengthened (up to 39 and 52 hr, respectively) the free-running period of the rhythm. To determine whether high concentrations of inhibitor could stop the pacemaker, long pulse treatments of various durations (up to 44 hr) were applied and the subsequent phase of the rhythm was assayed. The observed phases of the rhythm after the treatments were a function of the time of the end of the treatment pulse, but only for treatments which spanned subjective dawn. The results provide evidence that protein synthesis is required in a phase-dependent manner for motion of the circadian pacemaker to continue. Images

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

1992-01-01

18

Development of pigment-dispersing hormone-immunoreactive neurons in the American lobster: homology to the insect circadian pacemaker system?  

Microsoft Academic Search

We have examined the development of pigment-dispersing hormone (PDH)-immunoreactive neurons in embryos of the American lobster\\u000a Homarus americanus Milne Edwards, 1837 (Decapoda, Reptantia, Homarida) by using an antiserum against ?-PDH. This peptide is detectable in the\\u000a terminal medulla of the eyestalks and the protocerebrum where PDH immunoreactivity is present as early as 20% of embryonic\\u000a development. During ontogenesis, an elaborate

Steffen Harzsch; Heinrich Dircksen; Barbara S. Beltz

2009-01-01

19

A functional analysis of circadian pacemakers in nocturnal rodents  

Microsoft Academic Search

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

Colin S. Pittendrigh; Serge Daan

1976-01-01

20

Development of the mouse circadian pacemaker: Independence from environmental cycles  

Microsoft Academic Search

1.The freerunning period (t) of the circadian pacemaker underlying the wheel-running activity rhythm ofMus musculus was found to be unaffected by the periods of environmental cycles (maternal and light\\/dark) under which the mice are raised. Mice born to mothers entrained to periods (T) of 28 or 20 h (ratio of light to dark of 14\\/10) and maintained on those cycle

Fred C. Davis; Michael Menaker

1981-01-01

21

Calcium channels mediate phase shifts of the Bulla circadian pacemaker  

Microsoft Academic Search

1.Light-induced phase advances of the activity rhythm of theBulla ocular circadian pacemaker are blocked when the extracellular calcium concentration is reduced with EGTA to 0.13 µM. Phase advances are also blocked in low calcium solutions without EGTA ([Ca]M).2.The dependence of light-induced phase delays on extracellular calcium concentration in EGTA-free seawater was determined. Phase delays are blocked at calcium concentrations below

Sat Bir S. Khalsa; Gene D. Block

1988-01-01

22

Cellular mechanisms of circadian pacemaking: beyond transcriptional loops.  

PubMed

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

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

2013-01-01

23

A pdf Neuropeptide Gene Mutation and Ablation of PDF Neurons Each Cause Severe Abnormalities of Behavioral Circadian Rhythms in Drosophila  

Microsoft Academic Search

The mechanisms by which circadian pacemaker systems transmit timing information to control behavior are largely unknown. Here, we define two critical features of that mechanism in Drosophila. We first describe animals mutant for the pdf neuropeptide gene, which is expressed by most of the candidate pacemakers (LNv neurons). Next, we describe animals in which pdf neurons were selectively ablated. Both

Susan C. P. Renn; Jae H. Park; Michael Rosbash; Jeffrey C. Hall; Paul H. Taghert

1999-01-01

24

Pacemaker neurons within newborn spinal pain circuits  

PubMed Central

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

Li, Jie; Baccei, Mark L.

2011-01-01

25

Retrograde Bone Morphogenetic Protein Signaling Shapes a Key Circadian Pacemaker Circuit  

PubMed Central

The neuropeptide pigment-dispersing factor (PDF) synchronizes molecular oscillations within circadian pacemakers in the Drosophila brain. It is expressed in the small ventral lateral neurons (sLNvs) and large ventral lateral neurons, the former being indispensable for maintaining behavioral rhythmicity under free-running conditions. How PDF circuits develop the specific connectivity traits that endow such global behavioral control remains unknown. Here, we show that mature sLNv circuits require PDF signaling during early development, acting through its cognate receptor PDFR at postsynaptic targets. Yet, axonal defects by PDF knockdown are presynaptic and become apparent only after metamorphosis, highlighting a delayed response to a signal released early on. Presynaptic expression of constitutively active bone morphogenetic protein (BMP) receptors prevents pdfr mutants misrouting phenotype, while sLNv-restricted downregulation of BMP signaling components phenocopied pdf01. Thus, we have uncovered a novel mechanism that provides an early “tagging” of synaptic targets that will guide circuit refinement later in development.

Gorostiza, E. Axel; Ceriani, M. Fernanda

2013-01-01

26

Morphology and pigment-dispersing hormone immunocytochemistry of the accessory medulla, the presumptive circadian pacemaker of the cockroach Leucophaea maderae: a light- and electron-microscopic study  

Microsoft Academic Search

To provide a framework for a cellular analysis of the accessory medulla, which is the presumptive circadian pacemaker of hemimetabolous insects, we have studied this neuropil and its associated neuronal structures by light- and electron-microscopy in the cockroach Leucophaea maderae. The accessory medulla is situated at the ventromedial edge of the medulla and shows no evidence of a retinotopical organization.

Thomas Reischig; Monika Stengl

1996-01-01

27

Spontaneous Activity in Isolated Somata of Aplysia Pacemaker Neurons  

Microsoft Academic Search

Somata of pacemaker and nonpacemaker neurons were isolated by ligatures tied around the axons between the somata and the synaptic regions, and the transmembrane potentials of the isolated somata were recorded. Iso- lated somata of pacemaker neurons had a spontaneous discharge while isolated somata of nonpacemaker neurons were quiescent. In addition, the time course of accommodation in isolated somata of

BARBARA O. ALVING

1968-01-01

28

Asynchronous response of coupled pacemaker neurons  

PubMed Central

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.

Dodla, Ramana; Wilson, Charles J.

2009-01-01

29

Circadian rhythms in the morphology of neurons in Drosophila.  

PubMed

Neurons have an enormous capacity to adapt to changing conditions through the regulation of gene expression, morphology, and physiology. In the fruit fly Drosophila melanogaster, this plasticity includes recurrent changes taking place within intervals of a few hours during the day. The rhythmic alterations in the morphology of neurons described so far include changes in axonal diameter, branching complexity, synapse numbers, and the number of synaptic vesicles. The cycles of these changes have larger amplitude when the fly is exposed to light, but they persist in constant darkness and require the expression of the clock genes period and timeless, leading to the concept of circadian plasticity. The molecular mechanisms driving these cycles appear to require the expression of these genes either inside the neurons themselves or in other peripheral pacemaker cells. Loss-of-function mutations in period and timeless not only abolish the morphological rhythms, but also often cause abnormal axonal branching suggesting that circadian plasticity is relevant for the maintenance of normal morphology. Research into whether (1) circadian plasticity is a common feature of neurons in all animals and (2) our own neurons change shape between day and night will be of interest. PMID:21562943

Mehnert, Kerstin I; Cantera, Rafael

2011-05-13

30

Modeling the Emergence of Circadian Rhythms in a Clock Neuron Network  

PubMed Central

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.

Diambra, Luis; Malta, Coraci P.

2012-01-01

31

Substance p plays a critical role in photic resetting of the circadian pacemaker in the rat hypothalamus.  

PubMed

Glutamate is considered to be the primary neurotransmitter in the retinohypothalamic tract (RHT), which delivers photic information from the retina to the suprachiasmatic nucleus (SCN), the locus of the mammalian circadian pacemaker. However, substance P (SP) also has been suggested to play a role in retinohypothalamic transmission. In this study, we sought evidence that SP from the RHT contributes to photic resetting of the circadian pacemaker and further explored the possible interaction of SP with glutamate in this process. In rat hypothalamic slices cut parasagittally, electrical stimulation of the optic nerve in early and late subjective night produced a phase delay (2.4 +/- 0.5 hr; mean +/- SEM) and advance (2.6 +/- 0.3 hr) of the circadian rhythm of SCN neuronal firing activity, respectively. The SP antagonist L-703,606 (10 microm) applied to the slices during the nerve stimulation completely blocked the phase shifts. Likewise, a cocktail of NMDA (2-amino-5-phosphonopentanoic acid, 50 microm) and non-NMDA (6,7-dinitroquinoxaline-2,3-dione, 10 microm) antagonists completely blocked the shifts. Exogenous application of SP (1 microm) or glutamate (100 microm) to the slices in early subjective night produced a phase delay ( approximately 3 hr) of the circadian firing activity rhythm of SCN neurons. Coapplication of the NMDA and non-NMDA antagonist cocktail (as well as L-703,606) resulted in a complete blockade of the SP-induced phase delay, whereas L-703,606 (10 microm) had no effect on the glutamate-induced delay. These results suggest that SP, as well as glutamate, has a critical role in photic resetting. Furthermore, the results suggest that the two agonists act in series, SP working upstream of glutamate. PMID:11356889

Kim, D Y; Kang, H C; Shin, H C; Lee, K J; Yoon, Y W; Han, H C; Na, H S; Hong, S K; Kim, Y I

2001-06-01

32

Analysis of coupling between optic lobe circadian pacemakers in the cricket Gryllus bimaculatus  

Microsoft Academic Search

The coupling mechanism between weakly coupled two optic lobe circadian pacemakers in the cricket Gryllus bimaculatus was investigated by recording the locomotor activity, under light-dark cycles with various lengths, after the optic nerve was unilaterally severed. The activity rhythm split into two components under the light cycles different from 24 h: one was readily entrained to the light cycle and

K. Tomioka

1993-01-01

33

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

Microsoft Academic Search

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

M. R. Gorman; J. A. Elliott

2004-01-01

34

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

PubMed

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

Gorostiza, E Axel; Ceriani, M Fernanda

2013-01-01

35

A peripheral pacemaker drives the circadian rhythm of synaptic boutons in Drosophila independently of synaptic activity.  

PubMed

Circadian rhythms in the morphology of neurons have been demonstrated in the fly Drosophila melanogaster. One such rhythm is characterized by changes in the size of synaptic boutons of an identified flight motor neuron, with larger boutons during the day compared with those at night. A more detailed temporal resolution of this rhythm shows here that boutons grow at a time of increased locomotor activity during the morning but become gradually smaller during the day and second period of increased locomotor activity in the evening. We have experimentally manipulated the synaptic activity of the fly during short periods of the day to investigate whether changes in bouton size might be a consequence of the different levels of synaptic activity associated with the locomotion rhythm of the fly. In the late night and early morning, when the flies normally have an intense period of locomotion, the boutons grow independently of whether the flies are active or completely paralyzed. Bouton size is not affected by sleep-deprivation during the early night. The cycle in bouton size persists for 2 days even in decapitated flies, which do not move, reinforcing the notion that it is largely independent of synaptic activity, and showing that a pacemaker other than the main biological clock can drive it. PMID:18688648

Mehnert, Kerstin I; Cantera, Rafael

2008-08-08

36

Addition of a non-photic component to a light-based mathematical model of the human circadian pacemaker.  

PubMed

Mathematical models have become vital to the study of many biological processes in humans due to the complexity of the physiological mechanisms underlying these processes and systems. While our current mathematical representation of the human circadian pacemaker has proven useful in many experimental situations, it uses as input only a direct effect of light on the circadian pacemaker. Although light (a photic stimulus) has been shown to be the primary synchronizer of the circadian pacemaker across a number of species, studies in both animals and humans have confirmed the existence of non-photic effects that also contribute to phase shifting and entrainment. We modified our light-based circadian mathematical model to reflect evidence from these studies that the sleep-wake cycle and/or associated behaviors have a non-photic effect on the circadian pacemaker. In our representation, the sleep-wake cycle and its associated behaviors provides a non-photic drive on the circadian pacemaker that acts both independently and concomitantly with light stimuli. Further experiments are required to validate fully our model and to understand the exact effect of the sleep-wake cycle as a non-photic stimulus for the human circadian pacemaker. PMID:17531270

St Hilaire, Melissa A; Klerman, Elizabeth B; Khalsa, Sat Bir S; Wright, Kenneth P; Czeisler, Charles A; Kronauer, Richard E

2007-04-04

37

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

PubMed

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 (tau). 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 tau + 1 h) in one of three light:dark conditions: (i) approximately 25 lux; (ii) approximately 100 lux; and (iii) MLE: approximately 25 lux followed by approximately 100 lux, plus two 45-min bright light pulses of approximately 9,500 lux near the end of scheduled wakefulness. We found that lighting levels of approximately 25 lux were insufficient to entrain all subjects tested. Exposure to approximately 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

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

2007-05-14

38

Influence of photoperiodic history on clock genes and the circadian pacemaker in the rat retina.  

PubMed

The influence of seasonal lighting conditions on expression of clock genes and the circadian pacemaker was investigated in the rat retina. For this purpose, the 24-h profiles of nine clock genes (bmal1, clock, per1, per2, per3, dec1, dec2, cry1 and cry 2) and the arylalkylamine N-acetyltransferase gene as an indicator of the circadian pacemaker output were compared between light-dark periods of 8 : 16 and 16 : 8 h. The photoperiod influenced the daily patterns of the amount of transcript for per1, per3, dec2 and arylalkylamine N-acetyltransferase. This indicates that photoperiodic information modulates clock gene expression in addition to the circadian pacemaker of the retina. Under constant darkness, photoperiod-dependent changes in the daily profile of the level of transcript persisted for the arylalkylamine N-acetyltransferase gene but not for any of the clock genes. Hence, quantitative expression of each clock gene is influenced by the photoperiod only under the acute light-dark cycle, whereas the pacemaker is capable of storing photoperiodic information from past cycles. PMID:16420420

Rohleder, Nils; Langer, Christina; Maus, Christian; Spiwoks-Becker, Isabella; Emser, Angela; Engel, Lydia; Spessert, Rainer

2006-01-01

39

Firing Patterns and Transitions in Coupled Neurons Controlled by a Pacemaker  

NASA Astrophysics Data System (ADS)

To reveal the dynamics of neuronal networks with pacemakers, the firing patterns and their transitions are investigated in a ring HR neuronal network with gap junctions under the control of a pacemaker. Compared with the situation without pacemaker, the neurons in the network can exhibit various firing patterns as the external current is applied or the coupling strength of pacemaker varies. The results are beneficial for understanding the complex cooperative behaviour of large neural assemblies with pacemaker control.

Li, Mei-Sheng; Lu, Qi-Shao; Duan, Li-Xia; Wang, Qing-Yun

2008-08-01

40

Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day.  

PubMed Central

1. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker for circadian rhythms in mammals. The 24 h pacemaker is endogenous to the SCN and persists for multiple cycles in the suprachiasmatic brain slice. 2. While serotonin is not endogenous to the SCN, a major midbrain hypothalamic afferent pathway is serotonergic. Within this tract the dorsal raphe nucleus sends direct projections to the ventrolateral portions of the SCN. We investigated a possible regulatory role for serotonin in the mammalian circadian system by examining its effect, when applied at projection sites, on the circadian rhythm of neuronal activity in rat SCN in vitro. 3. Eight-week-old male rats from our inbred colony, housed on a 12 h light: 12 h dark schedule, were used. Hypothalamic brain slices containing the paired SCN were prepared in the day and maintained in glucose and bicarbonate-supplemented balanced salt solution for up to 53 h. 4. A 10(-11) ml drop of 10(-6) M-serotonin (5-hydroxytryptamine (5-HT) creatinine sulphate complex) in medium was applied to the ventrolateral portion of one of the SCN for 5 min on the first day in vitro. The effect of the treatment at each of seven time points across the circadian cycle was examined. The rhythm of spontaneous neuronal activity was recorded extracellularly on the second and third days in vitro. Phase shifts were determined by comparing the time-of-peak of neuronal activity in serotonin- vs. media-treated slices. 5. Application of serotonin during the subjective day induced significant advances in the phase of the electrical activity rhythm (n = 11). The most sensitive time of treatment was CT 7 (circadian time 7 is 7 h after 'lights on' in the animal colony), when a 7.0 +/- 0.1 h phase advance was observed (n = 3). This phase advance was perpetuated on day 3 in vitro without decrement. Serotonin treatment during the subjective night had no effect on the timing of the electrical activity rhythm (n = 9). 6. The specificity of the serotonin-induced phase change was assessed by treating slices in the same manner with a microdrop of serotonergic agonists, 5-carboxamidotryptamine, that targets the 5-HT1 class of receptors, or 8-hydroxy-dipropylaminotetralin (8-OH DPAT), that acts on the 5-HT1A receptor subtype.(ABSTRACT TRUNCATED AT 400 WORDS)

Medanic, M; Gillette, M U

1992-01-01

41

Addition of a non-photic component to a light-based mathematical model of the human circadian pacemaker  

PubMed Central

Mathematical models have become vital to the study of many biological processes in humans due to the complexity of the physiological mechanisms underlying these processes and systems. While our current mathematical representation of the human circadian pacemaker has proven useful in many experimental situations, it uses as input only a direct effect of light on the circadian pacemaker. Although light (a photic stimulus) has been shown to be the primary synchronizer of the circadian pacemaker across a number of species, studies in both animals and humans have confirmed the existence of non-photic effects that also contribute to phase shifting and entrainment. We modified our light-based circadian mathematical model to reflect evidence from these studies that the sleep-wake cycle and/or associated behaviors have a non-photic effect on the circadian pacemaker. In our representation, the sleep-wake cycle and its associated behaviors provides a non-photic drive on the pacemaker that acts both independently and concomitantly with light stimuli. Further experiments are required to validate fully our model and to understand the exact effect of the sleep-wake cycle as a non-photic stimulus for the human circadian pacemaker.

St Hilaire, Melissa A.; Klerman, Elizabeth B.; Khalsa, Sat Bir; Wright, Kenneth P.; Czeisler, Charles A.; Kronauer, Richard E.

2011-01-01

42

Cell Culture and Transplantation of the Suprachiasmatic Circadian Pacemaker.  

National Technical Information Service (NTIS)

Circadian activity rhythms that have been eliminated by lesions of the suprachiasmatic nucleus (SCN) can be restored by fetal SCN grafts. Partial lesions of the host allow simultaneous expression of both donor and host rhythm. Because partial SCN ablation...

M. R. Ralph

1995-01-01

43

Developmental changes in pacemaker currents in mouse locus coeruleus neurons  

Microsoft Academic Search

The present study compares the electrophysiological properties and the primary pacemaker currents that flow during the interspike interval in locus coeruleus (LC) neurons from infant (P7–12days) and young adult (8–12weeks) mice. The magnitude of the primary pacemaker currents, which consist of an excitatory TTX-sensitive Na+ current and an inhibitory voltage-dependent K+ current, increased in parallel during development. We found no

Ramatis B. de Oliveira; Fernanda S. Gravina; Rebecca Lim; Alan M. Brichta; Robert J. Callister; Dirk F. van Helden

44

AKT and TOR Signaling Set the Pace of the Circadian Pacemaker  

PubMed Central

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

Zheng, Xiangzhong; Sehgal, Amita

2011-01-01

45

Cellular Analysis of Circadian Rhythmicity in Cultured SCN Neurons.  

National Technical Information Service (NTIS)

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

S. M. Reppert D. K. Welsh

1994-01-01

46

A functional analysis of circadian pacemakers in nocturnal rodents  

Microsoft Academic Search

Summary 1.This paper is an attempt to integrate in a general model the major findings reported earlier in this series on: lability and history dependence of circadian period, t (Pittendrigh and Daan, 1976 a); dependence of t and a on light intensity as described in Aschoff's Rule (Daan and Pittendrigh, 1976b); the interrelationships between t and phase response curves (Daan

Colin S. Pittendrigh; Serge Daan

1976-01-01

47

Characteristics of a circadian pacemaker in the suprachiasmatic nucleus  

Microsoft Academic Search

The nature of the circadian rhythms of the SCN in a hypothalamic island was examined in male rats by recording multiple unit activity from the SCN for longer durations. Successful continuous recording lasted up to 35 days. Neural activity of the SCN inside the island showed free-running rhythms whose periods were slightly longer than 24 h (Figs. 2, 3, Table

Shin-ichi T. Inouye; Hiroshi Kawamura

1982-01-01

48

Circadian variation in sensitivity of suprachiasmatic and lateral geniculate neurones to 5-hydroxytryptamine in the rat.  

PubMed Central

Extracellular single-unit recordings were obtained from neurones in the suprachiasmatic nuclei (s.c.n.) of the rat (a putative circadian pace-maker), the ventral lateral geniculate nucleus (v.l.g.n.) and the hippocampus. These areas receive a 5-hydroxytryptamine (5-HT) innervation from the raphe nuclei. Recording of neuronal activity in the s.c.n., v.l.g.n. and the hippocampus revealed a diurnal variation in the response to the ionophoresis of 5-HT. This variation was manifest as a 2-3-fold increase in post-synaptic sensitivity to 5-HT during the subjective dark (active) phase of the circadian cycle. In contrast there was no apparent circadian variation in the sensitivity of s.c.n., v.l.g.n. or hippocampal neurones to ionophoresed gamma-aminobutyric acid (GABA). Neuronal activity recorded in the s.c.n., v.l.g.n. and hippocampus also exhibited a circadian variation in the recovery from 5-HT-induced suppression of firing. This may reflect reuptake processes as recovery can be prolonged by ionophoresis of uptake blockers (imipramine or fluoxetine). Rats (n = 15) expressing circadian arrhythmicity in their rest-activity behaviour induced by long-term continuous illumination (150-200 lx) showed no apparent circadian variation in 5-HT sensitivity. This loss was accompanied by either the development of a 5-6-fold subsensitivity to ionophoresed 5-HT (eleven out of fifteen rats) or a 2-3-fold supersensitivity to ionophoresed 5-HT (four out of fifteen rats). A similar loss of circadian variation and the development of a subsensitivity to ionophoresed 5-HT was also found in three rats sustaining complete electrolytic lesions of the s.c.n. These changes were not found in rats (n = 4) with partial s.c.n. lesions. These results implicate the s.c.n., or fibres passing through it, in the circadian modulation of 5-HT sensitivity in neurones both intrinsic to the s.c.n. circadian pace-maker itself and in the hippocampus and lateral geniculate nucleus (regions remote from the s.c.n.).

Mason, R

1986-01-01

49

Role of Circadian Activation of Mitogen-Activated Protein Kinase in Chick Pineal Clock Oscillation  

Microsoft Academic Search

A circadian pacemaker generates a rhythm with a period of ;24 hr even in the absence of environmental time cues. Several photosensitive neuronal tissues such as the retina and pineal gland contain the autonomous circadian pacemaker together with the photic-input pathway responsible for entrainment of the pacemaker to the daily light\\/dark cycle. We show here that, in constant darkness, chick

Kamon Sanad; Yuichiro Hayashi; Yuko Harada; Toshiyuki Okano; Yoshitaka Fukada

2000-01-01

50

Pacemaker  

MedlinePLUS

... Search Form Advanced Search Search the NHLBI, use radio buttons below to select whole site or Disease and Conditions Index only NHLBI Entire ... What Is ... Who Needs How Does a Pacemaker Work During Pacemaker Surgery After Pacemaker Surgery What Are ...

51

The human circadian pacemaker can see by the dawn's early light.  

PubMed

The authors' previous experiments have shown that dawn simulation at low light intensities can phase advance the circadian rhythm of melatonin in humans. The aim of this study was to compare the effect of repeated dawn signals on the phase position of circadian rhythms in healthy participants kept under controlled light conditions. Nine men participated in two 9-day laboratory sessions under an LD cycle 17.5:6.5 h, < 30:0 lux, receiving 6 consecutive daily dawn (average illuminance 155 lux) or control light (0.1 lux) signals from 0600 to 0730 h (crossover, random-order design). Two modified constant routine protocols before and after the light stimuli measured salivary melatonin (dim light melatonin onset DLMOn and offset DLMOff) and rectal temperature rhythms (midrange crossing time [MRCT]). Compared with initial values, participants significantly phase delayed after 6 days under control light conditions (at least -42 min DLMOn, -54 min DLMOff, -41 min MRCT) in spite of constant bedtimes. This delay was not observed with dawn signals (+10 min DLMOn, +2 min DLMOff, 0 min MRCT). Given that the endogenous circadian period of the human circadian pacemaker is slightly longer than 24 h, the findings suggest that a naturalistic dawn signal is sufficient to forestall this natural delay drift. Zeitgeber transduction and circadian system response are hypothesized to be tuned to the time-rate-of-change of naturalistic twilight signals. PMID:11039921

Danilenko, K V; Wirz-Justice, A; Kräuchi, K; Weber, J M; Terman, M

2000-10-01

52

Circadian pacemaker times gonadotropin release in free-running female hamsters.  

PubMed

Female golden hamsters (Mesocricetus auratus) were housed individually on a photoperiod of LD 6:18 (lights 1000-1600 h). Estrous cyclicity was interrupted for an average of 16 wk after which cycles resumed spontaneously. Such animals are photorefractory, remaining cyclic on normally nonstimulatory photoperiods. Photorefractory females were exposed to continuous darkness in which estrous cyclicity in the population rapidly became asynchronous as each hamster's "day" assumed the endogenous periodicity (tau) of her circadian clock. Tau usually approximated but rarely equaled 24 h. Successive estrous cycles in each animal possessed a periodicity of 4 tau. Preovulatory luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release occurred at a specific time of the animal's circadian day, bearing a discrete phase relationship of 2 to 3 h to the circadian rhythm of locomotor activity. Thus, although seemingly asynchronous with respect to laboratory time, peak preovulatory gonadotropin release on proestrus in free-running hamsters was synchronized with respsect to circadian time. We conclude that a circadian pacemaker times preovulatory gonadotropin release in hamsters. PMID:7188838

Stetson, M H; Anderson, P J

1980-01-01

53

Pigment-Dispersing Hormone Shifts the Phase of the Circadian Pacemaker of the Cockroach Leucophaea maderae  

Microsoft Academic Search

An antiserum against the crustacean neuropeptide pigment- dispersing hormone stains a small set of neurons in the optic lobes of several hemimetabolous and holometabolous insects. These cells, the primary branches of which in the optic lobe lie in the accessory medulla, fulfill several criteria predicted for neurons of the circadian clock. For example, in fruit flies they express timeless and

Bernhard Petri; Monika Stengl

1997-01-01

54

Emergence of Noise-Induced Oscillations in the Central Circadian Pacemaker  

PubMed Central

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.

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

2010-01-01

55

Photoperiodic plasticity in circadian clock neurons in insects.  

PubMed

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

Shiga, Sakiko

2013-08-23

56

Central Control of Circadian Phase in Arousal-Promoting Neurons  

PubMed Central

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

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

2013-01-01

57

Central control of circadian phase in arousal-promoting neurons.  

PubMed

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

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

2013-06-24

58

Circadian rhythm of blood pressure in patients dependent on ventricular demand pacemakers.  

PubMed

The reported circadian rhythm of blood pressure variability with a rise in pressure before awakening has been the subject of controversy. Previous studies have suggested that since heart rate continues to fall before awakening while blood pressure is rising these physiological variables are subject to different control mechanisms. To evaluate further the dissociation of heart rate and blood pressure changes in a group of patients with a fixed heart rate, 11 patients who were dependent on ventricular demand pacemakers underwent intra-arterial ambulatory blood pressure monitoring. Nine aged matched control subjects followed the same protocol. Circadian curves plotted from pooled hourly mean data showed that despite a fixed heart rate the circadian pattern persisted, although attenuated, with blood pressure rising several hours before its rapid rise on awakening. Physiological testing showed that despite a fixed heart rate systolic blood pressure rose in response to bicycle exercise, there was a postural fall in the blood pressure on tilting and a modified Valsalva response. There was considerable beat to beat variability resulting presumably from asychronous pacing. Hour to hour changes did not contribute to the differences between the two groups and were not responsible for attenuation of the circadian rhythm. It is concluded that blood pressure and heart rate control mechanisms may be dissociated, particularly in the period before awakening. PMID:6743428

Davies, A B; Gould, B A; Cashman, P M; Raftery, E B

1984-07-01

59

Light-mediated TIM Degradation within Drosophila Pacemaker Neurons (s-LNvs) is neither Necessary nor Sufficient for Delay Zone Phase Shifts  

PubMed Central

SUMMARY Circadian systems are entrained and phase shifted by light. In Drosophila, the model of light-mediated phase shifting begins with photon capture by cryptochrome (CRY) followed by rapid timeless (TIM) degradation. In this study, we focused on phase delays and assayed TIM degradation within individual brain clock neurons in response to light pulses in the early night. Surprisingly, there was no detectable change in TIM staining intensity within the eight pacemaker s-LNvs. This indicates that TIM degradation within s-LNvs is not necessary for phase delays, and similar assays in other genotypes indicate that it is also not sufficient. In contrast, more dorsal circadian neurons appear light-sensitive in the early night. Because CRY is still necessary within the s-LNvs for phase shifting, the results challenge the canonical cell-autonomous molecular model and raise the question of how the pacemaker neuron transcription-translation clock is reset by light in the early night.

Tang, Chih-Hang Anthony; Hinteregger, Erica; Shang, Yuhua; Rosbash, Michael

2011-01-01

60

Pacemaker phase control versus masking by light: setting the circadian chronotype in dual Octodon degus.  

PubMed

There are two main processes involved in the expression of circadian rhythmicity: entrainment and masking. Whereas the first operates via the central pacemaker to anticipate predictable environmental conditions, masking (mainly induced by light) functions as a direct modulator of the circadian output signal induced by nonpredictable events. The Chilean rodent Octodon degus presents both diurnal and nocturnal chronotypes when given free access to an exercise wheel. Two steady-entrainment phases and graded masking by light seem to generate the wide variability of chronotypes in this species. The aim of this study was to characterize the differential masking by light according to the individual chronotypes, their stability over time, and the influence of wheel running availability and ambient temperature upon the degus' nocturnality. To this end, diurnal and nocturnal degus were subjected to ultradian cycles (1:1-h light-dark [LD]), with and without wheel running availability, and under both normal and high diurnal ambient temperature cycles. The present results show that diurnal and nocturnal degus present a stable masking by light, each according to its respective chronotype. Thus, whereas diurnal animals increased their activity with light, in nocturnal degus light induced a sharp drop in wheel running activity. These two types of masking responses appeared not only when the animals were synchronized to the 12:12-h LD cycle, but also under ultradian cycles. Different masking effects persisted when wheel running was made unavailable and when the animals shifted their circadian activity patterns in response to ultradian cycles or to diurnal exposure to high temperatures. In conclusion, our results show that the positive and negative masking effects of light on diurnal and nocturnal degus, respectively, seem to occur independently of relative phase control by the central pacemaker or the negative masking induced by high environmental temperatures. PMID:20795881

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

2010-08-01

61

Circadian Remodeling of Neuronal Circuits Involved in Rhythmic Behavior  

PubMed Central

Clock output pathways are central to convey timing information from the circadian clock to a diversity of physiological systems, ranging from cell-autonomous processes to behavior. While the molecular mechanisms that generate and sustain rhythmicity at the cellular level are well understood, it is unclear how this information is further structured to control specific behavioral outputs. Rhythmic release of pigment dispersing factor (PDF) has been proposed to propagate the time of day information from core pacemaker cells to downstream targets underlying rhythmic locomotor activity. Indeed, such circadian changes in PDF intensity represent the only known mechanism through which the PDF circuit could communicate with its output. Here we describe a novel circadian phenomenon involving extensive remodeling in the axonal terminals of the PDF circuit, which display higher complexity during the day and significantly lower complexity at nighttime, both under daily cycles and constant conditions. In support to its circadian nature, cycling is lost in bona fide clockless mutants. We propose this clock-controlled structural plasticity as a candidate mechanism contributing to the transmission of the information downstream of pacemaker cells.

Fernandez, Maria Paz; Berni, Jimena; Ceriani, Maria Fernanda

2008-01-01

62

Circadian regulation of the na(+)/k(+)-ATPase alpha subunit in the visual system is mediated by the pacemaker and by retina photoreceptors in Drosophila melanogaster.  

PubMed

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

Damulewicz, Milena; Rosato, Ezio; Pyza, Elzbieta

2013-09-10

63

Distinct synaptic dynamics of heterogeneous pacemaker neurons in an oscillatory network  

PubMed Central

Many rhythmically active networks involve heterogeneous populations of pacemaker neurons with potentially distinct synaptic outputs that can be differentially targeted by extrinsic inputs or neuromodulators, thereby increasing possible network output patterns. In order to understand the roles of heterogeneous pacemaker neurons, we characterized differences in synaptic output from the anterior burster (AB) and pyloric dilator (PD) neurons in the lobster pyloric network. These intrinsically distinct neurons are strongly electrically coupled, co-active and constitute the pyloric pacemaker ensemble. During pyloric oscillations, the pacemaker neurons produce compound inhibitory synaptic connections to the follower lateral pyloric (LP) and pyloric constrictor (PY) neurons, which fire out of phase with AB/PD and with different delay times. Using pharmacological blockers, we separated the synapses originating from the AB and PD neurons and investigated their temporal dynamics. These synapses exhibited distinct short-term dynamics, depending on the presynaptic neuron type, and had different relative contributions to the total synaptic output depending on waveform shape and cycle frequency. However, paired comparisons revealed that the amplitude or dynamics of synapses from either the AB or PD neuron did not depend on the postsynaptic neuron type, LP or PY. To address the functional implications of these findings, we examined the correlation between synaptic inputs from the pacemakers and the burst onset phase of the LP and PY neurons in the ongoing pyloric rhythm. These comparisons showed that the activity of the LP and PY neurons are influenced by the peak phase and amplitude of the synaptic inputs from the pacemaker neurons.

Rabbah, Pascale; Nadim, Farzan

2008-01-01

64

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

Microsoft Academic Search

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

Helena Illnerová; Ji?í Van??ek

1982-01-01

65

The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker  

PubMed Central

Temporal restriction of feeding can phase-shift behavioral and physiological circadian rhythms in mammals. These changes in biological rhythms are postulated to be brought about by a food-entrainable oscillator (FEO) that is independent of the suprachiasmatic nucleus. However, the neural substrates of FEO have remained elusive. Here, we carried out an unbiased search for mouse brain region(s) that exhibit a rhythmic expression of the Period genes in a feeding-entrainable manner. We found that the compact part of the dorsomedial hypothalamic nucleus (DMH) demonstrates a robust oscillation of mPer expression only under restricted feeding. The oscillation persisted for at least 2 days even when mice were given no food during the expected feeding period after the establishment of food-entrained behavioral rhythms. Moreover, refeeding after fasting rapidly induced a transient mPer expression in the same area of DMH. Taken in conjunction with recent findings (i) that behavioral expression of food-entrainable circadian rhythms is blocked by cell-specific lesions of DMH in rats and (ii) that DMH neurons directly project to orexin neurons in the lateral hypothalamus, which are essential for proper expression of food-entrained behavioral rhythms, the present study suggests that DMH plays a key role as a central FEO in the feeding-mediated regulation of circadian behaviors.

Mieda, Michihiro; Williams, S. Clay; Richardson, James A.; Tanaka, Kohichi; Yanagisawa, Masashi

2006-01-01

66

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

National Technical Information Service (NTIS)

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 pace-maker cells. The major effects on the p...

A. Watanabe S. Obara T. Akiyama

1969-01-01

67

In vivo circadian rhythms in gonadotropin-releasing hormone neurons.  

PubMed

Although it is generally accepted that the circadian clock provides a timing signal for the luteinizing hormone (LH) surge, mechanistic explanations of this phenomenon remain underexplored. It is known, for example, that circadian locomotor output cycles kaput (clock) mutant mice have severely dampened LH surges, but whether this phenotype derives from a loss of circadian rhythmicity in the suprachiasmatic nucleus (SCN) or altered circadian function in gonadotropin-releasing hormone (GnRH) neurons has not been resolved. GnRH neurons can be stimulated to cycle with a circadian period in vitro and disruption of that cycle disturbs secretion of the GnRH decapeptide. We show that both period-2 (PER2) and brain muscle Arnt-like-1 (BMAL1) proteins cycle with a circadian period in the GnRH population in vivo. PER2 and BMAL1 expression both oscillate with a 24-hour period, with PER2 peaking during the night and BMAL1 peaking during the day. The population, however, is not as homogeneous as other oscillatory tissues with only about 50% of the population sharing peak expression levels of BMAL1 at zeitgeber time 4 (ZT4) and PER2 at ZT16. Further, a light pulse that induced a phase delay in the activity rhythm of the GnRH-eGFP mice caused a similar delay in peak expression levels of BMAL1 and PER2. These studies provide direct evidence for a functional circadian clock in native GnRH neurons with a phase that closely follows that of the SCN. PMID:19786732

Hickok, Jason R; Tischkau, Shelley A

2009-09-26

68

Phase Synchronization in Electrically Coupled Different Neuronal Pacemakers with the Chay Model  

NASA Astrophysics Data System (ADS)

We study the phase synchronization in different electrically coupled neuronal pacemakers with the Chay model. The numerical simulation results and the definition of the mean frequency show that phase synchronization is equal to the mean frequency locking. Nearly complete synchronization of different two coupled neuronal pacemakers is also investigated. It is shown that the cross-correlation of the membrane potential variables is suitable to judge the nearly complete synchronization.

Shi, Xia; Lu, Qi-Shao

2005-03-01

69

The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats  

Microsoft Academic Search

Aims Adverse cardiovascular events in humans occur with a day\\/night pattern, presumably related to a daily pattern of behaviours or endogenous circadian rhythms in cardiovascular variables. Healthy humans possess a scale-invariant\\/fractal structure in heartbeat fluctuations that exhibits an endogenous circadian rhythm and changes towards the structure observed in cardiovascular disease at the circadian phase corresponding to the time of the

Kun Hu; Frank A. J. L. Scheer; Ruud M. Buijs; Steven A. Shea

2008-01-01

70

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

PubMed Central

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

CASTEL, MONA; MORRIS, JOHN F.

2000-01-01

71

Circadian Regulation of Olfactory Receptor Neurons in the Cockroach Antenna  

PubMed Central

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.

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

2013-01-01

72

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

PubMed

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

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

2013-09-30

73

Setting clock speed in mammals: the CK1? tau mutation in mice accelerates the circadian pacemaker by selectively destabilizing PERIOD proteins  

PubMed Central

Summary The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period lengthened in CK1??/?, whereas CK1?tau/tau shortened circadian period of behaviour in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1?tau/tau also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1?tau acted by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Together, these whole animal and biochemical studies explain how tau, as a gain-of-function mutation, acts at a specific circadian phase to promote degradation of PERIOD proteins, and thereby accelerate the mammalian clockwork in brain and periphery.

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

2013-01-01

74

Integer multiple spiking in neuronal pacemakers without external periodic stimulation  

NASA Astrophysics Data System (ADS)

An integer multiple spiking, whose interspike intervals (ISIs) were mostly located at the integer multiples of a basic ISI, was observed in the experiment on a neuronal pacemaker without external periodic stimulation. It was observed between the period 1 spiking and the subthreshold oscillation when extra-cellular calcium concentration ([Ca++]o) was changed as a control parameter. A Hopf bifurcation point across which the period 1 spiking changed into the subthreshold oscillation directly was observed in the corresponding parameter region in the deterministic Chay model. In the stochastic Chay model, if the parameter vc (corresponding to [Ca++]o in the experiment) was changed across the Hopf bifurcation point, the integer multiple spiking, appeared between the period 1 spiking and the subthreshold oscillation, was simulated. It exhibited similar characters to those in the experiment and was verified to be caused by autonomous stochastic resonance (ASR). The result revealed the sequence of firing patterns near the Hopf bifurcation point and indicated that ASR was probably the cause of the generation of the integer multiple spiking in the experiment.

Gu, H.; Ren, W.; Lu, Q.; Wu, S.; Yang, M.; Chen, W.

2001-06-01

75

Drosophila pacemaker neurons require G-protein signaling and GABAergic inputs to generate 24hr behavioral rhythms  

PubMed Central

Summary Intercellular signaling is important for accurate circadian rhythms. In Drosophila, the small ventral lateral neurons (s-LNvs) are the dominant pacemaker neurons and set the pace of most other clock neurons in constant darkness. Here we show that two distinct G-protein signaling pathways are required in LNvs for 24hr rhythms. Reducing signaling in LNvs via the G-alpha subunit Gs, which signals via cAMP, or via the G-alpha subunit Go, which we show signals via Phospholipase 21c, lengthens the period of behavioral rhythms. In contrast, constitutive Gs or Go signaling makes most flies arrhythmic. Using dissociated LNvs in culture, we found that Go and the metabotropic GABAB-R3 receptor are required for the inhibitory effects of GABA on LNvs and that reduced GABAB-R3 expression in vivo lengthens period. Although no clock neurons produce GABA, hyper-exciting GABAergic neurons disrupts behavioral rhythms and s-LNv molecular clocks. Therefore, s-LNvs require GABAergic inputs for 24hr rhythms.

Dahdal, David; Reeves, David C.; Ruben, Marc; Akabas, Myles H.; Blau, Justin

2010-01-01

76

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

PubMed

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

Umatani, Chie; Abe, Hideki; Oka, Yoshitaka

2013-02-06

77

Neuronal influence on peripheral circadian oscillators in pupal Drosophila prothoracic glands  

PubMed Central

Rhythmic expression of period (per) and timeless (tim) genes in central circadian pacemaker neurons and prothoracic gland cells, part of the peripheral circadian oscillators in flies, may synergistically control eclosion rhythms, but their oscillatory profiles remain unclear. Here we show differences and interactions between peripheral and central oscillators using per-luciferase and cytosolic Ca2+ reporter (yellow cameleon) imaging in organotypic prothoracic gland cultures with or without the associated central nervous system. Isolated prothoracic gland cells exhibit light-insensitive synchronous per-transcriptional rhythms. In prothoracic gland cells associated with the central nervous system, however, per transcription is markedly amplified following 12-h light exposure, resulting in the manifestation of day–night rhythms in nuclear PER immunostaining levels and spontaneous Ca2+ spiking. Unlike PER expression, nuclear TIM expression is associated with day–night cycles that are independent of the central nervous system. These results demonstrate that photoreception and synaptic signal transduction in/from the central nervous system coordinate molecular 'gears' in endocrine oscillators to generate physiological rhythms.

Morioka, Eri; Matsumoto, Akira; Ikeda, Masayuki

2012-01-01

78

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

Microsoft Academic Search

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

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

2004-01-01

79

Prokineticin Receptor 2 (Prokr2) Is Essential for the Regulation of Circadian Behavior by the Suprachiasmatic Nuclei  

Microsoft Academic Search

The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential

Haydn M. Prosser; Allan Bradley; Johanna E. Chesham; Francis J. P. Ebling; Michael H. Hastings; Elizabeth S. Maywood

2007-01-01

80

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

PubMed Central

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

Carpenter, David O.

1967-01-01

81

Circadian rhythms in mouse suprachiasmatic nucleus explants on multimicroelectrode plates  

Microsoft Academic Search

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

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

1997-01-01

82

Pineal and hypothalamic pacemakers: Their role in regulating circadian rhythmicity in Japanese quail  

Microsoft Academic Search

Neither pinealectomy nor administration of melatoninvia silastic capsules had any effect on free-running circadian rhythms of locomotor activity in Japanese quail (Coturnix coturnix japonica). The quail, like the chicken, therefore differs from sparrows and starlings in which pinealectomy dramatically disrupts free-running rhythms. Nevertheless, it seems unlikely that there are fundamental differences in circadian organisation within the Class Aves. The effects

S. M. Simpson; B. K. Follett

1981-01-01

83

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

Microsoft Academic Search

Circadian oscillations in mammalian physiology and behavior are regulated by an endogenous biological clock. Here we show that loss of the PAS protein MOP3 (also known as BMAL1) in mice results in immediate and complete loss of circadian rhythmicity in constant darkness. Additionally, locomotor activity in light–dark (LD) cycles is impaired and activity levels are reduced in Mop3?\\/? mice. Analysis

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

2000-01-01

84

CENTRAL AND PERIPHERAL CIRCADIAN CLOCKS IN MAMMALS  

PubMed Central

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

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

2013-01-01

85

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

Microsoft Academic Search

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

Derk-Jan Dijk; Charles A. Czeisler

1995-01-01

86

Development and Control of the Circadian Pacemaker for Melatonin Release in the Chicken Pineal Gland  

Microsoft Academic Search

Melatonin (MT) release from explanted pineal glands of 3- to 20-week-old chicken was investigated in a 5-day perifusion system. Both the chicken and the explanted glands were exposed to various environmental lighting regimens. Observations: (1) The explanted chicken pineal is sensitive to direct light. Continuous illumination during thein vitroperiod abolishes the circadian rhythm of the MT secretion in 3 days.

Valér Csernus; Meenakshi Ghosh; Béla Mess

1998-01-01

87

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

Microsoft Academic Search

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

David J. Earnest; Vincent M. Cassone

2005-01-01

88

Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus  

Microsoft Academic Search

The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides

Samuel Bernard; Didier Gonze; Branka Cajavec; Hanspeter Herzel; Achim Kramer

2007-01-01

89

Mutations for activity level in Drosophila jambulina perturbed its pacemaker that controls circadian eclosion rhythm  

NASA Astrophysics Data System (ADS)

Mutations for activity level, designated hpa and hra, in Drosophila jambulina altered properties of the pacemaker controlling eclosion rhythm. Entrainment of eclosion rhythm was studied in light-dark (LD) cycles of 12:12 h at 28°C. The wild type strain entrained to LD cycles but the hpa or hra strain did not. When these strains were released from constant light (LL) to constant darkness (DD), the wild type strain free-ran while other two strains were arrhythmic. Temperature cycles entrained the wild type and hpa strain in DD and LL, and when transferred to constant temperature following thermoperiodic entrainment, the wild type strain free-ran in DD, while the hpa strain free-ran in LL as if the input of LL was essential for its free-running state. Temperature cycles entrained the hra strain in DD but not in LL, and free-running rhythmicities were never established, suggesting that the hra mutation has altered the basic properties of its pacemaker.

Joshi, Sunil; Hodgar, Raju; Kanojia, Manish; Chatale, Bal; Parihar, Viju; Joshi, Dilip

2002-01-01

90

Circadian Rhythms  

Microsoft Academic Search

1997 marks the 25th anniversary of the discovery of the master circadian pacemaker in mammals in the hypothalamic suprachiasmatic nucleus. Remarkable progress has been made over the last 25 years in elucidating the physiological mechanisms involved in the entrainment, generation and expression of circadian rhythms at the cellular and systems levels. The recent discovery and cloning of the first mammalian

Fred W. Turek

1998-01-01

91

Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker  

PubMed Central

Human motor control systems orchestrate complex scale-invariant patterns of activity over a wide range of time scales (minutes to hours). The neural mechanisms underlying scale-invariance are unknown in humans. In rats, the master circadian pacemaker [suprachiasmatic nucleus (SCN)] is crucially involved in scale-invariant activity fluctuations over multiple time scales from minutes to 24 h. Aging and Alzheimer's disease (AD) are associated with progressive dysfunction of the SCN. Thus, if the SCN is responsible for the scale-invariant activity fluctuations in humans, we predict disturbances of scale-invariant activity fluctuations in elderly humans and even more pronounced disturbances in elderly humans with AD. To test these hypotheses, we studied spontaneous daytime activity patterns in 13 young adults (mean ± SD: 25.5 ± 6.1 y); 13 elderly people with early-stage AD (68.5 ± 6.1 y) matched with 13 elderly controls (68.6 ± 6.1 y); and 14 very old people with late-stage AD (83.9 ± 6.7 y) matched with 12 very old controls (80.8 ± 8.6 y). In young adults, activity exhibited robust scale-invariant correlations across all tested time scales (minutes to 8 h). The scale-invariant correlations at 1.5–8 h declined with age (P = 0.01) and were significantly reduced in the elderly (P = 0.04) and very old controls (P = 0.02). Remarkably, an age-independent AD effect further reduced the scale-invariant correlations at 1.5–8 h (P = 0.04), leading to the greatest reduction of the scale-invariant correlations in very old people with late-stage AD—resembling closely the loss of correlations at large time scales in SCN-lesioned animals. Thus, aging and AD significantly attenuate the scale invariance of activity fluctuations over multiple time scales. This attenuation may reflect functional changes of the SCN.

Hu, Kun; Van Someren, Eus J. W.; Shea, Steven A.; Scheer, Frank A. J. L.

2009-01-01

92

Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase  

PubMed Central

To evaluate the contribution of neural pathways to the determination of the circadian oscillator phase in peripheral organs, we assessed lateralization of clock gene expression in Syrian hamsters induced to split rhythms of locomotor activity by exposure to constant light. We measured the ratio of haPer1, haPer2, and haBmal1 mRNA on the high vs. low (H/L) side at 3-h intervals prior to the predicted activity onset (pAO). We also calculated expression on the sides ipsilateral vs. contralateral (I/C) to the side of the suprachiasmatic nucleus (SCN) expressing higher haPer1. The extent of asymmetry in split hamsters varied between specific genes, phases, and organs. Although the magnitude of asymmetry in peripheral organs was never as great as that in the SCN, we observed significantly greater lateralization of clock gene expression in the adrenal medulla and cortex, lung, and skeletal muscle, but not in liver or kidney, of split hamsters than of unsplit controls. We observed fivefold lateralization of expression of the clock-controlled gene, albumin site D-element binding protein (Dbp), in skeletal muscle (H/L: 10.7 ± 3.7 at 3 h vs. 2.2 ± 0.3 at 0 h pAO; P = 0.03). Furthermore, tyrosine hydroxylase expression was asymmetrical in the adrenal medulla of split (H/L: 1.9 ± 0.5 at 0 h) vs. unsplit hamsters (1.2 ± 0.04; P < 0.05). Consistent with a model of neurally controlled gene expression, we found significant correlations between the phase angle between morning and evening components (?me) and the level of asymmetry (H/L or I/C). Our results indicate that neural pathways contribute to, but cannot completely account for, SCN regulation of the phase of peripheral oscillators.

Mahoney, Carrie E.; Brewer, Daniel; Costello, Mary K.; Brewer, Judy McKinley

2010-01-01

93

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

PubMed

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

Abe, Y; Ushirogawa, H; Tomioka, K

1997-10-01

94

Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2\\/3 metabotropic glutamate receptors  

Microsoft Academic Search

Glutamate released from retinal ganglion cells conveys information about the daily light:dark cycle to master circadian pacemaker neurons within the suprachiasmatic nucleus that then synchronize internal circadian rhythms with the external day-length. Glutamate activation of ionotropic glutamate receptors in the suprachiasmatic nucleus is well established, but the function of the metabotropic glutamate receptors that are also located in this nucleus

Robert L. Gannon; Mark J. Millan

2011-01-01

95

Afterhyperpolarization Regulates Firing Rate in Neurons of the Suprachiasmatic Nucleus  

Microsoft Academic Search

Cluster I neurons of the suprachiasmatic nucleus (SCN), which are thought to be pacemakers supporting circadian activity, fire sponta- neous action potentials that are followed by a monophasic afterhyperpolarization (AHP). Using a brain slice preparation, we have found that the AHP has a shorter duration in cells firing at higher frequency, consistent with circadian modulation of the AHP. The AHP

Robin K. Cloues; William A. Sather

96

Resetting of peripheral circadian clock by prostaglandin E2  

Microsoft Academic Search

In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is thought to drive peripheral oscillators by controlling neuronal and humoral signals that can entrain the peripheral clocks. Here, we show that prostaglandin E2 (PGE2), a proinflammatory compound known to have diverse biological effects, is able to act as an in vivo

Yoshiki Tsuchiya; Itsunari Minami; Hiroshi Kadotani; Eisuke Nishida

2005-01-01

97

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

PubMed Central

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

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

2008-01-01

98

Respiratory pattern generator model using Ca ++-induced Ca++ release in neurons shows both pacemaker and reciprocal network properties  

Microsoft Academic Search

There are two contradictory explanations for central respiratory rhythmogenesis. One suggests that respiratory rhythm emerges from interaction between inspiratory and expiratory neural semicenters that inhibit each other and thereby provide reciprocal rhythmic activity (Brown 1914). The other uses bursting pacemaker activity of individual neurons to produce the rhythm (Feldman and Cleland 1982). Hybrid models have been developed to reconcile these

Witali L. Dunin-barkowski; A. L. Escobar; Andrew T. Lovering; John M. Orem

2003-01-01

99

Innervation of Gonadotropin-Releasing Hormone Neurons by Peptidergic Neurons Conveying Circadian or Energy Balance Information in the Mouse  

PubMed Central

Background Secretion of gonadotropin-releasing hormone (GnRH) produced in neurons in the basal forebrain is the primary regulator of reproductive maturation and function in mammals. Peptidergic signals relating to circadian timing and energy balance are an important influence on the reproductive axis. The aim of this study was to investigate the innervation of GnRH neurons by peptidergic neurons. Methodology/Principal Findings Immunohistochemistry and confocal microscopy were used to detect appositions of peptidergic fibers (NPY, ?-endorphin, MCH) associated with energy balance and metabolic status in transgenic mice expressing a green fluorescent protein reporter construct in GnRH neurons. The frequency of these appositions was compared to those of vasoactive intestinal peptide (VIP), a hypothalamic neuropeptide likely to convey circadian timing information to the GnRH secretory system. The majority of GnRH neurons (73–87%) were closely apposed by fibers expressing NPY, ?-endorphin, or MCH, and a significant proportion of GnRH neurons (28%) also had close contacts with VIP-ir fibers. Conclusions/Significance It is concluded that GnRH neurons in the mouse receive a high frequency of direct modulatory inputs from multiple hypothalamic peptide systems known to be important in conveying circadian information and signalling energy balance.

Ward, Ian A.; Anderson, Susan I.; Spergel, Daniel J.; Smith, Paul A.; Ebling, Francis J. P.

2009-01-01

100

Roles of PER immunoreactive neurons in circadian rhythms and photoperiodism in the blow fly, Protophormia terraenovae.  

PubMed

Several hypothetical models suggest that the circadian clock system is involved in the photoperiodic clock mechanisms in insects. However, there is no evidence for this at a neuronal level. In the present study, whether circadian clock neurons were involved in photoperiodism was examined by surgical ablation of small area in the brain and by immunocytochemical analysis in the blow fly Protophormia terraenovae. Five types of PER-immunoreactive cells, dorsal lateral neurons (LN(d)), large ventral lateral neurons (l-LN(v)), small ventral lateral neurons (s-LN(v)), lateral dorsal neurons (DN(l)) and medial dorsal neurons (DN(m)) were found, corresponding to period-expressing neurons in Drosophila melanogaster. Four l-LN(v)s and four s-LN(v)s were bilaterally double-labelled with antisera against pigment-dispersing factor (PDF) and PER. When the anterior base of the medulla in the optic lobe, where PDF-immunoreactive somata (l-LN(v) and s-LN(v)) are located, was bilaterally ablated, 55% of flies showed arrhythmic or obscure activity patterns under constant darkness. Percentages of flies exhibiting a rhythmic activity pattern decreased along with the number of small PDF-immunoreactive somata (i.e. s-Ln(v)). When regions containing small PDF somata (s-LN(v)) were bilaterally ablated, flies did not discriminate photoperiod, and diapause incidences were 48% under long-day and 55% under short-day conditions. The results suggest that circadian clock neurons, s-LN(v)s, driving behavioural rhythms might also be involved in photoperiodism, and that circadian behavioural rhythms and photoperiodism share neural elements in their underlying mechanisms. PMID:19252004

Shiga, Sakiko; Numata, Hideharu

2009-03-01

101

Circadian Rhythm of Redox State Regulates Excitability in Suprachiasmatic Nucleus Neurons  

PubMed Central

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

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

2012-01-01

102

The Visual Input Stage of the Mammalian Circadian Pacemaking System: II. The Effect of Light and Drugs on Retinal Function  

Microsoft Academic Search

Acute light pulses as well as long-term light exposure may not only modulate photoreceptive properties, but also induce reversible or irreversible damage to the retina, depending on exposure conditions. Illuminance levels in laboratory animal colonies and manipulations of lighting regimens in circadian rhythm research can threaten retinal structure and physiology, and may therefore modify zeitgeber input to the central circadian

Michael Terman; Charlotte E. Remé; Anna Wirz-Justice

1991-01-01

103

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

SciTech Connect

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

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

1997-05-01

104

A Constant Light-Genetic Screen Identifies KISMET as a Regulator of Circadian Photoresponses  

PubMed Central

Circadian pacemakers are essential to synchronize animal physiology and behavior with the day?night 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 day?night cycle.

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

2009-01-01

105

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

Microsoft Academic Search

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

Marilyn J. Duncan

2007-01-01

106

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

PubMed Central

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

Ha, Joon; Kuznetsov, Alexey

2013-01-01

107

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

PubMed

A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in human neurodegenerative diseases--was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. ATX2 formed a complex with TYF and promoted its interaction with polyadenylate-binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing and reveals that this protein functions as an activator of PER translation in circadian neurons. PMID:23687048

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

2013-05-17

108

A Bonhoeffer-van der Pol oscillator model of locked and non-locked behaviors of living pacemaker neurons  

Microsoft Academic Search

A recent investigation of the influence of periodic inhibitory trains on a crayfish pacemaker neuron showed not only well-known locked periodic responses but also intermittent, messy, and hopping responses. This communication studies the responses of the Bonhoeffer-van der Pol (BVP) model with self-sustained oscillation when exposed to periodic pulse trains inputs. The analysis is similar to that used in crayfish

Taishin Nomura; Shunsuke Sato; Shinji Doi; José Pedro Segundo; Michael D. Stiber

1993-01-01

109

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

PubMed

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

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

2013-06-27

110

Circadian and other rhythmic activity of neurones in the ventromedial nuclei and lateral hypothalamic area.  

PubMed Central

1. The frequency of firing was simultaneously recorded from single neurones of the ventromedial nuclei (VMN) and the lateral hypothalamic area (LHA) in urethane anaesthetized rats for many hours. 2. There were circadian changes of VMN and LHA neurone activity. The pattern of this circadian rhythm is as follows: throughout the day LHA neurones show higher activity than that of VMN, as indicated by higher frequency and more fluctuations in their rates of firing. In late afternoon the discharge rate of LHA neurones increases further, showing oscillations of short duration. In the early evening hours LHA neurone activity gradually goes down, as the VMN neurones become active. Throughout the night, VMN neurones are more active than those of LHA, just the opposite of the day period. In early morning hours VMN neurones gradually become quiet, while LHA neurones begin to show activity. 3. Superimposed on the circadian rhythm, at certain periods of the day, VMN and LHA neurones showed short duration oscillations in rate of firing, roughly every 7-15 sec and every 3-5 min. 4. Activities in neurones of the VMN and LHA were reciprocally related; a decrease in firing rate of one was associated with an increase in the other. This phenomenon was shown clearly by analysis of auto- and cross-correlation functions of firing patterns of VMN and LHA neurones. 5. The effects of stimulations of the prefrontal cortex and splanchnic afferents on VMN and LHA neurones depended on the basic firing frequency, thus they varied with the time of day. Definite relationships exist between basic firing frequency of a cell and the magnitude of changes evoked by these stimuli. Reactions of VMN and LHA neurones were the opposite in most instances. Septal stimulations (at more than 10/sec) always produced inhibition of LHA neurone activity. 6. Intravenous injection of glucose inhibited LHA neurones and accelerated firing of VMN cells. This was true during the day period as well as at night when background activities of VMN and LHA neurones were different from that of the day. 7. Stimulation of the septal area with subthreshold pulses at a low rate (1-0.3/sec) suppressed or altered oscillations in firing frequency of LHA neurones. Severance of connection between LHA and structures caudal thereto had no effect on LHA neurone firing rates or rhythms. Sections between the septal area and LHA, however, abolished or greatly altered the oscillatory rhythms of LHA cell activity, although spontaneous discharges continued at a somewhat lower rate for periods of hours. 8. Stimulation of suprachiasmatic nuclei with weak intensity and low frequency also changed oscillatory fluctuations in firing of LHA neurones. 9. Possible origins of circadian rhythm and oscillations of short duration in firing pattern of VMN and LHA neurones were discussed.

Koizumi, K; Nishino, H

1976-01-01

111

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

Microsoft Academic Search

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

Thomas Reischig; Monika Stengl

2003-01-01

112

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

PubMed

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

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

2007-10-01

113

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

Microsoft Academic Search

Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a

Linus T.-Y. Tsai; Roland J. Bainton; Justin Blau; Ulrike Heberlein

2004-01-01

114

Ghrelin-immunopositive hypothalamic neurons tie the circadian clock and visual system to the lateral hypothalamic arousal center  

PubMed Central

Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system.

Horvath, Tamas L.; Abizaid, Alfonso; Dietrich, Marcelo O.; Li, Ying; Takahashi, Joseph S.; Bass, Joseph

2012-01-01

115

The Role of Kisspeptin and RFRP-3 Neurons in the Circadian-Timed Preovulatory Luteinizing Hormone Surge  

PubMed Central

Many aspects of female reproduction often require intricate timing, ranging from temporal regulation of reproductive hormone secretion to the precise timing of sexual behavior. In particular, in rodents and other species, ovulation is triggered by a surge in pituitary luteinizing hormone (LH) secretion that is governed by a complex interaction between circadian signals arising in the hypothalamus and ovarian-derived estradiol signals acting on multiple brain circuitries. These circadian and hormonal pathways converge to stimulate a precisely-timed surge in gonadotropin-releasing hormone (GnRH) release (i.e., positive feedback), thereby triggering the preovulatory LH surge. Reflecting its control by afferent circadian signals, the preovulatory LH surge occurs at a specific time of day, typically late afternoon in nocturnal rodents. Although the specific mechanisms mediating the hormonal and circadian regulation of GnRH/LH release have remained poorly understood, recent findings now suggest that estradiol and circadian signals govern specific reproductive neuropeptide circuits in the hypothalamus, including the newly-identified kisspeptin and RFamide-related peptide-3 (RFRP-3) neuronal populations. Neurons producing kisspeptin, the protein product of the Kiss1 gene, and RFRP-3 have been shown to provide excitatory and inhibitory input to GnRH neurons, respectively, and are also influenced by sex steroid and circadian signals. Here, we integrate classic and recent findings to form a new working model for the neuroendocrine regulation of the circadian-timed preovulatory LH surge in rodents. This model proposes kisspeptin and RFRP-3 neuronal populations as key nodal points for integrating and transducing circadian and hormonal signals to the reproductive axis, thereby governing the precisely-timed LH surge.

Khan, Azim R.; Kauffman, Alexander S.

2011-01-01

116

Circadian control of membrane excitability in Drosophila melanogaster lateral ventral clock neurons  

PubMed Central

Drosophila circadian rhythms are controlled by a neural circuit containing ?150 clock neurons. While much is known about mechanisms of autonomous cellular oscillation, the connection between cellular oscillation and functional outputs that control physiological and behavioral rhythms is poorly understood. To address this issue, we performed whole-cell patch-clamp recordings on lateral ventral clock neurons (LNvs), including large and small LNvs (lLNvs, sLNvs), in situ in adult fly whole-brain explants. We found two distinct sizes of action potentials (APs) in more than 50% of lLNvs that fire APs spontaneously, and determined that large APs originate in the ipsilateral optic lobe and small APs in the contralateral. lLNv resting membrane potential (RMP), spontaneous AP firing rate, and membrane resistance are cyclically regulated as a function of time-of-day in 12hr:12hr light:dark conditions (LD). lLNv RMP becomes more hyperpolarized as time progresses from dawn to dusk with a concomitant decrease in spontaneous AP firing rate and membrane resistance. From dusk to dawn, lLNv RMP becomes more depolarized, with spontaneous AP firing rate and membrane resistance remaining stable. In contrast, circadian defective per0 null mutant lLNv membrane excitability is nearly constant in LD. Over 24hr in constant darkness (DD), wild-type lLNv membrane excitability is not cyclically regulated, although RMP gradually becomes slightly more depolarized. sLNv RMP is most depolarized around lights-on, with substantial variability centered around lights-off in LD. Our results indicate that LNv membrane excitability encodes time-of-day via a circadian clock-dependent mechanism, and likely plays a critical role in regulating Drosophila circadian behavior.

Cao, Guan; Nitabach, Michael N.

2009-01-01

117

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

PubMed Central

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.

Picot, Marie; Cusumano, Paola; Klarsfeld, Andre; Ueda, Ryu; Rouyer, Francois

2007-01-01

118

PDF receptor expression reveals direct interactions between circadian oscillators in Drosophila.  

PubMed

Daily rhythms of behavior are controlled by a circuit of circadian pacemaking neurons. In Drosophila, 150 pacemakers participate in this network, and recent observations suggest that the network is divisible into M and E oscillators, which normally interact and synchronize. Sixteen oscillator neurons (the small and large lateral neurons [LNvs]) express a neuropeptide called pigment-dispersing factor (PDF) whose signaling is often equated with M oscillator output. Given the significance of PDF signaling to numerous aspects of behavioral and molecular rhythms, determining precisely where and how signaling via the PDF receptor (PDFR) occurs is now a central question in the field. Here we show that GAL4-mediated rescue of pdfr phenotypes using a UAS-PDFR transgene is insufficient to provide complete behavioral rescue. In contrast, we describe a approximately 70-kB PDF receptor (pdfr) transgene that does rescue the entire pdfr circadian behavioral phenotype. The transgene is widely but heterogeneously expressed among pacemakers, and also among a limited number of non-pacemakers. Our results support an important hypothesis: the small LNv cells directly target a subset of the other crucial pacemaker neurons cells. Furthermore, expression of the transgene confirms an autocrine feedback signaling by PDF back to PDF-expressing cells. Finally, the results present an unexpected PDF receptor site: the large LNv cells appear to target a population of non-neuronal cells that resides at the base of the eye. PMID:20394051

Im, Seol Hee; Taghert, Paul H

2010-06-01

119

The spike trains of inhibited pacemaker neurons seen through the magnifying glass of nonlinear analyses.  

PubMed

This communication describes the new information that may be obtained by applying nonlinear analytical techniques to neurobiological time-series. Specifically, we consider the sequence of interspike intervals Ti (the "timing") of trains recorded from synaptically inhibited crayfish pacemaker neurons. As reported earlier, different postsynaptic spike train forms (sets of timings with shared properties) are generated by varying the average rate and/or pattern (implying interval dispersions and sequences) of presynaptic spike trains. When the presynaptic train is Poisson (independent exponentially distributed intervals), the form is "Poisson-driven" (unperturbed and lengthened intervals succeed each other irregularly). When presynaptic trains are pacemaker (intervals practically equal), forms are either "p:q locked" (intervals repeat periodically), "intermittent" (mostly almost locked but disrupted irregularly), "phase walk throughs" (intermittencies with briefer regular portions), or "messy" (difficult to predict or describe succinctly). Messy trains are either "erratic" (some intervals natural and others lengthened irregularly) or "stammerings" (intervals are integral multiples of presynaptic intervals). The individual spike train forms were analysed using attractor reconstruction methods based on the lagged coordinates provided by successive intervals from the time-series Ti. Numerous models were evaluated in terms of their predictive performance by a trial-and-error procedure: the most successful model was taken as best reflecting the true nature of the system's attractor. Each form was characterized in terms of its dimensionality, nonlinearity and predictability. (1) The dimensionality of the underlying dynamical attractor was estimated by the minimum number of variables (coordinates Ti) required to model acceptably the system's dynamics, i.e. by the system's degrees of freedom. Each model tested was based on a different number of Ti; the smallest number whose predictions were judged successful provided the best integer approximation of the attractor's true dimension (not necessarily an integer). Dimensionalities from three to five provided acceptable fits. (2) The degree of nonlinearity was estimated by: (i) comparing the correlations between experimental results and data from linear and nonlinear models, and (ii) tuning model nonlinearity via a distance-weighting function and identifying the either local or global neighborhood size. Lockings were compatible with linear models and stammerings were marginal; nonlinear models were best for Poisson-driven, intermittent and erratic forms. (3) Finally, prediction accuracy was plotted against increasingly long sequences of intervals forecast: the accuracies for Poisson-driven, locked and stammering forms were invariant, revealing irregularities due to uncorrelated noise, but those of intermittent and messy erratic forms decayed rapidly, indicating an underlying deterministic process. The excellent reconstructions possible for messy erratic and for some intermittent forms are especially significant because of their relatively low dimensionality (around 4), high degree of nonlinearity and prediction decay with time. This is characteristic of chaotic systems, and provides evidence that nonlinear couplings between relatively few variables are the major source of the apparent complexity seen in these cases. This demonstration of different dimensions, degrees of nonlinearity and predictabilities provides rigorous support for the categorization of different synaptically driven discharge forms proposed earlier on the basis of more heuristic criteria. This has significant implications. (1) It demonstrates that heterogeneous postsynaptic forms can indeed be induced by manipulating a few presynaptic variables. (2) Each presynaptic timing induces a form with characteristic dimensionality, thus breaking up the preparation into subsystems such that the physical variables in each operate as one PMID:9759964

Segundo, J P; Sugihara, G; Dixon, P; Stiber, M; Bersier, L F

1998-12-01

120

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

PubMed Central

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

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

2011-01-01

121

Oscillatory Mechanisms Underlying the Drosophila Circadian Clock  

NSDL National Science Digital Library

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

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

2003-11-18

122

Silent plateau potentials, rhythmic bursts, and pacemaker firing: Three patterns of activity that coexist in quadristable subthalamic neurons  

PubMed Central

Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near –40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (–67 to –60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.

Kass, Jason I.; Mintz, Isabelle M.

2006-01-01

123

Genetics of Circadian Rhythms in Mammalian Model Organisms  

PubMed Central

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

Lowrey, Phillip L.; Takahashi, Joseph S.

2013-01-01

124

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

Microsoft Academic Search

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

Leo Sher

2004-01-01

125

Heart pacemaker - discharge  

MedlinePLUS

Cardiac pacemaker implantation - discharge; Artificial pacemaker - discharge; Permanent pacemaker - discharge; Internal pacemaker - discharge; Cardiac resynchronization therapy - discharge; CRT - discharge; Biventricular pacemaker - discharge

126

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

PubMed

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

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

2011-03-08

127

Neurobiology of food anticipatory circadian rhythms  

Microsoft Academic Search

Mistlberger, R.E. Neurobiology of food anticipatory circadian rhythms. Physiol Behav 00(00):000–000, 2011. 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.

Ralph E. Mistlberger

2011-01-01

128

The blue light photoreceptor CRYPTOCHROME is expressed in a subset of circadian oscillator neurons in the Drosophila CNS  

PubMed Central

In the fruit fly Drosophila melanogaster, CRYPTOCHROME (CRY) functions as a photoreceptor to entrain circadian oscillators to light-dark cycles and as a transcription factor to maintain circadian oscillator function in certain peripheral tissues. Given the importance of CRY to circadian clock function, we expected this protein to be expressed in all oscillator cells, yet CRY cellular distribution and subcellular localization has not been firmly established. Here we investigate CRY spatial expression in the brain using a newly developed CRY antibody and a novel set of cry deletion mutants. We find that CRY is expressed in s-LNvs, l-LNvs and a subset of LNds and DN1s, but not DN2s and DN3s. CRY is present in both the nucleus and cytoplasm of these neurons, and its subcellular localization does not change over the circadian cycle. Although CRY is absent in DN2s and DN3s, cry promoter activity and/or cry mRNA accumulation can be detected in these neurons, suggesting that CRY levels are regulated post-transcriptionally. Oscillators in DN2s and DN3s entrain to environmental light-dark cycles, which implies that they are entrained indirectly by retinal photoreceptors, extra-retinal photoreceptors or other CRY expressing cells.

Benito, Juliana; Houl, Jerry H.; Roman, Gregg W.; Hardin, Paul E.

2008-01-01

129

Solitary and gregarious locusts differ in circadian rhythmicity of a visual output neuron.  

PubMed

Locusts demonstrate remarkable phenotypic plasticity driven by changes in population density. This density dependent phase polyphenism is associated with many physiological, behavioral, and morphological changes, including observations that cryptic solitarious (solitary-reared) individuals start to fly at dusk, whereas gregarious (crowd-reared) individuals are day-active. We have recorded for 24-36 h, from an identified visual output neuron, the descending contralateral movement detector (DCMD) of Schistocerca gregaria in solitarious and gregarious animals. DCMD signals impending collision and participates in flight avoidance maneuvers. The strength of DCMD's response to looming stimuli, characterized by the number of evoked spikes and peak firing rate, varies approximately sinusoidally with a period close to 24 h under constant light in solitarious locusts. In gregarious individuals the 24-h pattern is more complex, being modified by secondary ultradian rhythms. DCMD's strongest responses occur around expected dusk in solitarious locusts but up to 6 h earlier in gregarious locusts, matching the times of day at which locusts of each type are most active. We thus demonstrate a neuronal correlate of a temporal shift in behavior that is observed in gregarious locusts. Our ability to alter the nature of a circadian rhythm by manipulating the rearing density of locusts under identical light-dark cycles may provide important tools to investigate further the mechanisms underlying diurnal rhythmicity. PMID:22653888

Gaten, Edward; Huston, Stephen J; Dowse, Harold B; Matheson, Tom

2012-06-01

130

Oscillatory Mechanisms Underlying the Murine Circadian Clock  

NSDL National Science Digital Library

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

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

2003-11-18

131

How coupling determines the entrainment of circadian clocks  

NASA Astrophysics Data System (ADS)

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

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

2011-08-01

132

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

PubMed Central

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

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

2011-01-01

133

Studies on bursting pacemaker potential activity in molluscan neurons. III. Effects of hormones.  

PubMed

Vertebrate peptides and hormones have been appled to a number of identified neurosecretory and ono-neurosecretory cells in two molluscan preparations. Active peptide hormones included vasopressin and analogues. Active steriod hormones included aldosterone and hydrocortisone. Peptide effects were present at 10-9 M concentration of peptide, were confined to two neurosecrotory cells and consisted of long lasting changes in the membrane properties of these cells (characterized either by the initiation or potentiation of bursting pacemaker potential activity in these cells). The regulatory changes in membrane properties induced by the peptides were unlike the transient conductance changes produced by conventional neurotransmitters. Steroid effects were observed at 10-6M concentration of steroid and consisted of an increase in membrane potential and conductance which was dependent on the species of divalent cations present. The net effect of peptide activation would be to increase the release of neurosecretory material form the cell terminals, while the net effect of the steroids would be to decrease the release of this material. The results obtained with these invertebrate preparations may serve to describe new forms of cellular communication in the nervous system whereby peptides and steroids modulate electrical activity. PMID:1122383

Barker, J L; Ifshin, M S; Gainer, N

1975-02-14

134

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

Microsoft Academic Search

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

Jens C. Rekling; Jack L. Feldman

1998-01-01

135

Circadian rhythm of temperature preference and its neural control in Drosophila  

PubMed Central

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.

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

2012-01-01

136

A single compartment model of pacemaking in dissasociated Substantia nigra neurons : Stability and energy analysis.  

PubMed

Spontaneous oscillations in the mid-brain dopaminergic neurons are an important feature of motor control. The degeneration of these neurons is involved in movement disorders, particularly Parkinson's Disease. Modelling of this activity is an important part of developing an understanding of the pathogenic process. We develop a mathematical paradigm to describe this activity with a single compartment approach and a CellML version is made publicly available. The model explicitly describes the dynamics of the transmembrane potential with changes in the levels of important cations and is consistent with two major observations in the literature regarding its behaviour in the presence of channel blockers. Stability of the model behaviour is determined from the properties of its Monodromy matrix. We also discuss from the perspective of energy, a pharmacological intervention suggested in the treatment of Parkinson's Disease. PMID:23686304

Francis, Febe; García, Míriam R; Middleton, Richard H

2013-05-19

137

A simple model for circadian timing by mammals.  

PubMed

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

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

2009-01-01

138

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

PubMed Central

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

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

2011-01-01

139

Endogenous Rhythms in Period1 Mutant Suprachiasmatic Nuclei In Vitro Do Not Represent Circadian Behavior  

PubMed Central

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1?/?) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1?/? mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1+/+) mice. While some neurons in Per1?/? SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1?/? SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1?/? SCN.

Pendergast, Julie S.; Friday, Rio C.; Yamazaki, Shin

2009-01-01

140

The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior.  

PubMed Central

DBP, a PAR leucine zipper transcription factor, accumulates according to a robust circadian rhythm in liver and several other tissues of mouse and rat. Here we report that DBP mRNA levels also oscillate strongly in the suprachiasmatic nucleus (SCN) of the hypothalamus, believed to harbor the central mammalian pacemaker. However, peak and minimum levels of DBP mRNA are reached about 4 h earlier in the SCN than in liver, suggesting that circadian DBP expression is controlled by different mechanisms in SCN and in peripheral tissues. Mice homozygous for a DBP-null allele display less locomotor activity and free-run with a shorter period than otherwise isogenic wild-type animals. The altered locomotor activity in DBP mutant mice and the highly rhythmic expression of the DBP gene in SCN neurons suggest that DBP is involved in controlling circadian behavior. However, since DBP-/- mice are still rhythmic and since DBP protein is not required for the circadian expression of its own gene, dbp is more likely to be a component of the circadian output pathway than a master gene of the clock.

Lopez-Molina, L; Conquet, F; Dubois-Dauphin, M; Schibler, U

1997-01-01

141

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

PubMed Central

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.

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

2008-01-01

142

Circadian clocks and cell division  

PubMed Central

Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription and translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO).

2010-01-01

143

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

PubMed

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. PMID:15277592

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

2004-08-01

144

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

Microsoft Academic Search

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

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

2006-01-01

145

Interactions between bilaterally paired components of the cockroach circadian system  

Microsoft Academic Search

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

Terry L. Page

1978-01-01

146

Circadian control of neuroendocrine circuits regulating female reproductive function.  

PubMed

Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge. PMID:22661968

Williams, Wilbur P; Kriegsfeld, Lance J

2012-05-21

147

Heart pacemaker  

MedlinePLUS

... of breath. Some, pacemakers can be used to stop a heart rate that is too fast ( tachycardia ) or that ... et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College ...

148

A Gq-Ca2+ axis controls circuit-level encoding of circadian time in the suprachiasmatic nucleus.  

PubMed

The role of intracellular transcriptional/post-translational feedback loops (TTFL) within the circadian pacemaker of the suprachiasmatic nucleus (SCN) is well established. In contrast, contributions from G-coupled pathways and cytosolic rhythms to the intercellular control of SCN pacemaking are poorly understood. We therefore combined viral transduction of SCN slices with fluorescence/bioluminescence imaging to visualize GCaMP3-reported circadian oscillations of intracellular calcium [Ca2+]i alongside activation of Ca2+ /cAMP-responsive elements. We phase-mapped them to the TTFL, in time and SCN space, and demonstrated their dependence upon G-coupled vasoactive intestinal peptide (VIP) signaling. Pharmacogenetic manipulation revealed the individual contributions of Gq, Gs, and Gi to cytosolic and TTFL circadian rhythms. Importantly, activation of Gq-dependent (but not Gs or Gi) pathways in a minority of neurons reprogrammed [Ca2+]i and TTFL rhythms across the entire SCN. This reprogramming was mediated by intrinsic VIPergic signaling, thus revealing a Gq/[Ca2+]i-VIP leitmotif and unanticipated plasticity within network encoding of SCN circadian time. PMID:23623697

Brancaccio, Marco; Maywood, Elizabeth S; Chesham, Johanna E; Loudon, Andrew S I; Hastings, Michael H

2013-04-25

149

A Gq-Ca2+ Axis Controls Circuit-Level Encoding of Circadian Time in the Suprachiasmatic Nucleus  

PubMed Central

Summary The role of intracellular transcriptional/post-translational feedback loops (TTFL) within the circadian pacemaker of the suprachiasmatic nucleus (SCN) is well established. In contrast, contributions from G-coupled pathways and cytosolic rhythms to the intercellular control of SCN pacemaking are poorly understood. We therefore combined viral transduction of SCN slices with fluorescence/bioluminescence imaging to visualize GCaMP3-reported circadian oscillations of intracellular calcium [Ca2+]i alongside activation of Ca2+/cAMP-responsive elements. We phase-mapped them to the TTFL, in time and SCN space, and demonstrated their dependence upon G-coupled vasoactive intestinal peptide (VIP) signaling. Pharmacogenetic manipulation revealed the individual contributions of Gq, Gs, and Gi to cytosolic and TTFL circadian rhythms. Importantly, activation of Gq-dependent (but not Gs or Gi) pathways in a minority of neurons reprogrammed [Ca2+]i and TTFL rhythms across the entire SCN. This reprogramming was mediated by intrinsic VIPergic signaling, thus revealing a Gq/[Ca2+]i-VIP leitmotif and unanticipated plasticity within network encoding of SCN circadian time.

Brancaccio, Marco; Maywood, Elizabeth S.; Chesham, Johanna E.; Loudon, Andrew S.I.; Hastings, Michael H.

2013-01-01

150

Quantitative Analyses of Circadian Gene Expression in Mammalian Cell Cultures  

Microsoft Academic Search

The central circadian pacemaker is located in the hypothalamus of mammals, but essentially the same oscillating system operates in peripheral tissues and even in immortalized cell lines. Using luciferase reporters that allow automated monitoring of circadian gene expression in mammalian fibroblasts, we report the collection and analysis of precise rhythmic data from these cells. We use these methods to analyze

Mariko Izumo; Takashi R. Sato; Martin Straume; Carl Hirschie Johnson

2006-01-01

151

Drosophila CRY Is a Deep Brain Circadian Photoreceptor  

Microsoft Academic Search

cry (cryptochrome) is an important clock gene, and recent data indicate that it encodes a critical circadian photoreceptor in Drosophila. A mutant allele, cryb, inhibits circadian photoresponses. Restricting CRY expression to specific fly tissues shows that CRY expression is needed in a cell-autonomous fashion for oscillators present in different locations. CRY overexpression in brain pacemaker cells increases behavioral photosensitivity, and

Patrick Emery; Ralf Stanewsky; Charlotte Helfrich-Förster; Myai Emery-Le; Jeffrey C. Hall; Michael Rosbash

2000-01-01

152

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

PubMed

We examined the effect of photoperiod on the expression of circadian clock genes period (per) and timeless (tim), using quantitative real-time polymerase chain reaction (PCR), and the effect of photoperiod on subcellular distribution of PERIOD (PER), using immunocytochemistry, in the blow fly, Protophormia terraenovae. Under both short-day and long-day conditions, the mRNA levels of per and tim in the brain oscillated, and their peaks and troughs occurred around lights-off and lights-on, respectively. The oscillations persisted even under constant darkness. In the large ventral lateral neurons (l-LN(v)s), small ventral lateral neurons (s-LN(v)s), dorsal lateral neurons (LN(d)s), and medial dorsal neurons (DN(m)s), the subcellular distribution of PER-immunoreactivity changed with time. The number of cells with PER-immunoreactivity in the nucleus was highest 12 h after lights-off and lowest 12 h after lights-on, regardless of photoperiod, suggesting that PER nuclear translocation entrains to photoperiod. When temporal changes in the nuclear localization of PER were compared, the neurons could be classified into 2 groups: the l-LN(v)s were similar to the s-LN(v)s, and the LN(d)s were similar to DN(m)s. In LN(d)s and DN(m)s, decreasing rates of the number of cells with PER immunoreactivity in the nucleus per brain from the maximum were large as compared with those in l-LN(v)s and s-LN(v)s under short-day conditions. These results suggest that photoperiodic information is reflected in the expression patterns of circadian clock genes per and tim and in the subcellular distribution of PER. This observation suggests that the 2 different groups of clock neurons respond to photoperiod in slightly different manners. PMID:20396905

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

2010-04-16

153

Resetting of peripheral circadian clock by prostaglandin E2.  

PubMed

In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is thought to drive peripheral oscillators by controlling neuronal and humoral signals that can entrain the peripheral clocks. Here, we show that prostaglandin E2 (PGE2), a proinflammatory compound known to have diverse biological effects, is able to act as an in vivo clock-resetting agent. We find that in cultured NIH3T3 fibroblasts, PGE2 is able to induce transient expression of Period 1 messenger RNA and the following circadian oscillation of clock gene expression. Furthermore, we demonstrate that intraperitoneal administration of PGE2 results in the phase shift of circadian gene expression in mouse peripheral tissues in a time-dependent manner. This phase shift is also induced by the EP1/EP3 agonist sulprostone but not by the EP2 agonist butaprost. The PGE2-induced phase shift is inhibited by the EP1 antagonist SC-51322. These results suggest that PGE2 acts as an in vivo clock-resetting factor by means of the EP1 subtype of PGE receptors. PMID:15723041

Tsuchiya, Yoshiki; Minami, Itsunari; Kadotani, Hiroshi; Nishida, Eisuke

2005-03-01

154

Glucocorticoids as entraining signals for peripheral circadian oscillators.  

PubMed

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

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

2012-08-14

155

Radioisotope Powered Cardiac Pacemakers  

Microsoft Academic Search

Over 50, 000 implantable cardiac pacemakers are in use to rehabilitate patients with heart block. The chemical batteries powering these pacemakers usually fail within a few years. A variety of nuclear batteries, with the potential of providing long-lived (10 - 20 years) pacemaker power, are under development. This paper reviews the status of this development. Nuclear-powered pacemakers have reached the

F. N. Huffman; J. J. Migliore; W. J. Robinson; J. C. Norman

1974-01-01

156

The Mammalian Circadian Timekeeping System  

Microsoft Academic Search

In most mammalian species, physiological processes undergo daily oscillations that are controlled by the circadian timekeeping\\u000a system. This system consists of a master pacemaker located in brain’s suprachiasmatic nucleus (SCN) and peripheral slave oscillators\\u000a in virtually all body cells. The SCN, whose phase is entrained by daily light-dark cycles, imposes overt rhythms in behaviour\\u000a and physiology by a variety of

U. Schibler

157

Mammalian circadian signaling networks and therapeutic targets  

Microsoft Academic Search

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

Andrew C Liu; Warren G Lewis; Steve A Kay

2007-01-01

158

Circadian modulation of sleep in rodents.  

PubMed

Sleep is regulated by circadian and homeostatic processes. The sleep homeostat keeps track of the duration of prior sleep and waking and determines the intensity of sleep. In mammals, the homeostatic process is reflected by the slow waves in the non-rapid eye movement (NREM) sleep electroencephalogram (EEG). The circadian process is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus and provides the sleep homeostat with a circadian framework. This review summarizes the changes in sleep obtained after different chronobiological interventions (changes in photoperiod, light availability, and running wheel availability), the influence of mutations or lesions in clock genes on sleep, and research on the interaction between sleep homeostasis and the circadian clock. Research in humans shows that the period of consolidated waking during the day is a consequence of the interaction between an increasing homeostatic sleep drive and a circadian signal, which promotes waking during the day and sleep during the night. In the rat, it was shown that, under constant homeostatic sleep pressure, with similar levels of slow waves in the NREM sleep EEG at all time points of the circadian cycle, still a small circadian modulation of the duration of waking and NREM sleep episodes was observed. Under similar conditions, humans show a clear circadian modulation in REM sleep, whereas in the rat, a circadian modulation in REM sleep was not present. Therefore, in the rat, the sleep homeostatic modulation in phase with the circadian clock seems to amplify the relatively weak circadian changes in sleep induced by the circadian clock. Knowledge about the interaction between sleep and the circadian clock and the circadian modulation of sleep in other species than humans is important to better understand the underlying regulatory mechanisms. PMID:22877667

Yasenkov, Roman; Deboer, Tom

2012-01-01

159

Presynaptic irregularity and pacemaker inhibition  

Microsoft Academic Search

It is known (e.g., Perkel et al., 1964) that when a pacemaker neuron elicits IPSP's in another, there are domains called “paradoxical segments” where in the steady-state i) faster inhibitory discharges determine faster inhibited ones, and ii) pre- and postsynaptic spikes are “locked” in an invariant forward-and-backward positioning in time, spikes alternating in the ratios 1:1 (1 pere for 1

A. F. Kohn; A. Freitas da Rocha; J. P. Segundo

1981-01-01

160

CHEMICAL PACEMAKERS  

PubMed Central

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

Hadidian, Zareh; Hoagland, Hudson

1939-01-01

161

Pacemakers and Implantable Defibrillators  

MedlinePLUS

... arrhythmia is serious, you may need a cardiac pacemaker or an implantable cardioverter defibrillator (ICD). They are ... are implanted in your chest or abdomen. A pacemaker helps control abnormal heart rhythms. It uses electrical ...

162

Pacemakers (Beyond the Basics)  

MedlinePLUS

... for permanent cardiac pacing Infections involving cardiac implantable electronic devices Modes of cardiac pacing: Nomenclature and selection ... PI PICTURES Pacemaker photo PI INTRODUCTION Pacemakers are electronic devices that stimulate the heart with electrical impulses ...

163

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

PubMed

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. PMID:11596048

Loesel, R; Homberg, U

2001-10-15

164

Neuronal Activity Is Required for the Circadian Rhythm of Vasopressin Gene Transcription in the Suprachiasmatic Nucleus in Vitro  

Microsoft Academic Search

Arginine vasopressin (AVP) is synthesized in and secreted by the suprachiasmatic nucleus (SCN) in a circadian pattern. Transcription of the AVP gene in organotypic cultures of rat SCN was studied by using an intronic in situ hybridization. AVP gene transcription in the cultured SCN maintained a daily rhythm with a peak in the daytime. Inhibition of spon- taneous activity by

HIROSHI ARIMA; SHIRLEY B. HOUSE; HAROLD GAINER; GRETI AGUILERA

2002-01-01

165

Scedosporium apiospermum pacemaker endocarditis  

Microsoft Academic Search

A patient developed a fungal pacemaker infection with Scedosporium apiospermum following a series of pacemaker manipulations. Despite percutaneous removal of the pacemaker system and subsequent operative extraction of the atrial thrombus, his course was complicated by persistent sepsis, pulmonary septic emboli and bilateral frontal lobe infarction, following which treatment was withdrawn.

Hong Foo; Sze-Yuan Ooi; Robert Giles; Philip Jones

2009-01-01

166

The Statistical Analysis of Circadian Phase and Amplitude in Constant-Routine Core-Temperature Data  

Microsoft Academic Search

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

Emery N. Brown; Charles A. Czeisler

1992-01-01

167

A variant affecting miRNAs binding in the circadian gene Neuronal PAS domain protein 2 (NPAS2) is not associated with breast cancer risk.  

PubMed

Disruption of the circadian rhythm has been reported to increase the risk of breast cancer. A single nucleotide polymorphism (SNP) rs2305160 in Neuronal PAS domain protein 2 (NPAS2), the largest circadian gene, was identified as a breast cancer susceptibility locus. In the current study, we found a novel functional SNP (rs3739008) located at 3'UTR of NPAS2 and the C to T changing of the SNP may disrupt the binding of microRNA- (miR-) 17-5p and miR-519e to the 3'UTR of NPAS2. We then typed this SNP in case-control studies of both Chinese and Germany populations to test its putative associations with breast cancer risk. However, we failed to find any significant associations by different genetic models (dominant genetic model, adjusted OR = 1.13, 95% CI = 0.95-1.35 for the Chinese population and adjusted OR = 0.99, 95% CI = 0.85-1.16 for the Germany population). Although we did not find significant associations at population levels from both Chinese and Germany case-control studies, due to the functional relevance of rs3739008 on NASP2 expression, it will be promising to investigate the influence of this variant on clinical characteristics of breast cancer and breast cancer survival. PMID:21140207

Wang, Furu; Hu, Zhibin; Yang, Rongxi; Tang, Jinhai; Liu, Yao; Hemminki, Kari; Sutter, Christian; Wappenschmidt, Barbara; Niederacher, Dieter; Arnold, Norbert; Meindl, Alfons; Bartram, Claus R; Schmutzler, Rita K; Burwinkel, Barbara; Shen, Hongbing

2010-12-08

168

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

Microsoft Academic Search

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

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

2007-01-01

169

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

PubMed

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

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

2013-01-24

170

Light and peptidergic eclosion hormone neurons stimulate a rapid eclosion response that masks circadian emergence in Drosophila  

PubMed Central

Summary Light signals can entrain circadian clocks, but they can also mask aspects of the circadian output. We have analyzed the masking effects of a lights-on (LOn) signal on Drosophila eclosion. The LOn response results in 12–21% of the flies that emerge on a given day eclosing within 10 min of the LOn signal. Flies that lack the neuropeptide eclosion hormone (EH), or in which its release is inhibited by the tetanus toxin light chain, lack the response. Optic photoreceptors in both the ocelli and the compound eyes appear to be required for the response. The LOn signal has two effects: (1) it drastically reduces the interval between EH release and eclosion, presumably by suppressing a transient descending inhibition that immediately follows EH release, and (2) it stimulates premature EH release. The LOn signal does not influence the latency of wing spreading, an EH-regulated post-ecdysis behavior.

McNabb, Susan L.; Truman, James W.

2009-01-01

171

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

PubMed

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

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

2011-02-23

172

Circadian light  

PubMed Central

The present paper reflects a work in progress toward a definition of circadian light, one that should be informed by the thoughtful, century-old evolution of our present definition of light as a stimulus for the human visual system. This work in progress is based upon the functional relationship between optical radiation and its effects on nocturnal melatonin suppression, in large part because the basic data are available in the literature. Discussed here are the fundamental differences between responses by the visual and circadian systems to optical radiation. Brief reviews of photometry, colorimetry, and brightness perception are presented as a foundation for the discussion of circadian light. Finally, circadian light (CLA) and circadian stimulus (CS) calculation procedures based on a published mathematical model of human circadian phototransduction are presented with an example.

2010-01-01

173

Effects of circadian disruption on cardiometabolic system  

PubMed Central

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

Ruger, Melanie; Scheer, Frank A.J.L.

2011-01-01

174

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

Microsoft Academic Search

BACKGROUND: The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between

Kazuhiro Yagita; Iori Yamanaka; Noriaki Emoto; Koichi Kawakami; Shoichi Shimada

2010-01-01

175

Distribution of Circadian Photoreceptors in the Compound Eye of the Cricket Gryllus bimaculatus  

Microsoft Academic Search

Adult male crickets (Gryllus bimaculatus) show a nocturnal circadian locomotor rhythm, which is driven by the pacemaker in the optic lamina-medulla complex and synchronizes to the light-dark (LD) cycle received by the compound eye. To see whether there was any specially differentiated circadian photoreceptor area in the eye, we examined the effect of a partial reduction of various areas of

Kenji Tomioka; Yasuo Okada; Yoshihiko Chiba

1990-01-01

176

Influence of 50 Hz magnetic fields on circadian rhythm of the suprachiasmatic nucleus activity  

Microsoft Academic Search

Extremely low frequency (ELF) magnetic fields (MF), such as 50 Hz or 60 Hz magnetic fields, have been shown to suppress the nocturnal production of pineal melatonin. The amount of melatonin produced in the pineal gland changes according to the circadian rhythm. The suprachiasmatic nuclei (SCN) of anterior hypothalamus are supposed to be the site of a master circadian pacemaker

O. Hiwaki

1998-01-01

177

The circadian rhythm and photosensitivity of small impulses of the Bulla eye  

Microsoft Academic Search

The eye of the mollusk Bulla gouldiana contains a pacemaker that generates a circadian rhythm in compound action potentials (CAPs) in the optic nerve. In this paper, we present evidence of a second circadian rhythm in the optic nerve of the eye maintained in darkness at 15 °C. This is a rhythm in the frequency of small (10–40 µV) neural

Michael E. Geusz; Terry L. Page

1990-01-01

178

Cannabinoids and hamster circadian activity rhythms.  

PubMed

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

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

2008-05-28

179

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

PubMed

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

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

2013-08-28

180

Influence of Valinomycin on Circadian Leaf Movements of Phaseolus  

PubMed Central

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

Bunning, E.; Moser, I.

1972-01-01

181

Central control of peripheral circadian oscillators.  

PubMed

The suprachiasmatic nucleus of the hypothalamus and at least two other unidentified central pacemakers regulate the temporal structure of a circadian network that involves almost every organ in the body. Phase control is central to the efficient function of this system. Individual circadian oscillators in tissues and organs in the periphery bear adaptive phase relationships to the external light cycle, the central pacemakers and to each other. The known signals that regulate and maintain these phase relationships come from the autonomic nervous system, the pineal and adrenal glands, behavioral cycles of feeding and activity and the rhythm of body temperature. It is likely that there are many unknown signals as well. Disrupting the network can produce severe pathology. PMID:23537900

Menaker, Michael; Murphy, Zachary C; Sellix, Michael T

2013-03-26

182

The Role of Extracellular Calcium in Generating and in Phase-Shifting the Bulla Ocular Circadian Rhythm  

Microsoft Academic Search

Since extracellular calcium is known to be involved in the entrainment of the circadian pacemaker in the retina of Bulla gouldiana, we have assessed the requirement for extracellular calcium in the generation of the circadian rhythm. To enable us to assay the state of the pacemaker during low-calcium treatment, which often obscures rhythmicity, long-duration pulses of low-calcium artificial seawater (no

Sat Bir S. Khalsa; Martin R. Ralph; Gene D. Block

1993-01-01

183

[Molecular mechanisms of circadian clock functioning].  

PubMed

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

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

184

Hypothalamic neurosecretory and circadian vasopressinergic neuronal systems in the blind cone-rod homeobox knockout mouse (crx(-/-) ) and the 129sv wild-type mouse.  

PubMed

Vasopressin (AVP) is both a neuroendocrine hormone located in magnocellular neurosecretory neurons of the hypothalamus of mammals but also a neurotransmitter/neuromodulator in the parvocellular suprachiasmatic nucleus (SCN). The SCN is the endogenous clock of the brain and exhibits a prominent circadian AVP rhythm. We have in this study of the brown 129sv mouse and the visual blind cone-rod homeobox gene knock out mouse (Crx(-/-) ) with degeneration of the retinal rods and cones, but a preserved non-image forming optic system, studied the temporal Avp expression in both the neurosecretory magnocellular and parvocellular vasopressinergic systems in both genotypes. We here present a detailed mapping of all classical hypothalamopituitary and accessory magnocellular nuclei and neurons in the hypothalamus by use of immunohistochemistry and in situ hybridization in both genotypes. Semiquantitative in situ hybridization revealed a very high expression of Avp mRNA in all the magnocellular nuclei compared with a much lower level in the parvocellular suprachiasmatic nucleus. In a series of mice killed every 4 hours, the Avp mRNA expression in the SCN showed a significant daily rhythm with a zenith at late day time and nadir during the dark in both the Crx(-/-) and the wild type mouse. None of the magnocellular neurosecretory neurons exhibited a diurnal vasopressin expression. Light stimulation of both genotypes during the dark period did not change the Avp expression in the SCN. This shows that Avp expression in the mouse SCN is independent of Crx-regulated photoreceptor systems. J. Comp. Neurol. 521:4061-4074, 2013. © 2013 Wiley Periodicals, Inc. PMID:23784879

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

2013-12-01

185

Implementation of pigment-dispersing factor-immunoreactive neurons in a standardized atlas of the brain of the cockroach Leucophaea maderae.  

PubMed

The cockroach Leucophaea maderae is an established model in circadian rhythm research. Its circadian clock is located in the accessory medulla of the brain. Pigment-dispersing factor-immunoreactive (PDF-ir) neurons of the accessory medulla act as circadian pacemakers controlling locomotor activity rhythms. To characterize the neuronal network of the circadian system in L. maderae, the PDF-ir neurons were implemented into a standardized three-dimensional atlas of the cockroach brain. Serial confocal images from 20 wholemount brains were used for the construction of the atlas comprising 21 neuropils. Two different standardization protocols were employed: the iterative shape averaging (ISA) procedure using an affine transformation followed by iterative non-rigid registrations, and the virtual insect brain (VIB) protocol employing local non-rigid transformations after global and local rigid transformations. Quantitative analysis of the 20 brains revealed that volumes of the accessory medulla are directly correlated with the volumes of the medulla, the protocerebral bridge, and the upper division of the central body, suggesting functional connections among these neuropils. For a standardized reconstruction of the circadian pacemaker network, the ISA protocol was used to register PDF-ir neurons in the standard cockroach brain. The registration revealed that two PDF-ir arborization areas in the brain are highly interconnected with other PDF-ir projection sites and appear to be contacted both by fibers in the posterior and the anterior optic commissures. The distances between PDF-ir branching areas show specific numerical relationships that might be physiologically relevant for temporal encoding. PMID:20878779

Wei, Hongying; el Jundi, Basil; Homberg, Uwe; Stengl, Monika

2010-10-15

186

A migrating pacemaker  

PubMed Central

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.

Gale, C; Mulley, G

2005-01-01

187

Bradycardia and Permanent Pacemakers  

Microsoft Academic Search

The investigation and management of bradycardia is an increasingly complex topic, but with the development of pacemakers there are few areas of medicine that offer such substantial improvements in patients' quality of life. About 400,000 pacemakers are implanted worldwide per year; about 270 are implanted per million population in the UK, 370 per million in Europe as a whole and

Vince Paul

2002-01-01

188

A migrating pacemaker.  

PubMed

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. PMID:15749800

Gale, C P; Mulley, G P

2005-03-01

189

Neurophysiological Analysis of Circadian Rhythm Entrainment.  

National Technical Information Service (NTIS)

This program of research identified a number of novel roles for peptides and neurotransmitters found in the suprachiasmatic nuclei (SCN), in the regulation of SCN neuronal activity and behavioral circadian rhythms. Major findings included the observations...

B. Rusak

1996-01-01

190

Circadian control of the sleep–wake cycle  

Microsoft Academic Search

It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling across time zones, they experience the stubborn influence

Domien G. M. Beersma; Marijke C. M. Gordijn

2007-01-01

191

AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation  

Microsoft Academic Search

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

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

2009-01-01

192

Neurons and networks in daily rhythms  

Microsoft Academic Search

Biological pacemakers dictate our daily schedules in physiology and behaviour. The molecules, cells and networks that underlie these circadian rhythms can now be monitored using long-term cellular imaging and electrophysiological tools, and initial studies have already suggested a theme — circadian clocks may be crucial for widespread changes in brain activity and plasticity. These daily changes can modify the amount

Erik D. Herzog

2007-01-01

193

The Circadian Clock System in the Mammalian Retina  

PubMed Central

Daily rhythms are a ubiquitous feature of living systems. Generally, these rhythms are not just passive consequences of cyclic fluctuations in the environment, but instead originate within the organism. In mammals, including humans, the master pacemaker controlling 24-hour rhythms is localized in the suprachiasmatic nuclei of the hypothalamus. This circadian clock is responsible for the temporal organization of a wide variety of functions, ranging from sleep and food intake, to physiological measures such as body temperature, heart rate and hormone release. The retinal circadian clock was the first extra-SCN circadian oscillator to be discovered in mammals and several studies have now demonstrated that many of the physiological, cellular, and molecular rhythms that are present within the retina are under the control of a retinal circadian clock, or more likely a network of hierarchically organized circadian clocks that are present within this tissue.

Tosini, Gianluca; Pozdeyev, Nikita; Sakamoto, Katsuhiko; Iuvone, P. Michael

2008-01-01

194

A circadian clock nanomachine that runs without transcription or translation.  

PubMed

The biochemical basis of circadian timekeeping is best characterized in cyanobacteria. The structures of its key molecular players, KaiA, KaiB, and KaiC are known and these proteins can reconstitute a remarkable circadian oscillation in a test tube. KaiC is rhythmically phosphorylated and its phospho-status is a marker of circadian phase that regulates ATPase activity and the oscillating assembly of a nanomachine. Analyses of the nanomachines have revealed how their timing circuit is ratcheted to be unidirectional and how they stay in synch to ensure a robust oscillator. These insights are likely to elucidate circadian timekeeping in higher organisms, including how transcription and translation could appear to be a core circadian timer when the true pacemaker is an embedded biochemical oscillator. PMID:23571120

Egli, Martin; Johnson, Carl Hirschie

2013-04-06

195

Circadian and Homeostatic Control of Rapid Eye Movement (REM) Sleep: Promotion of REM Tendency by the Suprachiasmatic Nucleus  

Microsoft Academic Search

The daily timing of rapid eye movement (REM) sleep reflects an interaction between the circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) and a homeostatic process that induces compensatory REM sleep in response to REM sleep loss. Whether the circadian variation in REM sleep propensity is caused by active promotion, inhibition, or passive gating of REM sleep

Sarah W. Wurts; Dale M. Edgar

2000-01-01

196

Let there be “more” light: enhancement of light actions on the circadian system through non-photic pathways  

Microsoft Academic Search

Circadian rhythms are internally generated circa 24h rhythms. The phase of the circadian pacemaker in mammals can be adjusted by external stimuli such as the daily cycle of light, as well as by internal stimuli such as information related to the physiological and behavioral status of the organism, collectively called “non-photic stimuli”. We review a large number of studies regarding

P. Yannielli; M. E. Harrington

2004-01-01

197

Circadian modulation of interval timing in mice.  

PubMed

Temporal perception is fundamental to environmental adaptation in humans and other animals. To deal with timing and time perception, organisms have developed multiple systems that are active over a broad range of order of magnitude, the most important being circadian timing, interval timing and millisecond timing. The circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is driven by a self-sustaining oscillator with a period close to 24h. Time estimation in the second-to-minutes range--known as interval timing--involves the interaction of the basal ganglia and the prefrontal cortex. In this work we tested the hypothesis that interval timing in mice is sensitive to circadian modulations. Animals were trained following the peak-interval (PI) procedure. Results show significant differences in the estimation of 24-second intervals at different times of day, with a higher accuracy in the group trained at night, which were maintained under constant dark (DD) conditions. Interval timing was also studied in animals under constant light (LL) conditions, which abolish circadian rhythmicity. Mice under LL conditions were unable to acquire temporal control in the peak interval procedure. Moreover, short time estimation in animals subjected to circadian desynchronizations (modeling jet lag-like situations) was also affected. Taken together, our results indicate that short-time estimation is modulated by the circadian clock. PMID:21078306

Agostino, Patricia V; do Nascimento, Micaela; Bussi, Ivana L; Eguía, Manuel C; Golombek, Diego A

2010-11-12

198

Electrode for Artificial Pacemaker.  

National Technical Information Service (NTIS)

The patent discloses an electrode for implantation in the heart to control atrio-ventricular block by artificial pacemaker including plural electrically conductive wires grouped in a bundle with spring metal arcuate prongs formed on one end thereof. A she...

G. M. Thomas J. W. Boretos D. C. Syracuse J. A. Clark A. J. Vita

1977-01-01

199

Pacemaker lead endocarditis  

PubMed Central

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

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

2003-01-01

200

The “Funny” Pacemaker Current  

Microsoft Academic Search

\\u000a Cellular and molecular mechanisms underlying cardiac pacemaking have long been the object of intense investigation, and several\\u000a issues concerning the exact role of individual processes involved in this important function are still not fully resolved.\\u000a Since its original discovery over 30 years ago, the “funny” (I\\u000a f) current of cardiac pacemaker cells has been the focus of a keen interest

Andrea Barbuti; Annalisa Bucchi; Raffaella Milanesi; Georgia Bottelli; Alessia Crespi; Dario DiFrancesco

201

Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression  

Microsoft Academic Search

Background: Circadian rhythm disturbances are fre- quently found in depressed subjects. Although it has been presumed that these disturbances may reflect a disorder of the circadian pacemaker, this has never been estab- lished. The suprachiasmatic nucleus (SCN) is the pace- maker of the circadian timing system in mammals, and arginine vasopressin (AVP) is one of its major neuro- peptides. As

Jiang-Ning Zhou; Rixt F. Riemersma; Unga A. Unmehopa; Witte J. G. Hoogendijk; Joop J. van Heerikhuize; Michel A. Hofman; Dick F. Swaab

2001-01-01

202

Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms  

PubMed Central

Three mammalian Period (Per) genes, termed Per1, Per2, and Per3, have been identified as structural homologues of the Drosophila circadian clock gene, period (per). The three Per genes are rhythmically expressed in the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. The phases of peak mRNA levels for the three Per genes in the SCN are slightly different. Light sequentially induces the transcripts of Per1 and Per2 but not of Per3 in mice. These data and others suggest that each Per gene has a different but partially redundant function in mammals. To elucidate the function of Per1 in the circadian system in vivo, we generated two transgenic rat lines in which the mouse Per1 (mPer1) transcript was constitutively expressed under the control of either the human elongation factor-1? (EF-1?) or the rat neuron-specific enolase (NSE) promoter. The transgenic rats exhibited an ?0.6–1.0-h longer circadian period than their wild-type siblings in both activity and body temperature rhythms. Entrainment in response to light cycles was dramatically impaired in the transgenic rats. Molecular analysis revealed that the amplitudes of oscillation in the rat Per1 (rPer1) and rat Per2 (rPer2) mRNAs were significantly attenuated in the SCN and eyes of the transgenic rats. These results indicate that either the level of Per1, which is raised by overexpression, or its rhythmic expression, which is damped or abolished in over expressing animals, is critical for normal entrainment of behavior and molecular oscillation of other clock genes.

Numano, Rika; Yamazaki, Shin; Umeda, Nanae; Samura, Tomonori; Sujino, Mitsugu; Takahashi, Ri-ichi; Ueda, Masatsugu; Mori, Akiko; Yamada, Kazunori; Sakaki, Yoshiyuki; Inouye, Shin-Ichi T.; Menaker, Michael; Tei, Hajime

2006-01-01

203

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

SciTech Connect

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.

Woolum, J.C.; Strumwasser, F.

1980-09-01

204

Role of melatonin in the regulation of human circadian rhythms and sleep.  

PubMed

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders. PMID:12622846

Cajochen, C; Kräuchi, K; Wirz-Justice, A

2003-04-01

205

Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2/3 metabotropic glutamate receptors.  

PubMed

Glutamate released from retinal ganglion cells conveys information about the daily light:dark cycle to master circadian pacemaker neurons within the suprachiasmatic nucleus that then synchronize internal circadian rhythms with the external day-length. Glutamate activation of ionotropic glutamate receptors in the suprachiasmatic nucleus is well established, but the function of the metabotropic glutamate receptors that are also located in this nucleus is not known. Therefore, in this study we evaluated agonists and antagonists acting at orthosteric or allosteric sites for mGluR5 and mGluR2/3 metabotropic glutamate receptors for their ability to modulate light-induced phase advances and delays of hamster circadian activity rhythms. mGluR5 allosteric antagonists fenobam, MPEP and MTEP, each 10 mg/kg, potentiated light-induced phase advances of hamster circadian activity rhythms, while the mGluR5 agonists CHPG, (S)-3,5-DHPG or positive allosteric modulator CDPPB had no effect. Neither mGluR5 agonists nor antagonists had any effect on light-induced phase delays of activity rhythms. The competitive mGluR2/3 antagonist LY341495, 10 mg/kg, also potentiated light-induced phase advances, but inhibited light-induced phase delays. The mGluR2/3 agonists LY354740 and LY404039 were without effect on phase advances while a third agonist LY379268, 10 mg/kg, inhibited both light-induced advances and delays. Finally, mGluR2/3 agonists LY379268 and LY404039 also inhibited light-induced phase delays of activity rhythms. These results suggest that during light-induced phase advances, mGluR2/3 and mGluR5 receptors act to negatively modulate the effects of light on the circadian pacemaker or its output(s). mGluR5 receptors do not appear to be involved during light-induced phase delays. In contrast, the role for mGluR2/3 receptors during phase delays is more complicated as both agonists and antagonists inhibit light-induced phase delays. Dysfunctions in human circadian rhythms have been implicated in some forms of depression, and metabotropic glutamate receptor ligands, which are also being evaluated for antidepressant activity, are shown here to be capable of modifying light-induced phase shifts of circadian activity rhythms. PMID:20831878

Gannon, Robert L; Millan, Mark J

2010-09-08

206

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

PubMed Central

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

Hafner, Marc; Koeppl, Heinz; Gonze, Didier

2012-01-01

207

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

PubMed

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

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

2007-08-08

208

Radiation effect on implanted pacemakers  

SciTech Connect

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.

Pourhamidi, A.H.

1983-10-01

209

[Defecation syncope following pacemaker implantation].  

PubMed

A case of syncope is reported, where hemodynamic responses compatible with pacemaker syndrome occurred during defecation. A 73 year old female received a VVI pacemaker for complete heart block. Subsequently she sustained repeated episodes of defecation syncope. Hemodynamic investigations revealed an abnormal blood pressure drop occurring at the overshoot phase of the Valsalva maneuver in association with alternation of sinus and pacemaker rhythm. This modified Valsalva response in the presence of contributing factors, such as hypovolemia and nitroglycerin therapy manifested as defecation syncope. The abnormal condition was treated by eliminating the contributing factors, and by programming a low pacemaker frequency, thus precluding sinus-pacemaker alterations. PMID:9064621

Rudas, L; Kardos, A; Halmai, L; Török, T; Pap, I; Hegedüs, Z

1997-01-12

210

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

Microsoft Academic Search

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

Jakob Wolfart; Henrike Neuhoff; Oliver Franz; Jochen Roeper

2001-01-01

211

Circadian desynchronization.  

PubMed

The suprachiasmatic nucleus (SCN) coordinates via multiple outputs physiological and behavioural circadian rhythms. The SCN is composed of a heterogeneous network of coupled oscillators that entrain to the daily light-dark cycles. Outside the physiological entrainment range, rich locomotor patterns of desynchronized rhythms are observed. Previous studies interpreted these results as the output of different SCN neural subpopulations. We find, however, that even a single periodically driven oscillator can induce such complex desynchronized locomotor patterns. Using signal analysis, we show how the observed patterns can be consistently clustered into two generic oscillatory interaction groups: modulation and superposition. In seven of 17 rats undergoing forced desynchronization, we find a theoretically predicted third spectral component. Combining signal analysis with the theory of coupled oscillators, we provide a framework for the study of circadian desynchronization. PMID:22419981

Granada, Adrián E; Cambras, Trinitat; Díez-Noguera, Antoni; Herzel, Hanspeter

2010-11-17

212

Circadian desynchronization  

PubMed Central

The suprachiasmatic nucleus (SCN) coordinates via multiple outputs physiological and behavioural circadian rhythms. The SCN is composed of a heterogeneous network of coupled oscillators that entrain to the daily light–dark cycles. Outside the physiological entrainment range, rich locomotor patterns of desynchronized rhythms are observed. Previous studies interpreted these results as the output of different SCN neural subpopulations. We find, however, that even a single periodically driven oscillator can induce such complex desynchronized locomotor patterns. Using signal analysis, we show how the observed patterns can be consistently clustered into two generic oscillatory interaction groups: modulation and superposition. In seven of 17 rats undergoing forced desynchronization, we find a theoretically predicted third spectral component. Combining signal analysis with the theory of coupled oscillators, we provide a framework for the study of circadian desynchronization.

Granada, Adrian E.; Cambras, Trinitat; Diez-Noguera, Antoni; Herzel, Hanspeter

2011-01-01

213

Reuse of permanent cardiac pacemakers.  

PubMed Central

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

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

1985-01-01

214

[Functional relationship between circadian rhythm and control of food intake].  

PubMed

Living things on the earth including bacteria, plants and animals show circadian rhythms in their behaviors and physiological phenomena, and these circadian rhythms are usually synchronized with environmental changes having the period of 24 h on the earth. In mammals including human beings, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, and generates a circadian rhythm of food intake. Sometimes the circadian oscillation of the SCN is disturbed with physical and psychological stressors. This review describes the functional relationship in respect to connections between the circadian oscillator in the SCN and food regulatory centers and neurons in the brain focusing on its mechanism in human beings, and a possible involvement of the circadian oscillator of the SCN in the abnormality of the appetite control. PMID:11268586

Nagai, K

2001-03-01

215

Pacemaker infective endocarditis  

Microsoft Academic Search

We identified 33 patients with definite pacemaker endocarditis—that is, with direct evidence of infective endocarditis, based on surgery or autopsy histologic findings of or bacteriologic findings (Gram stain or culture) of valvular vegetation or electrode-tip wire vegetation. Most of the patients (75%) were ?60 years of age (mean 66 ± 3; range 21 to 86). Pouch hematoma or inflammation was

Patrice Cacoub; Pascal Leprince; Patrick Nataf; Pierre Hausfater; Richard Dorent; Bertrand Wechsler; Valéria Bors; Alain Pavie; Jean Charles Piette; Iradj Gandjbakhch

1998-01-01

216

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

Microsoft Academic Search

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

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

2004-01-01

217

Circadian Timekeeping in BALB\\/c and C57BL\\/6 Inbred Mouse Strains  

Microsoft Academic Search

Circadian rhythms of locomotion (wheel-running activity) in 12 inbred mouse strains were recorded for interstrain dif- ferences in 7DD, the endogenous (free-running) period of the circadian pacemaker measured in constant environmental darkness. The results indicate that 1 or more genetic loci influence the value of Tag, and a large (50 min) difference in mean rDD between 2 of the strains,

William J. Schwartz; Pamela Zimmerman

1990-01-01

218

An Abrupt Shift in the Day\\/Night Cycle Causes Desynchrony in the Mammalian Circadian Center  

Microsoft Academic Search

The suprachiasmatic nucleus (SCN) is the neuroanatomical locus of the mammalian circadian pacemaker. Here we demonstrate that an abrupt shift in the light\\/dark (LD) cycle disrupts the synchronous oscillation of circadian components in the rat SCN. The phases of the RNA cycles of the period genes Per1 and Per2 and the cryptochrome gene Cry1 shifted rapidly in the ventrolateral, photoreceptive

Mamoru Nagano; Akihito Adachi; Ken-ichi Nakahama; Toru Nakamura; Masako Tamada; Elizabeth Meyer-Bernstein; Amita Sehgal; Yasufumi Shigeyoshi

2003-01-01

219

The corticotropin-releasing factor (CRF)(1) receptor antagonists CP154,526 and DMP695 inhibit light-induced phase advances of hamster circadian activity rhythms.  

PubMed

The circadian activity of corticotropin releasing factor (CRF) and the hypothalamic-pituitary-adrenal axis is controlled by the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus. However, the reciprocal influence of CRF and the hypothalamic-pituitary-adrenal axis upon the circadian pacemaker is less well established. Therefore, in the present study, we tested two nonpeptidergic antagonists at CRF(1) receptors for their ability to modulate photic resetting of pacemaker time (phase). CP154,526 dose dependently and significantly inhibited light-induced phase advances in hamster circadian activity rhythms late in the subjective night by approximately 60% at a maximally effective dose of 20 mg/kg delivered intraperitoneally. Likewise, a further CRF(1) receptor antagonist, DMP695, inhibited phase advances by approximately 40% at a dose of 10 mg/kg. The attenuation of phase shifts by CP154,526 was specific to phase advances as light-induced phase delays of the circadian pacemaker achieved early in the subjective night were not affected by CP154,526 (20 mg/kg). We also tested one of the CRF(1) receptor antagonists for its potential ability to reset the pacemaker in the absence of light and found that CP154,526 did not elicit a nonphotic phase shifts in circadian activity rhythms at circadian times (CT) 2, 8, 14, 18, or 22. In conclusion, CRF(1) receptor antagonists selectively modulate the effect of light on the circadian pacemaker late at night. These novel data emphasize the suspected critical link between CRF and the hypothalamic-pituitary-adrenal axis, on the one hand, and stress (including stress caused by jet-lag) and depression on the other. These results also suggest that CRF(1) antagonists may not only improve affect but also counter the circadian disruption associated with depression and other stress-related disorders. PMID:16551464

Gannon, Robert L; Millan, Mark J

2006-03-21

220

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

NASA Astrophysics Data System (ADS)

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

Ivanov, Plamen Ch.

2005-03-01

221

The circadian system of crayfish: a developmental approach.  

PubMed

Adult crayfish exhibit a variety of overt circadian rhythms. However, the physiological mechanisms underlying the overt rhythms are controversial. Research has centered on two overt rhythms: the motor activity and the retinal sensitivity rhythms of the genus Procambarus. The present work reviews various studies undertaken to localize pacemakers and mechanisms of entrainment responsible for these two rhythms in adult organisms of this crustacean decapod. It also describes an ontogenetic approach to the problem by means of behavioral, electrophysiological, and neurochemical experiments. The results of this approach confirm previous models proposed for adult crayfish, based on a number of circadian pacemakers distributed in the central nervous system. However, the coupling of rhythmicity between these independent oscillators might be complex and dependent on the interaction between serotonin (5-HT), light, and the crustacean hyperglycemic hormone (CHH). The latter compound has, up until now, not been considered as an agent in the genesis and synchronization of the retinal sensitivity rhythm. PMID:12539159

Fanjul-Moles, María Luisa; Prieto-Sagredo, Julio

2003-02-15

222

Circadian Regulation of Cortisol Release in Behaviorally Split Golden Hamsters  

PubMed Central

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 approximately12 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 approximately12 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.

Lilley, Travis R.; Wotus, Cheryl; Taylor, Daniel; Lee, Jennifer M.

2012-01-01

223

21 CFR 870.3700 - Pacemaker programmers.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Pacemaker programmers. 870.3700 Section 870...Cardiovascular Prosthetic Devices § 870.3700 Pacemaker programmers. (a) Identification. A pacemaker programmer is a device used to...

2013-04-01

224

21 CFR 870.3670 - Pacemaker charger.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Pacemaker charger. 870.3670 Section 870.3670...Cardiovascular Prosthetic Devices § 870.3670 Pacemaker charger. (a) Identification. A pacemaker charger is a device used...

2013-04-01

225

Modeling cardiac pacemakers with relaxation oscillators  

NASA Astrophysics Data System (ADS)

A modified van der Pol oscillator model was designed in order to reproduce the time series of the action potential generated by a natural pacemaker of the heart (i.e., the SA or the AV node). The main motivation was that the models published up to now were not altogether adequate for research on the heart. Based on either the classical van der Pol oscillator or other nonlinear oscillators, these models were interesting rather because of the physical phenomena that could be obtained (chaos and synchronization). However, they were unable to simulate many important physiological features of true physiological action potentials. We based our research on the experience of other groups which modeled neuronal oscillators. There complex nonlinear oscillators were used whose most important feature was a certain topology of the phase space. In our case, we modified the phase space of the classical van der Pol oscillator by adding two fixed points: a saddle and a node. In addition, a damping term asymmetric with respect to the voltage was introduced. Introduction of these new features into the van der Pol oscillator allowed to change the firing frequency of the pacemaker node without changing the length of the refractory period - an important physiological detail. We also show different ways of changing the pacemaker rhythm. A comparison of the properties of the signal obtained from our model with the features of the action potentials measured by other groups is made.

Grudzi?ski, Krzysztof; ?ebrowski, Jan J.

2004-05-01

226

Effects of circadian disruption on the cardiometabolic system  

Microsoft Academic Search

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

Melanie Rüger; Frank A. J. L. Scheer

2009-01-01

227

[Sport for pacemaker patients].  

PubMed

Sport activity is an important issue in many patients with a pacemaker either because they performed sport activities before pacemaker implantation to reduce the cardiovascular risk or to improve the course of an underlying cardiovascular disease (e.g. coronary artery disease, heart failure) by sports. Compared to patients with an implantable cardioverter defibrillator (ICD) the risks from underlying cardiovascular disease (e.g. ischemia, heart failure), arrhythmia, lead dysfunction or inappropriate therapy are less important or absent. Sport is contraindicated in dyspnea at rest, acute heart failure, new complex arrhythmia, acute myocarditis and acute myocardial infarction, valvular disease with indications for intervention and surgery and comorbidities which prevent physical activity. Patients with underlying cardiovascular disease (including hypertension) should preferably perform types and levels of physical activity that are aerobic (with dynamic exercise) such as running, swimming, cycling instead of sport with high anaerobic demands and high muscular workload. In heart failure, studies demonstrated advantages of isometric sport that increases the amount of muscle, thereby preventing cardiac cachexia. Sport with a risk of blows to the chest or physical contact (e.g. boxing, rugby, martial arts) should be avoided. Implantation, programming and follow-up should respect specific precautions to allow optimal physical activity with a pacemaker including implantation of bipolar leads on the side contralateral to the dominant hand, individual programming of the upper sensor and tracking rate and regular exercise testing. PMID:22854824

Israel, C W

2012-06-01

228

What role do pacemakers play in the generation of respiratory rhythm?  

PubMed

The pacemaker hypothesis that specialized neurons with conditional oscillatory- bursting properties are obligatory for respiratory rhythm generation in vitro has gained widespread acceptance, despite lack of direct proof. Here we critique the pacemaker hypothesis and provide an alternative explanation for rhythmogenesis based on emergent network properties. Pacemaker neurons in the preBötC depend on either persistent Na+ current I(NaP) or Ca(2+)-activated nonspecific cationic current (I(CAN)). Activity in slice preparations and synaptically- isolated pacemaker neurons undergo similar frequency modulation by perturbations including hypoxia and changes in external K+. These data have been used to argue that pacemaker cells must be rhythmogenic, but may simply reflect the action of these perturbations on intrinsic membrane properties throughout the preBötC and does not constitute proof that pacemakers necessarily drive the rhythm with synaptic coupling in place. Likewise, bath-applied drugs, such as riluzole (RIL) and flufenamic acid (FFA), attenuate I(NaP) and I(CAN), respectively, throughout the slice. Thus, when these drugs stop the rhythm, a widespread depression of excitability is likely the underlying cause, not selective blockade of bursting-pacemaker activity. We propose that rhythmogenesis is an emergent network property, wherein recurrent synaptic excitation initiates a positive feedback cycle among interneurons and that intrinsic currents like I(CAN) and I(NaP) promote inspiratory burst generation by augmenting synaptic excitation in the context of network activity. In this group-pacemaker framework, individual pacemaker neurons can be embedded but play the same role as every other network constituent. PMID:18085252

Del Negro, Christopher A; Pace, Ryland W; Hayes, John A

2008-01-01

229

A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract  

Microsoft Academic Search

Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show

KM Sanders

1996-01-01

230

Circadian System, Sleep and Endocrinology  

PubMed Central

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

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

2011-01-01

231

Pacemaker Interferentie Meetopstelling (System for Measuring Pacemaker Interference).  

National Technical Information Service (NTIS)

As a result of a growing number of questions from users of pacemakers and from suppliers as well as from users of potential sources of interference, research was conducted on problems of interference in pacemakers. A number of sources of interference (hig...

C. van Nimwegen J. Boter G. E. P. M. van Venrooij

1981-01-01

232

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

NASA Astrophysics Data System (ADS)

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.

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

2009-03-01

233

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

PubMed

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

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

2011-04-01

234

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

Microsoft Academic Search

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

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

2007-01-01

235

In vivo monitoring of multi-unit neural activity in the suprachiasmatic nucleus reveals robust circadian rhythms in Period1?/? mice.  

PubMed

The master pacemaker in the suprachiasmatic nucleus (SCN) controls daily rhythms of behavior in mammals. C57BL/6J mice lacking Period1 (Per1?/?) are an anomaly because their SCN molecular rhythm is weak or absent in vitro even though their locomotor activity rhythm is robust. To resolve the contradiction between the in vitro and in vivo circadian phenotypes of Per1?/? mice, we measured the multi-unit activity (MUA) rhythm of the SCN neuronal population in freely-behaving mice. We found that in vivo Per1?/? SCN have high-amplitude MUA rhythms, demonstrating that the ensemble of neurons is driving robust locomotor activity in Per1?/? mice. Since the Per1?/? SCN electrical activity rhythm is indistinguishable from wild-types, in vivo physiological factors or coupling of the SCN to a known or unidentified circadian clock(s) may compensate for weak endogenous molecular rhythms in Per1?/? SCN. Consistent with the behavioral light responsiveness of Per1?/? mice, in vivo MUA rhythms in Per1?/? SCN exhibited large phase shifts in response to light. Since the acute response of the MUA rhythm to light in Per1?/? SCN is equivalent to wild-types, an unknown mechanism mediates enhanced light responsiveness of Per1?/? mice. Thus, Per1?/? mice are a unique model for investigating the component(s) of the in vivo environment that confers robust rhythmicity to the SCN as well as a novel mechanism of enhanced light responsiveness. PMID:23717599

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

2013-05-22

236

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

PubMed Central

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

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

2013-01-01

237

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

Microsoft Academic Search

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

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

2010-01-01

238

Trends in Cardiac Pacemaker Batteries  

PubMed Central

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

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

2004-01-01

239

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

PubMed Central

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

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

2013-01-01

240

Circadian Role in Daily Pattern of Cardiovascular Risk  

NASA Astrophysics Data System (ADS)

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

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

2004-03-01

241

Quantification of Circadian Rhythms in Single Cells  

PubMed Central

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

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

2009-01-01

242

Runaway in a modern "soft top" pacemaker.  

PubMed

Although runaway pacemaker was a relatively common occurrence, modern pacemaker design has made it extremely rare. We report a case occurring with a modern "soft-top" pacemaker that resulted from a loss of hermeticity. Although the different treatment options are discussed, the definitive maneuvre is explantation of the faulty pacemakers PMID:9392822

Betts, T R; Thomas, R D; Hubbard, W N

1997-11-01

243

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

PubMed

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

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

2001-04-01

244

Quantification of Circadian Rhythms in Single Cells  

Microsoft Academic Search

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator.

Pål O. Westermark; David K. Welsh; Hitoshi Okamura; Hanspeter Herzel

2009-01-01

245

Plasticity and specificity of the circadian epigenome  

Microsoft Academic Search

Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of an appreciable portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate on how epigenetic processes are

Selma Masri; Paolo Sassone-Corsi

2010-01-01

246

Circadian adaptations to meal timing: neuroendocrine mechanisms  

PubMed Central

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

Patton, Danica F.; Mistlberger, Ralph E.

2013-01-01

247

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

Code of Federal Regulations, 2013 CFR

...false External transcutaneous cardiac pacemaker (noninvasive). 870.5550 Section...5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a device...

2013-04-01

248

Ryanodine-Sensitive Intracellular Ca2+ Channels in Rat Suprachiasmatic Nuclei Are Required for Circadian Clock Control of Behavior  

Microsoft Academic Search

Electrophysiological and calcium mobilization experiments have suggested that the intracellular calcium release channel ryanodine receptors (RyRs) are involved in the circadian rhythmicity of the suprachiasmatic nucleus (SCN). In the present report the authors provide behavioral evidence that RyRs play a specific and major role in the output of the molecular circadian clock in SCN neurons. They measured the circadian rhythm

Clara Mercado; Mauricio Díaz-Muñoz; Javier Alamilla; Karla Valderrama; Verónica Morales-Tlalpan; Raúl Aguilar-Roblero

2009-01-01

249

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

PubMed Central

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

Woolum, J C; Strumwasser, F

1980-01-01

250

Synaptic connections between eyelet photoreceptors and pigment dispersing factor-immunoreactive neurons of the blowfly Protophormia terraenovae.  

PubMed

Studies using various mutants of Drosophila melanogaster bearing defects in their visual system, including those of the retinal and extraretinal photoreceptor systems, have indicated that the extraretinal photoreceptor known as the Hofbauer-Buchner (H-B) eyelet plays an active, if subsidiary, role in the entrainment of circadian rhythms. In the present study, in the context of unraveling the function of extraretinal photoreception on circadian rhythms and photoperiodic responses, we searched for extraretinal photoreceptors in the blowfly, Protophormia terraenovae, and found that this fly has a homolog of the H-B eyelet. In addition, we show morphologically direct synaptic connections between the eyelet of P. terraenovae (called here Pt-eyelet, after the species' name) and pigment-dispersing factor (PDF)-immunoreactive neurons, which are putative circadian pacemaker neurons, by immunogold electron microscopy combined with intracellular dye injection. The Pt-eyelet was found to reside in the middle of the posterior surface of the optic lobe between the retina and the lamina, as does the H-B eyelet. This extraretinal photoreceptor was composed of at least four photoreceptor cells equipped with well-organized microvillar rhabdomeres. Rhodopsin 6-like immunoreactivity and also the response to light stimuli clearly showed the Pt-eyelet to be functional. The Pt-eyelet terminals in the accessory medulla exhibited synaptic bouton-like appearances and formed divergent multiple-contact output synapses. Synaptic contacts from the Pt-eyelet terminal to the PDF-immunoreactive neurons were identified by the presence of presynaptic ribbons and accumulated synaptic vesicles. Their possible function is discussed in relation to previous studies on circadian rhythm and photoperiodic response of P. terraenovae. PMID:16320242

Yasuyama, Kouji; Okada, Yoshinori; Hamanaka, Yoshitaka; Shiga, Sakiko

2006-01-10

251

Development of a Pacemaker Monitor with Cardiac Simulator.  

National Technical Information Service (NTIS)

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

T. O. Steiner

1975-01-01

252

Pacemaker endocarditis: an important clinical entity  

PubMed Central

Pacemaker endocarditis remains a rare but potentially life threatening complication of pacemaker implantation. This case illustrates a rare cause of pacemaker endocarditis, Serratia marcescens, the management difficulties that can be faced with such organisms, and the potential indolent nature of pacemaker lead associated endocarditis. A review of the current data for pacemaker endocarditis management suggests that treatment with antimicrobials alone is unlikely to be curative and explantation of the device is recommended in all cases of confirmed pacemaker endocarditis (by echocardiography, in correlation with the patient’s clinical condition and inflammatory markers).

De Silva, Kalpa; Fife, Amanda; Murgatroyd, Francis; Gall, Nicholas

2009-01-01

253

Daylight and Artificial Light Phase Response Curves for the Circadian Rhythm in Locomotor Activity of the Field Mouse Mus booduga  

Microsoft Academic Search

The sensitivity of the circadian pacemaker of the field mouse Mus booduga to diffuse daylight pulses of 15 min duration and 1000 lux intensity was measured in a series of experiments and a phase response curve (PRC) constructed. The PRC evoked was of type-I with significant quantitative differences compared to the PRCs constructed for other light stimuli (fluorescent and incandescent

V. K. Sharma; M. K. Chandrashekaran; P. Nongkynrih

1997-01-01

254

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

Microsoft Academic Search

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central

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

2010-01-01

255

Changing the Waveform of Circadian Rhythms: Considerations for Shift-Work  

PubMed Central

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.

Harrison, Elizabeth M.; Gorman, Michael R.

2012-01-01

256

Serotonin modulates circadian entrainment in Drosophila.  

PubMed

Entrainment of the Drosophila circadian clock to light involves the light-induced degradation of the clock protein timeless (TIM). We show here that this entrainment mechanism is inhibited by serotonin, acting through the Drosophila serotonin receptor 1B (d5-HT1B). d5-HT1B is expressed in clock neurons, and alterations of its levels affect molecular and behavioral responses of the clock to light. Effects of d5-HT1B are synergistic with a mutation in the circadian photoreceptor cryptochrome (CRY) and are mediated by SHAGGY (SGG), Drosophila glycogen synthase kinase 3beta (GSK3beta), which phosphorylates TIM. Levels of serotonin are decreased in flies maintained in extended constant darkness, suggesting that modulation of the clock by serotonin may vary under different environmental conditions. These data identify a molecular connection between serotonin signaling and the central clock component TIM and suggest a homeostatic mechanism for the regulation of circadian photosensitivity in Drosophila. PMID:15996552

Yuan, Quan; Lin, Fangju; Zheng, Xiangzhong; Sehgal, Amita

2005-07-01

257

Circadian changes in Drosophila motor terminals.  

PubMed

In Drosophila melanogaster, as in most other higher organisms, a circadian clock controls the rhythmic distribution of rest/sleep and locomotor activity. Here we report that the morphology of Drosophila flight neuromuscular terminals changes between day and night, with a rhythm in synaptic bouton size that continues in constant darkness, but is abolished during aging. Furthermore, arrhythmic mutations in the clock genes timeless and period also disrupt this circadian rhythm. Finally, these clock mutants also have an opposing effect on the nonrhythmic phenotype of neuronal branching, with tim mutants showing a dramatic hyperbranching morphology and per mutants having fewer branches than wild-type flies. These unexpected results reveal further circadian as well as nonclock related pleiotropic effects for these classic behavioral mutants. PMID:17443798

Mehnert, Kerstin I; Beramendi, Ana; Elghazali, Fahad; Negro, Paolo; Kyriacou, Charalambos P; Cantera, Rafael

2007-03-01

258

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

PubMed Central

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

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

2013-01-01

259

New Method Cuts Radiation During Pacemaker Procedure  

MedlinePLUS

... sharing features on this page, please enable JavaScript. New Method Cuts Radiation During Pacemaker Procedure: Study Electromagnetic ... X-Rays WEDNESDAY, Sept. 4 (HealthDay News) -- A new way of implanting pacemakers cuts radiation exposure for ...

260

Circadian clocks and metabolism.  

PubMed

Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health. PMID:23604478

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

2013-01-01

261

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

PubMed Central

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.

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

2010-01-01

262

Pacemaker-associated Bacillus cereus endocarditis.  

PubMed

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. PMID:22959918

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

2012-09-07

263

Fifty years of pacemaker advancements.  

PubMed

A 1957 power blackout in Minnesota prompted C. Walton Lillehei, MD, a pioneer in open heart surgery, to ask Earl Bakken, the co-founder of Medtronic, Inc., to create a battery-operated pacemaker for pediatric patients. That conversation led to the development of the first external battery-operated pacemaker. That first bulky device is far removed from the tiny implantable computers available to heart patients today. Now, the size of two silver dollars stacked on top of one another, a pacemaker is prescribed for a person whose heart beats too slowly or pauses irregularly. Slightly larger devices have more recently evolved from pacing and regulating the heartbeat to being able to provide therapeutic high voltage shocks when needed to stop runaway fast heart rates, recording heart activity, and other physiologic functions, even resynchronizing the heart's chambers-all while providing information on the patient's condition and device performance to the doctor remotely or in the office. PMID:20559931

Steinhaus, David

2008-11-04

264

Sacral neuromodulation and cardiac pacemakers  

Microsoft Academic Search

Introduction and hypothesis  Potential for cross-talk between cardiac pacemakers and sacral neuromodulation remains speculative.\\u000a \\u000a \\u000a \\u000a Methods  We present a case series of patients with cardiac pacemakers who underwent staged Interstim (Medtronic, Minneapolis, MN) implantation\\u000a and patients who had pulse generator implantation who later required cardiac pacemakers.\\u000a \\u000a \\u000a \\u000a \\u000a Results  No cross-talk was demonstrated in either group.\\u000a \\u000a \\u000a \\u000a Conclusions  Sacral neuromodulation appears to be safe in the setting of

Ted M. Roth

2010-01-01

265

Variation of electroencephalographic activity during non-rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans.  

PubMed Central

1. The circadian pacemaker regulates the timing, structure and consolidation of human sleep. The extent to which this pacemaker affects electroencephalographic (EEG) activity during sleep remains unclear. 2. To investigate this, a total of 1.22 million power spectra were computed from EEGs recorded in seven men (total, 146 sleep episodes; 9 h 20 min each) who participated in a one-month-long protocol in which the sleep-wake cycle was desynchronized from the rhythm of plasma melatonin, which is driven by the circadian pacemaker. 3. In rapid eye movement (REM) sleep a small circadian variation in EEG activity was observed. The nadir of the circadian rhythm of alpha activity (8.25-10.5 Hz) coincided with the end of the interval during which plasma melatonin values were high, i.e. close to the crest of the REM sleep rhythm. 4. In non-REM sleep, variation in EEG activity between 0.25 and 11.5 Hz was primarily dependent on prior sleep time and only slightly affected by circadian phase, such that the lowest values coincided with the phase of melatonin secretion. 5. In the frequency range of sleep spindles, high-amplitude circadian rhythms with opposite phase positions relative to the melatonin rhythm were observed. Low-frequency sleep spindle activity (12.25-13.0 Hz) reached its crest and high-frequency sleep spindle activity (14.25-15.5 Hz) reached its nadir when sleep coincided with the phase of melatonin secretion. 6. These data indicate that the circadian pacemaker induces changes in EEG activity during REM and non-REM sleep. The changes in non-REM sleep EEG spectra are dissimilar from the spectral changes induced by sleep deprivation and exhibit a close temporal association with the melatonin rhythm and the endogenous circadian phase of sleep consolidation.

Dijk, D J; Shanahan, T L; Duffy, J F; Ronda, J M; Czeisler, C A

1997-01-01

266

Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork  

PubMed Central

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions.

Li, Jian; Lu, Wei-Qun; Beesley, Stephen; Loudon, Andrew S. I.; Meng, Qing-Jun

2012-01-01

267

Aging differentially affects the re-entrainment response of central and peripheral circadian oscillators  

PubMed Central

Aging produces a decline in the amplitude and precision of 24h behavioral, endocrine, and metabolic rhythms, which are regulated in mammals by a central circadian pacemaker within the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. Disruption of the circadian system, as experienced during transmeridian travel, can lead to adverse health consequences, particularly in the elderly. To test the hypothesis that age-related changes in the response to simulated jetlag will reflect altered circadian function, we examined re-entrainment of central and peripheral oscillators from young and old PER2::luciferase mice. As in previous studies, locomotor activity rhythms in older mice required more days to re-entrain following a shift than younger mice. At the tissue level, effects of age on baseline entrainment were evident, with older mice displaying earlier phases for the majority of peripheral oscillators studied and later phases for cells within most SCN subregions. Following a 6h advance of the light:dark cycle, old mice displayed slower rates of re-entrainment for peripheral tissues but a larger, more rapid SCN response compared to younger mice. Thus, aging alters the circadian timing system in a manner that differentially affects the re-entrainment responses of central and peripheral circadian clocks. This pattern of results suggests that a major consequence of aging is a decrease in pacemaker amplitude, which would slow re-entrainment of peripheral oscillators and reduce SCN resistance to external perturbation.

Sellix, Michael T.; Evans, Jennifer A.; Leise, Tanya L.; Castanon-Cervantes, Oscar; Hill, DiJon D.; DeLisser, Patrick; Block, Gene D.; Menaker, Michael; Davidson, Alec J.

2012-01-01

268

Aging differentially affects the re-entrainment response of central and peripheral circadian oscillators.  

PubMed

Aging produces a decline in the amplitude and precision of 24 h behavioral, endocrine, and metabolic rhythms, which are regulated in mammals by a central circadian pacemaker within the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. Disruption of the circadian system, as experienced during transmeridian travel, can lead to adverse health consequences, particularly in the elderly. To test the hypothesis that age-related changes in the response to simulated jet lag will reflect altered circadian function, we examined re-entrainment of central and peripheral oscillators from young and old PER2::luciferase mice. As in previous studies, locomotor activity rhythms in older mice required more days to re-entrain following a shift than younger mice. At the tissue level, effects of age on baseline entrainment were evident, with older mice displaying earlier phases for the majority of peripheral oscillators studied and later phases for cells within most SCN subregions. Following a 6 h advance of the light:dark cycle, old mice displayed slower rates of re-entrainment for peripheral tissues but a larger, more rapid SCN response compared to younger mice. Thus, aging alters the circadian timing system in a manner that differentially affects the re-entrainment responses of central and peripheral circadian clocks. This pattern of results suggests that a major consequence of aging is a decrease in pacemaker amplitude, which would slow re-entrainment of peripheral oscillators and reduce SCN resistance to external perturbation. PMID:23152603

Sellix, Michael T; Evans, Jennifer A; Leise, Tanya L; Castanon-Cervantes, Oscar; Hill, DiJon D; DeLisser, Patrick; Block, Gene D; Menaker, Michael; Davidson, Alec J

2012-11-14

269

Mammalian circannual pacemakers.  

PubMed

Circannual clocks drive rhythms in reproduction and many other seasonal characteristics but the underlying control of these long-term oscillators remains a mystery. Now, we propose that circannual timing involves mechanisms that are integral to the ontogenetic life-history programme where annual transitions are generated by cell birth, death and tissue regeneration throughout the life cycle--the histogenesis hypothesis. The intrinsic cycle is then timed by cues from the environment. The concept is that in specific sites in the brain, pituitary and peripheral tissues, residual populations of progenitor cells (adult stem cells) synchronously initiate a phase of cell division to begin a cycle. The progeny cells then proliferate, migrate and differentiate, providing the substrate that drives physiological change over long time-spans (e.g. summer/winter); cell death may be required to trigger the next cycle. We have begun to characterise such a tissue-based timer in our Soay sheep model focusing on the pars tuberalis (PT) of the pituitary gland and the sub-ventricular zone of the mediobasal hypothalamus (MBH) as potential circannual pacemakers. The PT is of special interest because it is a melatonin-responsive tissue containing undifferentiated cells, strategically located at the gateway between the brain and pituitary gland. The PT also governs long-photoperiod activation of thyroid hormone dependant processes in the MBH required for neurogenesis. In sheep, exposure to long photoperiod markedly activates BrDU-labelled cell proliferation in the PT and MBH, and acts to entrain the circannual reproductive cycle. Variation in expression and co-ordination of multiple tissue timers may explain species differences in circannual rhythmicity. This paper is dedicated to the memory of Ebo Gwinner. PMID:21755671

Lincoln, G A; Hazlerigg, D G

2010-01-01

270

Efferent Projections of Prokineticin 2 Expressing Neurons in the Mouse Suprachiasmatic Nucleus  

PubMed Central

The suprachiasmatic nucleus (SCN) in the hypothalamus is the predominant circadian clock in mammals. To function as a pacemaker, the intrinsic timing signal from the SCN must be transmitted to different brain regions. Prokineticin 2 (PK2) is one of the candidate output molecules from the SCN. In this study, we investigated the efferent projections of PK2-expressing neurons in the SCN through a transgenic reporter approach. Using a bacterial artificial chromosome (BAC) transgenic mouse line, in which the enhanced green fluorescence protein (EGFP) reporter gene expression was driven by the PK2 promoter, we were able to obtain an efferent projections map from the EGFP-expressing neurons in the SCN. Our data revealed that EGFP-expressing neurons in the SCN, hence representing some of the PK2-expressing neurons, projected to many known SCN target areas, including the ventral lateral septum, medial preoptic area, subparaventricular zone, paraventricular nucleus, dorsomedial hypothalamic nucleus, lateral hypothalamic area and paraventricular thalamic nucleus. The efferent projections of PK2-expressing neurons supported the role of PK2 as an output molecule of the SCN.

Zhang, Chengkang; Truong, Kimberly K.; Zhou, Qun-Yong

2009-01-01

271

Lithium pacemaker batteries - an overview  

SciTech Connect

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.

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

1980-01-01

272

The possible roles of hyperpolarization-activated cyclic nucleotide channels in regulating pacemaker activity in colonic interstitial cells of Cajal.  

PubMed

BACKGROUND: Hyperpolarization-activated cyclic nucleotide (HCN) channels are pacemaker channels that regulate heart rate and neuronal rhythm in spontaneously active cardiac and neuronal cells. Interstitial cells of Cajal (ICCs) are also spontaneously active pacemaker cells in the gastrointestinal tract. Here, we investigated the existence of HCN channel and its role on pacemaker activity in colonic ICCs. METHODS: We performed whole-cell patch clamp, RT-PCR, and Ca(2+)-imaging in cultured ICCs from mouse mid colon. RESULTS: SQ-22536 and dideoxyadenosine (adenylate cyclase inhibitors) decreased the frequency of pacemaker potentials, whereas both rolipram (cAMP-specific phosphodiesterase inhibitor) and cell-permeable 8-bromo-cAMP increased the frequency of pacemaker potentials. CsCl, ZD7288, zatebradine, clonidine (HCN channel blockers), and genistein (a tyrosine kinase inhibitor) suppressed the pacemaker activity. RT-PCR revealed expression of HCN1 and HCN3 channels in c-kit and Ano1 positive colonic ICCs. In recordings of spontaneous intracellular Ca(2+) [Ca(2+)]i oscillations, rolipram and 8-bromo-cAMP increased [Ca(2+)]i oscillations, whereas SQ-22536, CsCl, ZD7288, and genistein decreased [Ca(2+)]i oscillations. CONCLUSIONS: HCN channels in colonic ICCs are tonically activated by basal cAMP production and participate in regulation of pacemaking activity. PMID:23780559

Shahi, Pawan Kumar; Choi, Seok; Zuo, Dong Chuan; Kim, Man Yoo; Park, Chan Guk; Kim, Young Dae; Lee, Jun; Park, Kyu Joo; So, Insuk; Jun, Jae Yeoul

2013-06-19

273

Requirement of Mammalian Timeless for Circadian Rhythmicity  

Microsoft Academic Search

Despite a central circadian role in Drosophila for the transcriptional regulator Timeless (dTim), the relevance of mammalian Timeless (mTim) remains equiv- ocal. Conditional knockdown of mTim protein expression in the rat suprachi- asmatic nucleus (SCN) disrupted SCN neuronal activity rhythms, and altered levels of known core clock elements. Full-length mTim protein (mTIM-fl) ex- hibited a 24-hour oscillation, whereas a truncated

Jessica W. Barnes; Shelley A. Tischkau; Jeffrey A. Barnes; Jennifer W. Mitchell; Penny W. Burgoon; Jason R. Hickok; Martha U. Gillette

2003-01-01

274

Circadian clock system in the pineal gland  

Microsoft Academic Search

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

Yoshitaka Fukada; Toshiyuki Okano

2002-01-01

275

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

Microsoft Academic Search

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

Kristin L Eckel-Mahan; Daniel R Storm

2009-01-01

276

A Molecular Model for Intercellular Synchronization in the Mammalian Circadian Clock  

Microsoft Academic Search

The mechanisms and consequences of synchrony among heterogeneous oscillators are poorly understood in biological systems. We present a multicellular, molecular model of the mammalian circadian clock that incorporates recent data implicating the neurotransmitter vasoactive intestinal polypeptide (VIP) as the key synchronizing agent. The model postulates that synchrony arises among circadian neurons because they release VIP rhythmically on a daily basis

Tsz-Leung To; Michael A. Henson; Erik D. Herzog; Francis J. Doyle

2007-01-01

277

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

PubMed

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. PMID:23010663

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

2012-10-01

278

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

PubMed Central

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 ?-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.

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

2012-01-01

279

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

PubMed Central

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 if disparate coupling assays index a common mechanism, we examined whether there is co-variation 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 non-responders (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 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 three distinct lighting conditions, suggesting a common mechanism wherein individual differences reflect variation in circadian coupling.

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

2013-01-01

280

The role of the circadian system in fractal neurophysiological control.  

PubMed

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

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

2013-04-10

281

Quantitative Analyses of Circadian Gene Expression in Mammalian Cell Cultures  

PubMed Central

The central circadian pacemaker is located in the hypothalamus of mammals, but essentially the same oscillating system operates in peripheral tissues and even in immortalized cell lines. Using luciferase reporters that allow automated monitoring of circadian gene expression in mammalian fibroblasts, we report the collection and analysis of precise rhythmic data from these cells. We use these methods to analyze signaling pathways of peripheral tissues by studying the responses of Rat-1 fibroblasts to ten different compounds. To quantify these rhythms, which show significant variation and large non-stationarities (damping and baseline drifting), we developed a new fast Fourier transform–nonlinear least squares analysis procedure that specifically optimizes the quantification of amplitude for circadian rhythm data. This enhanced analysis method successfully distinguishes among the ten signaling compounds for their rhythm-inducing properties. We pursued detailed analyses of the responses to two of these compounds that induced the highest amplitude rhythms in fibroblasts, forskolin (an activator of adenylyl cyclase), and dexamethasone (an agonist of glucocorticoid receptors). Our quantitative analyses clearly indicate that the synchronization mechanisms by the cAMP and glucocorticoid pathways are different, implying that actions of different genes stimulated by these pathways lead to distinctive programs of circadian synchronization.

Izumo, Mariko; Sato, Takashi R; Straume, Martin; Johnson, Carl Hirschie

2006-01-01

282

Pacemaker lead thrombo-endocarditis in an intravenous drug abuser  

Microsoft Academic Search

We report a 30-year-old male intravenous drug abuser presenting with persistent pacemaker lead thrombosis with superimposed pacemaker lead endocarditis. He underwent urgent surgery, but expired due to refractory sepsis. This case confirms that patients with pacemakers are at risk of developing pacemaker lead thrombosis. In addition, they are at high risk of developing pacemaker lead endocarditis if additional risk factors

Prashanth Panduranga; Mohammed Khamis Mukhaini

2011-01-01

283

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

PubMed Central

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

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

2012-01-01

284

Fat circadian biology  

PubMed Central

While adipose tissue has long been recognized for its major role in metabolism, it is now appreciated as an endocrine organ. A growing body of literature has emerged that identifies circadian mechanisms as a critical regulator of adipose tissue differentiation, metabolism, and adipokine secretory function in both health and disease. This concise review focuses on recent data from murine and human models that highlights the interplay between the core circadian regulatory proteins and adipose tissue in the context of energy, fat, and glucose metabolism. It will be important to integrate circadian mechanisms and networks into future descriptions of adipose tissue physiology.

Floyd, Z. Elizabeth

2009-01-01

285

A model of excitatory synaptic interactions between pacemakers. Its reality, its generality, and the principles involved  

Microsoft Academic Search

This is a model of the steady-state influence of one pacemaker neuron upon another across a synapse with EPSP's. Its postulates require firstly the spontaneous regularity of both cells, whose intervals are E and N, respectively. In addition, they require a special shortening or negative “delay” of the interspike interval by one or more EPSP's, with a V-shaped dependence of

J. P. Segundo; A. F. Kohn

1981-01-01

286

Circadian Rhythms in Urinary Functions: Possible Roles of Circadian Clocks?  

PubMed Central

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In this review, we briefly introduce circadian clocks and their organization in mammals. We then summarize known daily or circadian variations in urinary function. Importantly, recent findings by others as well as results obtained by us suggest an active role of circadian clock genes in various urinary functions. Finally, we discuss possible research avenues for the circadian control of urinary function.

Noh, Jong-Yun; Han, Dong-Hee; Yoon, Ji-Ae; Kim, Mi-Hee; Kim, Sung-Eun; Ko, Il-Gyu; Kim, Khae-Hawn; Kim, Chang-Ju

2011-01-01

287

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

National Technical Information Service (NTIS)

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

1975-01-01

288

Subthreshold Sodium Current from Rapidly Inactivating Sodium Channels Drives Spontaneous Firing of Tuberomammillary Neurons  

Microsoft Academic Search

A role for “persistent,” subthreshold, TTX-sensitive sodium current in driving the pacemaking of many central neurons has been proposed, but this has been impossible to test pharmacologically. Using isolated tuberomammillary neurons, we assessed the role of subthreshold sodium current in pacemaking by performing voltage-clamp experiments using a cell's own pacemaking cycle as voltage command. TTX-sensitive sodium current flows throughout the

Abraha Taddese; Bruce P. Bean

2002-01-01

289

Orexin Alike immunoreactivity in the hypothalamus and thalamus of the Syrian hamster (Mesocricetus auratus) and Siberian hamster ( Phodopus sungorus), with special reference to circadian structures  

Microsoft Academic Search

The orexins are recently discovered neuropeptides that reportedly play a role in energy homeostasis, in addition to various other physiological processes. The synthesis of orexin A undergoes diurnal variation in certain areas of the brain, while the mutation of the orexin receptor 2 gene has been implicated in canine narcolepsy. Since the circadian pacemaker in the suprachiasmatic nucleus modulates the

Paul A McGranaghan; Hugh D Piggins

2001-01-01

290

Circadian Rhythms - Keeping Times  

MedlinePLUS

... bodily functions. They have been linked to various sleep disorders, such as insomnia. Abnormal circadian rhythms have also ... clocks tick may lead researchers to treatments for sleep disorders, jet lag and other health problems. Learning more ...

291

Biophotonics: Circadian photonics  

NASA Astrophysics Data System (ADS)

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

Rea, Mark S.

2011-05-01

292

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2013 CFR

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

2013-04-01

293

21 CFR 870.1750 - External programmable pacemaker pulse generator.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false External programmable pacemaker pulse generator. 870.1750 ...870.1750 External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device...

2013-04-01

294

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2013 CFR

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

2013-04-01

295

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2010 CFR

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

2010-04-01

296

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2010 CFR

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

2009-04-01

297

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2010 CFR

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

2009-04-01

298

21 CFR 870.3720 - Pacemaker electrode function tester.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Pacemaker electrode function tester. 870...Prosthetic Devices § 870.3720 Pacemaker electrode function tester. (a) Identification. A pacemaker electrode function tester is a...

2013-04-01

299

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Pacemaker repair or replacement material. ...Prosthetic Devices § 870.3710 Pacemaker repair or replacement material. (a) Identification. A pacemaker repair or replacement material...

2013-04-01

300

21 CFR 870.3650 - Pacemaker polymeric mesh bag.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Pacemaker polymeric mesh bag. 870.3650 ...Cardiovascular Prosthetic Devices § 870.3650 Pacemaker polymeric mesh bag. (a) Identification. A pacemaker polymeric mesh bag is an implanted...

2013-04-01

301

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 false Indirect pacemaker generator function analyzer. 870...Devices § 870.3640 Indirect pacemaker generator function analyzer. (a) Identification. An indirect pacemaker generator function analyzer is...

2010-04-01

302

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2010 CFR

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

2010-04-01

303

21 CFR 870.3640 - Indirect pacemaker generator function analyzer.  

Code of Federal Regulations, 2010 CFR

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

2009-04-01

304

21 CFR 870.3730 - Pacemaker service tools.  

Code of Federal Regulations, 2010 CFR

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

2009-04-01

305

21 CFR 870.3710 - Pacemaker repair or replacement material.  

Code of Federal Regulations, 2010 CFR

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

2010-04-01

306

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

Code of Federal Regulations, 2010 CFR

...2009-04-01 false External transcutaneous cardiac pacemaker (noninvasive). 870.5550...870.5550 External transcutaneous cardiac pacemaker (noninvasive). (a) Identification. An external transcutaneous cardiac pacemaker (noninvasive) is a...

2009-04-01

307

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

Code of Federal Regulations, 2010 CFR

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

2010-04-01

308

21 CFR 870.3610 - Implantable pacemaker pulse generator.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 false Implantable pacemaker pulse generator. 870.3610 Section 870... § 870.3610 Implantable pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that has a...

2009-04-01

309

21 CFR 870.1750 - External programmable pacemaker pulse generator.  

Code of Federal Regulations, 2010 CFR

...false External programmable pacemaker pulse generator. 870.1750 Section 870...1750 External programmable pacemaker pulse generator. (a) Identification. An external programmable pacemaker pulse generators is a device that can...

2010-04-01

310

21 CFR 870.3610 - Implantable pacemaker pulse generator.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 false Implantable pacemaker pulse generator. 870.3610 Section 870... § 870.3610 Implantable pacemaker pulse generator. (a) Identification. An implantable pacemaker pulse generator is a device that has a...

2010-04-01

311

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2010 CFR

... 2010-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690 Food...Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an...

2010-04-01

312

21 CFR 870.3690 - Pacemaker test magnet.  

Code of Federal Regulations, 2010 CFR

... 2009-04-01 false Pacemaker test magnet. 870.3690 Section 870.3690 Food...Prosthetic Devices § 870.3690 Pacemaker test magnet. (a) Identification. A pacemaker test magnet is a device used to test an...

2009-04-01

313

Type and timing of permanent pacemaker failure.  

PubMed

Availability of lithium batteries will decrease the incidence of early pacemaker failure. Pacemaker malfunction, exclusive of that due to battery exhaustion, can still occur. Defined as any repeat surgical procedure required after initial implantation, pacemaker system failure occurred in 22 of 115 (19 percent) pacemaker patients. Failure occurred within the first month in 12 with ten being lead-related. Insertion site problems occurred in nine patients. Though most endocardial pacemaker complications occur early, patients continue to be at risk for as long as the units are in place. Despite improvements in the batteries, there continue to be sufficient problems with pacemakers to emphasize the need for selectivity in determining which patients receive permanent units. PMID:7067508

Reinhart, S; McAnulty, J H; Dobbs, J

1982-04-01

314

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

PubMed Central

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.

Eckel-Mahan, Kristin L; Storm, Daniel R

2009-01-01

315

Reconstruction of Hyman's second pacemaker.  

PubMed

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

Furman, Seymour; Szarka, George; Layvand, Dmitriy

2005-05-01

316

Lithium-iodine pacemaker cell  

SciTech Connect

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

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

1980-01-01

317

The nuclear pacemaker: Is renewed interest warranted  

SciTech Connect

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.

Parsonnet, V.; Berstein, A.D.; Perry, G.Y. (Newark Beth Israel Medical Center, NJ (USA))

1990-10-01

318

[Exercise test in patients with permanent pacemakers].  

PubMed

From June 1988 to June 1990 we studied fifty patients who had implantation of a pacemaker. (31 females and 19 males). All of them underwent stress test with Bruce's protocol. Patients were divided in two groups; pacemaker-independent (PI) and pacemaker-dependent (PD). Over 50% of the patients inhibited the pacemaker with their own rhythm, most of them had sinus dysfunction. Complete A-V block was predominant in PD. The group of PI achieved more mets and had more oxygen consumption. Blood pressure response was similar in both groups. PMID:1929668

Esturau, R; Iturralde, P; Férez, S; Galván, O; Rosado, J; Pérez, G; González Hermosillo, J A

319

Circadian Metabolic Regulation through Crosstalk between Casein Kinase 1? and Transcriptional Coactivator PGC-1?  

PubMed Central

Circadian clock coordinates behavior and physiology in mammals in response to light and feeding cycles. Disruption of normal clock function is associated with increased risk for cardiovascular and metabolic diseases, underscoring the emerging concept that temporal regulation of tissue metabolism is a fundamental aspect of energy homeostasis. We have previously demonstrated that transcriptional coactivator, peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?), coordinates circadian metabolic rhythms through simultaneous regulation of metabolic and clock gene expression. In this study, we found that PGC-1? physically interacts with, and is phosphorylated by, casein kinase 1? (CK1?), a core component of the circadian pacemaker. CK1? represses the transcriptional function of PGC-1? in cultured hepatocytes, resulting in decreased gluconeogenic gene expression and glucose secretion. At the molecular level, CK1? phosphorylation of PGC-1? within its arginine/serine-rich domain enhances its degradation through the proteasome system. Together, these results elucidate a novel mechanism through which circadian pacemaker transduces timing signals to the metabolic regulatory network that controls hepatic energy metabolism.

Li, Siming; Chen, Xiao-Wei; Yu, Lei; Saltiel, Alan R.

2011-01-01

320

21 CFR 870.3630 - Pacemaker generator function analyzer.  

Code of Federal Regulations, 2013 CFR

...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3630 Pacemaker generator function analyzer. (a) Identification. A pacemaker generator...

2013-04-01

321

Vasopressin antagonist disrupts the circadian rhythm of water intake on suprachiasmatic injection.  

PubMed

The present study makes an attempt to find out the action of arginine vasopressin (AVP) and its antagonist d-(CH2)5 Tyr (Me) AVP applied at the suprachiasmatic nuclei (SCN) on the circadian rhythm of water intake. Chronic implantation of a 22 G stainless steel cannula for injection was performed using a stereotaxic technique under Nembutal anesthesia. AVP and its antagonist were injected into the SCN of free-moving rats at the beginning of light and dark phases of the light-dark (LD) cycle. Injections of AVP during either phase did not disrupt the circadian pattern of water intake while the injections of the antagonist disrupted it. The findings are suggestive of the involvement of AVP as a mediator of the circadian rhythm of water intake at the level of the neural pacemaker, SCN. PMID:1394607

Reghunandanan, V; Reghunandanan, R; Marya, R K; Singh, P I

1992-10-01

322

Age-related attenuation of the evening circadian arousal signal in humans.  

PubMed

The human circadian pacemaker maintains timing and consolidation of sleep-wake behavior by opposing the build-up of homeostatic sleep pressure during the wake episode, particularly in the evening during the 'wake maintenance zone'. We tested whether age-related changes in sleep are a consequence of a weaker circadian arousal signal in the evening. Circadian rhythms and spectral components of the sleep EEG were investigated in 17 young (20-31 year) and 15 older (57-74 year) volunteers under constant posture conditions during a 40-h nap protocol (75/150 min sleep/wake schedule). Quantitative evidence for a weaker circadian arousal signal in aging arose from significantly more sleep occurring during the wake maintenance zone and higher subjective sleepiness ratings in the late afternoon and evening in the older group. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep together with less pronounced day-night differences in the lower alpha and spindle range of sleep EEG activity in the older group. Thus, our data indicate that age-related changes in sleep propensity are clearly related to a reduced circadian signal opposing the homeostatic drive for sleep. PMID:16182904

Münch, Mirjam; Knoblauch, Vera; Blatter, Katharina; Schröder, Carmen; Schnitzler, Corina; Kräuchi, Kurt; Wirz-Justice, Anna; Cajochen, Christian

2005-04-18

323

Bilaterally propagating waves of spontaneous activity arising from discrete pacemakers in the neonatal mouse cerebral cortex.  

PubMed

Spontaneous electrical activity that moves in synchronized waves across large populations of neurons plays widespread and important roles in nervous system development. The propagation patterns of such waves can encode the spatial location of neurons to their downstream targets and strengthen synaptic connections in coherent spatial patterns. Such waves can arise as an emergent property of mutually excitatory neural networks, or can be driven by a discrete pacemaker. In the mouse cerebral cortex, spontaneous synchronized activity occurs for approximately 72 h of development centered on the day of birth. It is not known whether this activity is driven by a discrete pacemaker or occurs as an emergent network property. Here we show that this activity propagates as a wave that is initiated at either of two homologous pacemakers in the temporal region, and then propagates rapidly across both sides of the brain. When these regions of origin are surgically isolated, waves do not occur. Therefore, this cortical spontaneous activity is a bilateral wave that originates from a discrete subset of pacemaker neurons. PMID:19263415

Lischalk, Jonathan W; Easton, Curtis R; Moody, William J

2009-06-01

324

Synchronization and entrainment of coupled circadian oscillators  

PubMed Central

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

Komin, N.; Murza, A. C.; Hernandez-Garcia, E.; Toral, R.

2011-01-01

325

Regional circadian period difference in the suprachiasmatic nucleus of the mammalian circadian center.  

PubMed

The suprachiasmatic nucleus (SCN) is the mammalian circadian rhythm center. Individual oscillating neurons have different endogenous circadian periods, but they are usually synchronized by an intercellular coupling mechanism. The differences in the period of each oscillating neuron have been extensively studied; however, the clustering of oscillators with similar periods has not been reported. In the present study, we artificially disrupted the intercellular coupling among oscillating neurons in the SCN and observed regional differences in the periods of the oscillating small-latticed regions of the SCN using a transgenic rat carrying a luciferase reporter gene driven by regulatory elements from a per2 clock gene (Per2::dluc rat). The analysis divided the SCN into two regions - a region with periods shorter than 24 h (short-period region, SPR) and another with periods longer than 24 h (long-period region, LPR). The SPR was located in the smaller medial region of the dorsal SCN, whereas the LPR occupied the remaining larger region. We also found that slices containing the medial region of the SCN generated shorter circadian periods than slices that contained the lateral region of the SCN. Interestingly, the SPR corresponded well with the region where the SCN phase wave is generated. We numerically simulated the relationship between the SPR and a large LPR. A mathematical model of the SCN based on our findings faithfully reproduced the kinetics of the oscillators in the SCN in synchronized conditions, assuming the existence of clustered short-period oscillators. PMID:23869693

Koinuma, Satoshi; Asakawa, Takeshi; Nagano, Mamoru; Furukawa, Keiichi; Sujino, Mitsugu; Masumoto, Koh-Hei; Nakajima, Yoshihiro; Hashimoto, Seiichi; Yagita, Kazuhiro; Shigeyoshi, Yasufumi

2013-07-22

326

Circadian Rhythms in the Mouse: A Connections Map  

NSDL National Science Digital Library

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

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

2003-08-05

327

Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture  

NASA Astrophysics Data System (ADS)

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

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

2012-09-01

328

Period and phase control in a multioscillatory circadian system (Iguana iguana).  

PubMed

The circadian system of the lizard Iguana iguana is composed of several independent pacemakers that work in concert: the pineal gland, retinae of the lateral eyes, and a fourth oscillator presumed to be located in the hypothalamus. These pacemakers govern the circadian expression of multiple behaviors and physiological processes, including rhythms in locomotor activity, endogenous body temperature, electroretinogram, and melatonin synthesis. The numerous, easily measurable rhythmic outputs make the iguana an ideal organism for examining the contributions of individual oscillators and their interactions in governing the expression of overt circadian rhythms. The authors have examined the effects of pinealectomy and enucleation on the endogenous body temperature rhythm (BTR) and locomotor activity rhythm (LAR) of juvenile iguanas at constant temperature both in LD cycles and in constant darkness (DD). They measured the periods (tau) of the circadian rhythms of LAR and BTR, the phase relationships between them in DD (psiAT), and the phase relationship between each rhythm and the light cycle (psiRL). Pinealectomy lengthened tau of locomotor activity in all animals tested and abolished the BTR in two-thirds of the animals. In those animals in which the BTR did persist following pinealectomy, tau lengthened to the same extent as that of locomotor activity. Pinealectomy also delayed the onset of activity with respect to its normal phase relationship with body temperature in DD. Enucleation alone had no significant effect on tau of LAR or BTR; however, after enucleation, BTR became 180 degrees out of phase from LAR in DD. After both pinealectomy and enucleation, 4 of 16 animals became arrhythmic in both activity and body temperature. Their data suggest that rhythmicity, period, and phase of overt circadian behaviors are regulated through the combined output of multiple endogenous circadian oscillators. PMID:14964703

Bartell, Paul A; Miranda-Anaya, Manuel; Menaker, Michael

2004-02-01

329

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

PubMed Central

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

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

2012-01-01

330

Neuroimmunology of the circadian clock  

Microsoft Academic Search

Circadian timekeeping is a ubiquitous feature of all eukaryotes which allows for the imposition of a biologically appropriate temporal architecture on an animal's physiology, behavior and metabolism. There is growing evidence that in mammals the processes of circadian timing are under the influence of the immune system. Such a role for the neuroimmune regulation of the circadian clock has inferences

Andrew N. Coogan; Cathy A. Wyse

2008-01-01

331

Food ingestion and circadian rhythmicity  

Microsoft Academic Search

Feeding is organised within the 24-h of the light – dark (LD) cycle. Food is ingested in a circadian manner in nature and in laboratory animals kept under constant conditions. The circadian rhythmicity in food ingestion is driven by a biological clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The circadian organisation of food ingestion not only allows animals to

Brahim Selmaoui; Louise Thibault

2006-01-01

332

Circadian rhythms and reproduction.  

PubMed

There is a growing recognition that the circadian timing system, in particular recently discovered clock genes, plays a major role in a wide range of physiological systems. Microarray studies, for example, have shown that the expression of hundreds of genes changes many fold in the suprachiasmatic nucleus, liver heart and kidney. In this review, we discuss the role of circadian rhythmicity in the control of reproductive function in animals and humans. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance, but there are sufficient redundancies in their function that many of the knockout mice produced do not show overt reproductive failure. Furthermore, important strain differences have emerged from the studies especially between the various Clock (Circadian Locomotor Output Cycle Kaput) mutant strains. Nevertheless, there is emerging evidence that the primary clock genes, Clock and Bmal1 (Brain and Muscle ARNT-like protein 1, also known as Mop3), strongly influence reproductive competency. The extent to which the circadian timing system affects human reproductive performance is not known, in part, because many of the appropriate studies have not been done. With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans. PMID:16940279

Boden, Michael J; Kennaway, David J

2006-09-01

333

Drosophila Ebony Activity is Required in Glia for the Circadian Regulation of Locomotor Activity  

PubMed Central

Summary Previous studies suggest that glia may be required for normal circadian behavior, but glial factors required for rhythmicity have not been identified in any system. We show here that a circadian rhythm in Drosophila Ebony (N-?-alanyl-biogenic amine synthetase) abundance can be visualized in adult glia and that glial expression of Ebony rescues the altered circadian behavior of ebony mutants. We demonstrate that molecular oscillator function and clock neuron output are normal in ebony mutants, verifying a role for Ebony downstream of the clock. Surprisingly, the ebony oscillation persists in flies lacking PDF neuropeptide, indicating it is regulated by an autonomous glial oscillator or another neuronal factor. The proximity of Ebony-containing glia to aminergic neurons and genetic interaction results suggest a function in dopaminergic signaling. We thus suggest a model for ebony function wherein Ebony glia participate in the clock control of dopaminergic function and the orchestration of circadian activity rhythms.

Suh, Joowon; Jackson, F. Rob

2007-01-01

334

Food Anticipatory Activity Behavior of Mice across a Wide Range of Circadian and Non-Circadian Intervals  

PubMed Central

When rodents are fed in a limited amount during the daytime, they rapidly redistribute some of their nocturnal activity to the time preceding the delivery of food. In rats, anticipation of a daily meal has been interpreted as a circadian rhythm controlled by a food-entrained oscillator (FEO) with circadian limits to entrainment. Lesion experiments place this FEO outside of the light-entrainable circadian pacemaker in the suprachiasmatic nucleus. Mice also anticipate a fixed daily meal, but circadian limits to entrainment and anticipation of more than 2 daily meals, have not been assessed. We used a video-based behavior recognition system to quantify food anticipatory activity in mice receiving 2, 3, or 6 daily meals at intervals of 12, 8, or 4-hours (h). Individual mice were able to anticipate as many as 4 of 6 daily meals, and anticipation persisted during meal omission tests. On the 6 meal schedule, pre-prandial activity and body temperature were poorly correlated, suggesting independent regulation. Mice showed a limited ability to anticipate an 18 h feeding schedule. Finally, mice showed concurrent circadian and sub-hourly anticipation when provided with 6 small meals, at 30 minute intervals, at a fixed time of day. These results indicate that mice can anticipate feeding opportunities at a fixed time of day across a wide range of intervals not previously associated with anticipatory behavior in studies of rats. The methods described here can be exploited to determine the extent to which timing of different intervals in mice relies on common or distinct neural and molecular mechanisms.

Luby, Matthew D.; Hsu, Cynthia T.; Shuster, Scott A.; Gallardo, Christian M.; Mistlberger, Ralph E.; King, Oliver D.; Steele, Andrew D.

2012-01-01

335

Mangalith: a new lithium pacemaker battery  

Microsoft Academic Search

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

G. Gerbier; G. Lehmann

1980-01-01

336

Self-organized pacemakers in birhythmic media  

NASA Astrophysics Data System (ADS)

A birhythmic dynamical system is characterized by two coexisting stable limit cycles. In this article, a general reaction-diffusion system close to a supercritical pitchfork-Hopf bifurcation is investigated, where a soft onset of birhythmicity is possible. We show that stable self-organized pacemakers, which give rise to target patterns, exist and represent a generic type of spatio-temporal patterns in such a system. This is verified by numerical simulations which also show the existence of breathing and swinging pacemaker solutions. Stable pacemakers inhibit the formation of other pacemakers in the system. The drift of self-organized pacemakers in media with spatial parameter gradients is analytically and numerically investigated. Furthermore, instabilities induced by phase slips are also considered.

Stich, Michael; Ipsen, Mads; Mikhailov, Alexander S.

2002-10-01

337

Pacemaker safety and long-distance running  

PubMed Central

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

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

2004-01-01

338

Characterizing a mammalian circannual pacemaker.  

PubMed

Many species express endogenous cycles in physiology and behavior that allow anticipation of the seasons. The anatomical and cellular bases of these circannual rhythms have not been defined. Here, we provide strong evidence using an in vivo Soay sheep model that the circannual regulation of prolactin secretion, and its associated biology, derive from a pituitary-based timing mechanism. Circannual rhythm generation is seen as the product of the interaction between melatonin-regulated timer cells and adjacent prolactin-secreting cells, which together function as an intrapituitary "pacemaker-slave" timer system. These new insights open the way for a molecular analysis of long-term timing mechanisms. PMID:17185605

Lincoln, Gerald A; Clarke, Iain J; Hut, Roelof A; Hazlerigg, David G

2006-12-22

339

microRNA modulation of circadian clock period and entrainment  

PubMed Central

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

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

340

Cardiac Pacemaker Infection: Surgical Management With and Without Extracorporeal Circulation  

Microsoft Academic Search

Background. Pacemaker infections are rare, but serious complications of pacemaker therapy. The generator pocket, the pacing leads, or both may be involved.Methods. We report on 12 patients with infected pacemaker systems. Four patients suffered from localized generator pocket infections, 6 had infected leads, and 2 patients had both. Pacemaker systems were completely removed in all patients. When the infection was

Markus J Wilhelm; Christof Schmid; Dieter Hammel; Sebastian Kerber; Heinz Michael Loick; Mathias Herrmann; Hans H Scheld

1997-01-01

341

Damaging effect of therapeutic radiation on programmable pacemakers  

SciTech Connect

Two series of present-day pacemakers were tested in vitro with pulsed x-ray radiation. The first series of 12 pacemakers consisted of 10 different types and models of demand pacemakers (VVI). The second series of 13 pacemakers had 9 different types and models of programmable pacemakers. Unlike the first series which showed only mild changes in frequency and pulse width, all but four of the programmable pacemakers presented sudden complete failure after different radiation doses. We conclude that direct pulse radiation at therapeutic levels of programmable pacemakers should be avoided.

Adamec, R.; Haefliger, J.M.; Killisch, J.P.; Niederer, J.; Jaquet, P.

1982-03-01

342

Genetic Interaction of Per1 and Dec1\\/2 in the Regulation of Circadian Locomotor Activity  

Microsoft Academic Search

In mammals, 24-h rhythms are controlled by a hierarchical system of endogenous clocks, with a circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that synchronizes peripheral oscillators throughout the body. The molecular clock machinery is regulated by interlocked transcriptional translational feedback loops (TTLs). The core TTL includes the transcriptional modulators PER (1-3) and CRY (1\\/2) that feed

Brid Bode; Ali Shahmoradi; Moritz J. Rossner; Henrik Oster

2011-01-01

343

Social influences on circadian rhythms and sleep in insects.  

PubMed

The diverse social lifestyle and the small and accessible nervous system of insects make them valuable for research on the adaptive value and the organization principles of circadian rhythms and sleep. We focus on two complementary model insects, the fruit fly Drosophila melanogaster, which is amenable to extensive transgenic manipulations, and the honey bee Apis mellifera, which has rich and well-studied social behaviors. Social entrainment of activity rhythms (social synchronization) has been studied in many animals. Social time givers appear to be specifically important in dark cavity-dwelling social animals, but here there are no other clear relationships between the degree of sociality and the effectiveness of social entrainment. The olfactory system is important for social entrainment in insects. Little is known, however, about the molecular and neuronal pathways linking olfactory neurons to the central clock. In the honey bee, the expression, phase, and development of circadian rhythms are socially regulated, apparently by different signals. Peripheral clocks regulating pheromone synthesis and the olfactory system have been implicated in social influences on circadian rhythms in the fruit fly. An enriched social environment increases the total amount of sleep in both fruit flies and honey bees. In fruit flies, these changes have been linked to molecular and neuronal processes involved in learning, memory, and synaptic plasticity. The studies on insects suggest that social influences on the clock are richer than previously appreciated and have led to important breakthroughs in our understanding of the mechanisms underlying social influences on sleep and circadian rhythms. PMID:22902124

Eban-Rothschild, Ada; Bloch, Guy

2012-01-01

344

Pacemakers charging using body energy  

PubMed Central

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

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

2010-01-01

345

Biological Clocks & Circadian Rhythms  

ERIC Educational Resources Information Center

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

Robertson, Laura; Jones, M. Gail

2009-01-01

346

Pacemaker failure associated with therapeutic radiation  

SciTech Connect

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.

Brooks, C.; Mutter, M.

1988-11-01

347

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

PubMed Central

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3? antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.

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

2011-01-01

348

Chimera Analysis of the Clock Mutation in Mice Shows that Complex Cellular Integration Determines Circadian Behavior  

PubMed Central

Summary The Clock mutation lengthens periodicity and reduces amplitude of circadian rhythms in mice. The effects of Clock are cell intrinsic and can be observed at the level of single neurons in the suprachiasmatic nucleus. To address how cells of contrasting genotype functionally interact in vivo to control circadian behavior, we have analyzed a series of Clock mutant mouse aggregation chimeras. Circadian behavior in Clock/ Clock + wild-type chimeric individuals was determined by the proportion of mutant versus normal cells. Significantly, a number of intermediate phenotypes, including Clock/+ phenocopies and novel combinations of the parental behavioral characteristics, were seen in balanced chimeras. Multivariate statistical techniques were used to quantitatively analyze relationships among circadian period, amplitude, and suprachiasmatic nucleus composition. Together, our results demonstrate that complex integration of cellular phenotypes determines the generation and expression of coherent circadian rhythms at the organismal level.

Low-Zeddies, Sharon S.; Takahashi, Joseph S.

2013-01-01

349

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

PubMed

The circadian clock controls cell proliferation in a number of healthy tissues where cell renewal and regeneration are critical for normal physiological function. The intestine is an organ that typically undergoes regular cycles of cell division, differentiation and apoptosis as part of its role in digestion and nutrient absorption. The aim of this study was to explore circadian clock regulation of cell proliferation and cell cycle gene expression in the zebrafish intestine. Here we show that the zebrafish gut contains a directly light-entrainable circadian pacemaker, which regulates the daily timing of mitosis. Furthermore, this intestinal clock controls the expression of key cell cycle regulators, such as cdc2, wee1, p21, PCNA and cdk2, but only weakly influences cyclin B1, cyclin B2 and cyclin E1 expression. Interestingly, food deprivation has little impact on circadian clock function in the gut, but dramatically reduces cell proliferation, as well as cell cycle gene expression in this tissue. Timed feeding under constant dark conditions is able to drive rhythmic expression not only of circadian clock genes, but also of several cell cycle genes, suggesting that food can entrain the clock, as well as the cell cycle in the intestine. Rather surprisingly, we found that timed feeding is critical for high amplitude rhythms in cell cycle gene expression, even when zebrafish are maintained on a light-dark cycle. Together these results suggest that the intestinal clock integrates multiple rhythmic cues, including light and food, to function optimally. PMID:24013905

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

2013-08-27

350

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

PubMed Central

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

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

2010-01-01

351

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

PubMed Central

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

Kino, Tomoshige

2013-01-01

352

Melatonin, the Pineal Gland, and Circadian Rhythms.  

National Technical Information Service (NTIS)

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

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

1993-01-01

353

Circadian variation in base rate measures of cardiac autonomic activity.  

PubMed

To investigate the role of the circadian pacemaker in autonomic modulation of base rate cardiac activity, 29 healthy subjects participated in a constant routine protocol. They were randomly divided into two groups in order to manipulate prior wakefulness. Group 1 started at 0900 hours immediately after a monitored sleep period, while group 2 started 12 h later. Measures of interbeat intervals (IBIs), respiratory sinus arrhythmia (RSA, an estimate of parasympathetic activity), pre-ejection period (PEP, an estimate of sympathetic activity), and core body temperature (CBT) were recorded continuously. Multilevel regression analyses (across-subjects) revealed significant 24- and/or 12-h sinusoidal circadian variation for CBT, IBI, and RSA, but not for PEP. Subject-specific 24+12 h sinusoidal fits demonstrated a convergence of phase distribution for IBI and RSA of group 1 similar to CBT, while PEP showed a relatively large (i.e. random) distribution of phase. In group 2, all cardiac measures showed large distributions of phase. Unexpected results in the cardiac measures were found in group 2, probably caused by group differences in prior activation. Also, effects of sleep deprivation were observed for IBI and RSA in group 2. Consequently, all cardiac measures revealed significant sinusoidal x group interactions, a result not shown in CBT. These findings were interpreted as an indication for circadian endogenous parasympathetic modulation of cardiac activity that is mainly confounded by prior wakefulness that extends 24 h, while the sympathetic modulation is relatively uncoupled from the endogenous circadian drive and mainly influenced by prior activation. PMID:15243746

van Eekelen, Alexander P J; Houtveen, Jan H; Kerkhof, Gerard A

2004-07-08

354

CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION  

PubMed Central

Objective The aim of this article is to review progress in understanding the mechanisms that underlie circadian and sleep rhythms, and their role in the pathogenesis and treatment of depression. Methods Literature was selected principally by Medline searches, and additional reports were identified based on ongoing research activities in the authors’ laboratory. Results Many physiological processes show circadian rhythms of activity. Sleep and waking are the most obvious circadian rhythms in mammals. There is considerable evidence that circadian and sleep disturbances are important in the pathophysiology of mood disorders. Depressed patients often show altered circadian rhythms, sleep disturbances, and diurnal mood variation. Chronotherapies, including bright light exposure, sleep deprivation, and social rhythm therapies, may be useful adjuncts in non-seasonal and seasonal depression. Antidepressant drugs have marked effects on circadian processes and sleep. Conclusions Recent progress in understanding chronobiological and sleep regulation mechanisms may provide novel insights and avenues into the development of new pharmacological and behavioral treatment strategies for mood disorders.

Germain, Anne; Kupfer, David J.

2008-01-01

355

Circadian Regulation of Glutathione Levels and Biosynthesis in Drosophila melanogaster  

PubMed Central

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

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

2012-01-01

356

Circadian Oscillations within the Hippocampus Support Memory Formation and Persistence  

PubMed Central

The ability to sustain memories over long periods of time, sometimes even a lifetime, is one of the most remarkable properties of the brain. Much knowledge has been gained over the past few decades regarding the molecular correlates of memory formation. Once a memory is forged, however, the molecular events that provide permanence are as of yet unclear. Studies in multiple organisms have revealed that circadian rhythmicity is important for the formation, stability, and recall of memories (Gerstner et al., 2009).The neuronal events that provide this link need to be explored further. This article will discuss the findings related to the circadian regulation of memory-dependent processes in the hippocampus. Specifically, the circadian-controlled mitogen-activated protein kinase (MAPK) and cAMP signal transduction pathway plays critical roles in the consolidation of hippocampus-dependent memory. A series of studies have revealed the circadian oscillation of this pathway within the hippocampus, an activity that is absent in memory-deficient, transgenic mice lacking Ca2+-stimulated adenylyl cyclases. Interference with these oscillations proceeding the cellular memory consolidation period impairs the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend upon reactivation of this signal transduction pathway in the hippocampus during the circadian cycle. New data reveals the dependence of hippocampal oscillation in MAPK activity on the suprachiasmatic nucleus, again underscoring the importance of this region in maintaining the circadian physiology of memory. Finally, the downstream ramification of these oscillations in terms of gene expression and epigenetics should be considered, as emerging evidence is pointing strongly to a circadian link between epigenetics and long-term synaptic plasticity.

Eckel-Mahan, Kristin L.

2012-01-01

357

Wavelet Based Event Detection in Pacemakers.  

National Technical Information Service (NTIS)

This paper presents a detection algorithm for pacemakers which is based on a signal model including a linear combination of descriptive functions. The functions are defined as different time scales of the two fundamental waveforms in the electrogram. An e...

M. Astrom S. Olmos L. Sornmo

2001-01-01

358

The Dynamics of Competing Cardiac Pacemakers  

NASA Astrophysics Data System (ADS)

The modern theory of the dynamics of interacting oscillators has been applied to the analysis of heartbeat interval sequences in order to understand and predict the patterns of occurrence and timing of cardiac rhythm disturbances. The principal new contributions resulting from this research include: (1) The derivation of the symbolic dynamics of uncoupled cardiac pacemakers. (2) The geometric formulation of the interaction of coupled cardiac pacemakers as trajectories on the torus. (3) The derivation of a geometrical transformation of the heart beat interval sequence to the coupling function linking the activity of competing cardiac pacemakers. (4) The development of a transformation of the sequence of heart beat intervals which discriminates cardiac arrhythmias which result from anomalous pathways in the conduction system from those which result from competing pacemakers. (5) The formulation and testing through clinical case studies of a mathematical model which relates changes in heart rate to changes in the frequency of the occurrence of cardiac arrhythmias.

de Paola, Robert

359

Mangalith: a new lithium pacemaker battery  

SciTech Connect

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.

Gerbier, G.; Lehmann, G.

1980-01-01

360

Creating a cardiac pacemaker by gene therapy  

Microsoft Academic Search

While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias\\u000a and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This\\u000a has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic\\u000a pacemakers. Advances in cardiac gene therapy have resulted in

Traian M. Anghel; Steven M. Pogwizd

2007-01-01

361

Creating a Cardiac Pacemaker by Gene Therapy  

Microsoft Academic Search

While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias\\u000a and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This\\u000a has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic\\u000a pacemakers. Advances in cardiac gene therapy have resulted in

Traian M. Anghel; Steven M. Pogwizd

362

Circadian clocks and neurodegenerative diseases: time to aggregate?  

PubMed

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

Hastings, Michael H; Goedert, Michel

2013-06-21

363

Circadian clocks and neurodegenerative diseases: time to aggregate??  

PubMed Central

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

Hastings, Michael H; Goedert, Michel

2013-01-01

364

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

Microsoft Academic Search

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

Suzanne Colbron; Mark Jones; Stephany M Biello

2002-01-01

365

THE ARTIFICIAL CARDIAC PACEMAKER. INDICATIONS FOR IMPLANTATION.  

PubMed

Extensive clinical experience has demonstrated that implantable cardiac pacemakers are safe and effective mechanisms for controlling symptoms and preventing the hazards of third degree heart block with Stokes-Adams syncope. Medical management of this disease does not provide reliable protection and life expectancy averages about two years after diagnosis. Hence the negligible surgical morbidity and mortality associated with pacemaker implantation justifies broad indications to implant one of the four commercially available battery-powered units. ELECTIVE IMPLANTATION OF A PACEMAKER SHOULD BE CONSIDERED IN PATIENTS WITH PERSISTENT THIRD DEGREE HEART BLOCK WHO HAVE HAD: One or more episodes of Stokes-Adams syncope; surgical injury to the conduction system, regardless of syncopal attacks; evidence of low cardiac output with cardiomegaly secondary to bradycardia. Few if any other cardiac arrythmias are satisfactorily controlled by an electrical pacemaker. Emergency pacemaker control is obviously necessary for patients developing intractable or recurrent bouts of asystole. During the interval until an implantable unit can be obtained and sterilized, the patient may be controlled by intravenous isoproterenol or by an external pacemaker attached to a transvenous catheter electrode, a precordial skin electrode or a percutaneous myocardial wire electrode. PMID:14236028

ROE, B B; BRUNS, D L

1964-12-01

366

Entrainment of Circadian Programs  

Microsoft Academic Search

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

Carl Hirschie Johnson; Jeffrey A. Elliott; Russell Foster

2003-01-01

367

A circadian biosignature in the labeled release data from Mars?  

NASA Astrophysics Data System (ADS)

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 rigorous methods of circadian rhythm analysis are laid out to determine whether an endogenous circadian rhythm was present. The data will be analyzed for any free-running rhythm deviating from the Martian diurnal cycle. The possibility that nutrient administration altered the phase (i.e., timing) of the LR oscillations (as has been observed in terrestrial microorganisms) will also be examined. Any indication that the signal may be of biological origin will be tested against the hypothesis that it was caused solely by temperature-induced changes (e.g., temperature-dependent changes in soil physical chemistry). The focus of this paper is to develop broadly accepted methodology to determine definitively whether the LR data exhibit circadian characteristics that imply the involvement of Martian biology.

Van Dongen, Hans P. A.; Miller, Joseph D.; Levin, Gilbert V.; Straat, Patricia A.

2005-09-01

368

Interactions of the serotonin and circadian systems: nature and nurture in rhythms and blues.  

PubMed

The serotonin and circadian systems are principal regulatory networks of the brain. Each consists of a unique set of neurons that make widespread neural connections and a defined gene network of transcriptional regulators and signaling genes that subserve serotonergic and circadian function at the genetic level. These master regulatory networks of the brain are extensively intertwined, with reciprocal circuit connections, expression of key genetic elements for serotonin signaling in clock neurons and expression of key clock genes in serotonergic neurons. The reciprocal connections of the serotonin and circadian systems likely have importance for neurobehavioral disorders, as suggested by their convergent contribution to a similar range of mood disorders including seasonal affective disorder (SAD), bipolar disorder, and major depression, and as suggested by their overlapping relationship with the developmental disorder, autism spectrum disorder. Here we review the neuroanatomical and genetic basis for serotonin-circadian interactions in the brain, their potential relationship with neurobehavioral disorders, and recent work examining the effects on the circadian system of genetic perturbation of the serotonergic system as well as the molecular and behavioral effects of developmental imprinting of the circadian system with perinatal seasonal light cycles. PMID:21963350

Ciarleglio, C M; Resuehr, H E S; McMahon, D G

2011-09-21

369

Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock.  

PubMed

Two genes, period (per) and timeless (tim), are required for production of circadian rhythms in Drosophila. The proteins encoded by these genes (PER and TIM) physically interact, and the timing of their association and nuclear localization is believed to promote cycles of per and tim transcription through an autoregulatory feedback loop. Here it is shown that TIM protein may also couple this molecular pacemaker to the environment, because TIM is rapidly degraded after exposure to light. TIM accumulated rhythmically in nuclei of eyes and in pacemaker cells of the brain. The phase of these rhythms was differentially advanced or delayed by light pulses delivered at different times of day, corresponding with phase shifts induced in the behavioral rhythms. PMID:8596937

Myers, M P; Wager-Smith, K; Rothenfluh-Hilfiker, A; Young, M W

1996-03-22

370

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

NASA Astrophysics Data System (ADS)

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.

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

2009-06-01

371

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

PubMed

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. PMID:19566247

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

2009-06-01

372

Making Circadian Cancer Therapy Practical  

Microsoft Academic Search

Practical circadian therapy for the cancer patient involves 3 spheres of intervention—improving lifestyle, optimizing internal biochemical milieu, and adjusting treatment times. The potential value of improving overall circadian functioning is shown in the work of Mormont et al in which pronounced rest—activity rhythms were associated with better survival in colorectal cancer patients receiving chronomodulated chemotherapy. Lifestyle interventions that may improve

Keith I. Block; Penny B. Block; Susan Reynolds Fox; Jamie Stouffer Birris; April Y. Feng; Michael de la Torre; Deva Nathan; Peter Tothy; Amanda K. Maki; Charlotte Gyllenhaal

2009-01-01

373

Circadian regulation of renal function  

Microsoft Academic Search

Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to

Dmitri Firsov; Olivier Bonny

2010-01-01

374

Short-Wavelength Countermeasures for Circadian Desynchrony.  

National Technical Information Service (NTIS)

Exposure to light at critical phases of the circadian cycle entrains circadian rhythms. Exposure of humans to bright light for an hour or more at the right phase of the circadian cycle produces significant phase shifts of circadian rhythms speeding recove...

H. C. Heller M. Smith

2008-01-01

375

The Circadian Clock Influences Heart Performance  

Microsoft Academic Search

Circadian clocks are believed to provide the selective advantage of anticipation, thus allowing organisms to respond efficiently to stimuli at the appropriate moment. Disrupted circadian rhythms have been found to affect a variety of basic physiological processes. However, the importance of the circadian clock in regulating heart performance remains undetermined. We hypothesized that the circadian clock plays a crucial role

Xi Wu; Zhiwei Liu; Guangsen Shi; Lijuan Xing; Xiaohan Wang; Xiwen Gu; Zhipeng Qu; Zhen Dong; Jing Xiong; Xiang Gao; Chenyu Zhang; Ying Xu

2011-01-01

376

21 CFR 870.3620 - Pacemaker lead adaptor.  

Code of Federal Regulations, 2013 CFR

...Classification. Class II (special controls). The special control for this device is the...the Submission of Research and Marketing Applications for Permanent Pacemaker...for Pacemaker Lead Adaptor 510(k) Submissions.â [45 FR...

2013-04-01

377

Treatment of superior vena caval obstruction following permanent pacemaker extraction.  

PubMed

Superior vena caval (SVC) obstruction following permanent pacemaker lead extraction is a serious but uncommon complication. This report describes the case of an 83-year-old man treated by balloon angioplasty and femoral pacemaker implantation. PMID:12520683

Newall, Nick; Stables, Rod; Palmer, Nick; Ramsdale, David

2002-12-01

378

[Titanium nitride cardiac pacemaker electrodes].  

PubMed

The sensing and pacing performance of pacemaker electrodes is characterized by the electrochemical properties of the electrodes/tissue layer; the usually smooth metallic electrode surface results in a high pass filter characteristic. Consequently, the detected intracardiac signals, which control the implantable systems, are not optimally matched to the spectral contents of the depolarisation signal. To avoid interference caused by noise (EMI, muscle potentials, etc.) a shift of the frequency of the band pass towards the lower frequency spectrum is required. As previously reported, the electrochemical properties of sintered and surface-treated electrodes prove the predicted improvement of sensing performance if titanium-nitride coated electrodes are used. Our results demonstrate their superiority above all the other electrodes presently known. The advantages can be referred to the micro-crystalline surface structure achieved by sputter-deposited electrode coatings and the kinetics of the ionic exchange. Furthermore, the acute thresholds achieved with the TiN-systems were significantly better than those of the smooth metallic surface. These results were also confirmed for chronic implants and are attributable to the known biocompatibility of titanium and its alloys. PMID:2775825

Schaldach, M; Hubmann, M; Hardt, R; Weikl, A

379

Disrupted circadian rhythms in VIP and PHI-deficient mice  

Microsoft Academic Search

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

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

380

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

PubMed Central

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

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

2011-01-01

381

Uniform pacemaker and ICD information system in the Netherlands  

Microsoft Academic Search

In the Netherlands the Central Pacemaker Patient Registry (CPPR) collects information of pacemaker and ICD (implantable cardio defibrillator) patients from all 109 Dutch hospitals. Many pacemaker clinics use a computer to store their implant and follow-up data in a database. Because the devices are getting more and more complex more clinical data is needed for optimal use of the device.

C. A. M. Hooijschuur; W. A. Dijk; W. van der Velde; B. Sanon; C. Ammeraal; W. R. M. Dassen; H. J. Spruijt

2002-01-01

382

Development of the pacemaker tissues of the heart  

Microsoft Academic Search

Pacemaker and conduction system myocytes play crucial roles in initiating and regulating the contraction of the cardiac chambers. Genetic defects, acquired diseases, and aging cause dysfunction of the pacemaker and conduction tissues, emphasizing the clinical necessity to understand the molecular and cellular mechanisms of their development and homeostasis. Although all cardiac myocytes of the developing heart initially possess pacemaker properties,

V. M. Christoffels; G. J. Smits; A. Kispert; A. F. M. Moorman

2010-01-01

383

[Activation of latent pacemakers in the guinea pig ureter].  

PubMed

Guinea pig's ureter rhythmogenic autonomous latent pacemaker was shown to generate a significantly higher-frequency rhythm than the pericystic pacemaker. The latent pacemakers of the ureter middle portion can be activated with a breach of electrical conductivity across the organ or with chemical agents (noradrenaline, histamine). PMID:11575129

Kazarian, K V; Vantsian, V Ts; Tiraian, A S; Akopian, R R

2001-07-01

384

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

PubMed Central

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

Boivin, DB

2000-01-01

385

How does calcium-dependent intracellular regulation of voltage-dependent sodium current increase the sensitivity to the oxadiazine insecticide indoxacarb metabolite decarbomethoxylated JW062 (DCJW) in insect pacemaker neurons?  

PubMed

Decarbomethoxylated JW062 (DCJW), the active component of the oxadiazine insecticide (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl] amino]carbonyl] indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate (DPX-JW062) (indoxacarb), was tested on 2 inward voltage-dependent sodium currents (named INa1 and INa2) expressed in short-term cultured dorsal unpaired median neurons of the cockroach Periplaneta americana. Under whole-cell voltage-clamp conditions, application of DCJW resulted in a biphasic dose-dependent inhibition of the global sodium current amplitude illustrating the differing sensitivity of sodium channels to DCJW. INa2 was less sensitive to DCJW [half-maximal inhibitory concentration (IC(50)) = 1.6 microM] compared with INa1 (IC(50) = 1.7 nM). Although a previous study demonstrated that INa1 was regulated by the cAMP/protein kinase A cascade, we showed that INa2 was mainly regulated in an opposite way by the activation of calcium-calmodulin-dependent protein phosphatase 2B (PP2B) and calcium-calmodulin-dependent protein kinase II (CaM-kinase II). Furthermore, we demonstrated that activation of CaM-kinase II by intracellular calcium via the calcium-calmodulin complex affected the sensitivity of INa2 channels to DCJW. By increasing the intracellular calcium concentration and/or using 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) (a calcium chelator), N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7) (a calmodulin inhibitor), cyclosporine A (a PP2B inhibitor), and 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) (a CaM-kinase II inhibitor), we revealed that activation of CaM-kinase II was involved in the modulation of the voltage dependence of steady-state inactivation and that the CaM-kinase II pathway activated by elevation of the intracellular calcium concentration might render INa2 channels approximately 3000-fold more sensitive to DCJW. These results indicated that manipulating specific intracellular signaling pathways involved in the regulation of sodium channels might have fundamental consequences for the sensitivity of insects to insecticides. This finding reveals an exciting research area that could lead to improvement in the efficiency of insecticides. PMID:20056780

Lavialle-Defaix, Céline; Moignot, Bénédicte; Legros, Christian; Lapied, Bruno

2010-01-07

386

Circadian rhythms and molecular noise  

NASA Astrophysics Data System (ADS)

Circadian rhythms, characterized by a period of about 24 h, are the most widespread biological rhythms generated autonomously at the molecular level. The core molecular mechanism responsible for circadian oscillations relies on the negative regulation exerted by a protein on the expression of its own gene. Deterministic models account for the occurrence of autonomous circadian oscillations, for their entrainment by light-dark cycles, and for their phase shifting by light pulses. Stochastic versions of these models take into consideration the molecular fluctuations that arise when the number of molecules involved in the regulatory mechanism is low. Numerical simulations of the stochastic models show that robust circadian oscillations can already occur with a limited number of mRNA and protein molecules, in the range of a few tens and hundreds, respectively. Various factors affect the robustness of circadian oscillations with respect to molecular noise. Besides an increase in the number of molecules, entrainment by light-dark cycles, and cooperativity in repression enhance robustness, whereas the proximity of a bifurcation point leads to less robust oscillations. Another parameter that appears to be crucial for the coherence of circadian rhythms is the binding/unbinding rate of the inhibitory protein to the promoter of the clock gene. Intercellular coupling further increases the robustness of circadian oscillations.

Gonze, Didier; Goldbeter, Albert

2006-06-01

387

Circadian rhythms and athletic performance.  

PubMed

Daily or circadian rhythmical oscillations occur in several physiological and behavioral functions that contribute to athletic performance. These functions include resting levels of sensory motor, perceptual, and cognitive performance and several neuromuscular, behavioral, cardiovascular, and metabolic variables. In addition, circadian rhythms have been reported in many indices of aerobic capacity, in certain physiological variables at different exercise levels, and, in a few studies, in actual athletic performance proficiency. Circadian rhythmicity in components of athletic performance can be modulated by workload, psychological stressors, motivation, "morningness/eveningness" differences, social interaction, lighting, sleep disturbances, the "postlunch dip" phenomenon, altitude, dietary constituents, gender, and age. These rhythms can significantly influence performance depending upon the time of day at which the athletic endeavor takes place. Disturbance of circadian rhythmicity resulting from transmeridian flight across several time zones can result in fatigue, malaise, sleep disturbance, gastrointestinal problems, and performance deterioration in susceptible individuals (circadian dysrhythmia or "jet-lag"). Factors influencing the degree of impairment and duration of readaptation include direction of flight, rhythm synchronizer intensity, dietary constituents and timing of meals, and individual factors such as morningness/eveningness, personality traits, and motivation. It is the intent of the authors to increase awareness of circadian rhythmic influences upon physiology and performance and to provide a scientific data base for the human circadian system so that coaches and athletes can make reasonable decisions to reduce the negative impact of jet-lag and facilitate readaptation following transmeridian travel. PMID:3906341

Winget, C M; DeRoshia, C W; Holley, D C

1985-10-01

388

Regional differences in the circadian modulation of human sleep spindle characteristics.  

PubMed

Electroencephalographic oscillations in the sleep spindle frequency range (11-16 Hz) are a key element of human nonrapid eye movement sleep. In the present study, sleep spindle characteristics along the anterior-posterior axis were analysed during and outside the circadian phase of melatonin secretion. Sleep electroencephalograms were recorded during naps distributed over the entire circadian cycle and analysed with two different methodological approaches, the classical fast Fourier transform in the frequency-domain and a new method for instantaneous spectral analysis, the fast time frequency transform that yields high-resolution parameters in the combined time-frequency-domain. During the phase of melatonin secretion, spindle density was generally increased and intraspindle frequency variation reduced. Furthermore, lower spindle frequencies were promoted: peak frequencies shifted towards the lower end of the spindle frequency range, and spindle amplitude was enhanced in the low-frequency range (11-14.25 Hz) and reduced in the high-frequency range (approximately 14.5-16 Hz). The circadian variation showed a clear dependence on brain topography such that it was maximal in the parietal and minimal in the frontal derivation. Our data provide evidence that the circadian pacemaker actively promotes low-frequency sleep spindles during the biological night with a parietal predominance. PMID:12859349

Knoblauch, Vera; Martens, Wim; Wirz-Justice, Anna; Kräuchi, Kurt; Cajochen, Christian

2003-07-01

389

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

PubMed

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

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

2013-07-03

390

Photorefractoriness in mammals: dissociating a seasonal timer from the circadian-based photoperiod response.  

PubMed

In seasonal animals, prolonged exposure to constant photoperiod induces photorefractoriness, causing spontaneous reversion in physiology to that of the previous photoperiodic state. This study tested the hypothesis that the onset of photorefractoriness is correlated with a change in circadian expression of clock genes in the suprachiasmatic nucleus (circadian pacemaker) and the pars tuberalis (PT, a melatonin target tissue). Soay sheep were exposed to summer photoperiod (16-h light) for either 6 or 30 wk to produce a photostimulated and photorefractory physiology, and seasonal changes were tracked by measuring the long-term prolactin cycles. Animals were killed at 4-h intervals throughout 24 h. Contrary to the hypothesis, the 24-h rhythmic expression of clock genes (Rev-erbalpha, Per1, Per2, Bmal1, Cry1) in the suprachiasmatic nucleus and PT reflected the ambient photoperiod/melatonin signal and not the changing physiology. Contrastingly, the PT expression of alpha-glycoprotein hormone subunit (alphaGSU) and betaTSH declined in photorefractory animals toward a short day-like endocrinology. We conclude that the generation of long-term endocrine cycles depends on the interaction between a circadian-based, melatonin-dependent timer that drives the initial photoperiodic response and a non-circadian-based timer that drives circannual rhythmicity in long-lived species. Under constant photoperiod the two timers can dissociate, leading to the apparent refractory state. PMID:15919753

Lincoln, Gerald A; Johnston, Jonathan D; Andersson, Hakan; Wagner, Gabriela; Hazlerigg, David G

2005-05-26

391

Circadian Desynchrony Promotes Metabolic Disruption in a Mouse Model of Shiftwork  

PubMed Central

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

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

2012-01-01

392

GW182 controls Drosophila circadian behavior and PDF-receptor signaling.  

PubMed

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

Zhang, Yong; Emery, Patrick

2013-04-10

393

Sleep Syncope: Treatment with a Permanent Pacemaker  

PubMed Central

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

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

2013-01-01

394

Sleep syncope: treatment with a permanent pacemaker.  

PubMed

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

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

2012-03-20

395

Circadian rhythms and tumor growth.  

PubMed

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

Greene, Michael W

2012-01-15

396

Biological Clocks and Circadian Rhythms  

NSDL National Science Digital Library

The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian rhythms, they are provided with opportunities to connect learning to experiences and observations from their own lives. This article describes how to reset the biological clock of a shamrock plant while shedding light on its circadian rhythms.

Robertson, Laura; Jones, M. G.

2009-02-01

397

CIRCADIAN RHYTHMS: Integrating Circadian Timekeeping with Cellular Physiology  

NSDL National Science Digital Library

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

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

2008-05-16

398

Role of cardiomyocyte circadian clock in myocardial metabolic adaptation  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

399

Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity.  

PubMed

Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes. We subjected male C57Bl/6J mice to constant light [12-h light-light (LL) cycle] to examine the effects of a disturbed circadian rhythm on energy metabolism and insulin sensitivity. In vivo electrophysiological recordings in the central pacemaker of the suprachiasmatic nuclei (SCN) revealed an immediate reduction in rhythm amplitude, stabilizing at 44% of normal amplitude values after 4 d LL. Food intake was increased (+26%) and energy expenditure decreased (-13%), and we observed immediate body weight gain (d 4: +2.4%, d 14: +5.0%). Mixed model analysis revealed that weight gain developed more rapidly in response to LL as compared to high fat. After 4 wk in LL, the circadian pattern in feeding and energy expenditure was completely lost, despite continuing low-amplitude rhythms in the SCN and in behavior, whereas weight gain had stabilized. Hyperinsulinemic-euglycemic clamp analysis revealed complete abolishment of normal circadian variation in insulin sensitivity in LL. In conclusion, a reduction in amplitude of the SCN, to values previously observed in aged mice, is sufficient to induce a complete loss of circadian rhythms in energy metabolism and insulin sensitivity. PMID:23303208

Coomans, Claudia P; van den Berg, Sjoerd A A; Houben, Thijs; van Klinken, Jan-Bert; van den Berg, Rosa; Pronk, Amanda C M; Havekes, Louis M; Romijn, Johannes A; van Dijk, Ko Willems; Biermasz, Nienke R; Meijer, Johanna H

2013-01-09

400

Disruption of the Circadian Output Molecule Prokineticin 2 Results in Anxiolytic and Antidepressant-like Effects in Mice  

PubMed Central

Disrupted circadian rhythms are strictly associated with mood disorders. The suprachiasmatic nucleus (SCN) is the master pacemaker that drives circadian rhythms in mammals. However, the underlying molecular connections of circadian rhythm and mood disorders are still poorly understood. Prokineticin 2 (PK2) is a signaling molecule that is critical for transmitting the circadian rhythms from the SCN. Previously, it is has been shown that the receptor for PK2 is expressed in virtually all of the primary SCN target areas, most of which are also involved in the mood regulation. In the current study, we investigated the role of PK2 in the regulation of anxiety and depression-related behaviors. Intracerebroventricular (ICV) infusion of PK2 increased anxiety-like behavior as assessed by light–dark box. ICV delivery of PK2 also led to increased depression-like behavior in the forced swimming test. Conversely, mice lacking the PK2 gene (PK2?/? mice) displayed significantly reduced anxiety and depression-like behaviors. Furthermore, PK2?/? mice showed impaired responses to new environments in terms of locomotor activity, arousal, body temperature, and food intake. Our studies, thus, indicate that PK2 signaling plays a critical role in the stress-related traits in mice, and establish a possible molecular link between circadian rhythms and mood regulation.

Li, Jia-Da; Hu, Wang-Ping; Zhou, Qun-Yong

2009-01-01

401

Cardiac pacemaker: 15 years of "new" interpretation.  

PubMed

After more than 15 years since the "new" interpretation of the Purkinje fibre's pacemaker current was proposed, much progress has been made in the understanding of the basic functional principles of cardiac pacemaking. We now know that, in both the SA node and Purkinje fibres, the diastolic depolarization is generated by the interplay of several ionic components, the key process being represented by the turning-on of the hyperpolarization-activated i(f) current towards the end of the action potential repolarization phase. The properties of i(f) are well suited not only to generate, but also to mediate the control of cardiac rate by autonomic transmitters. This control is exerted through modulation of adenylate-cyclase and of cAMP, and allows a fine and rapid adjustment of heart rate to the changing needs of our normal day-life. Still, several problems remain to be clarified : for example, it is not clear how the degree of involvement of i(f) and other components changes in different areas of the nodal region, and whether this process is under control of the autonomic nervous system; more importantly, it is still unknown if the pacemaking mechanisms are similar in the newborn and in the adult, or if developmental changes in the way pacemaker activity is generated and modulated exist. PMID:8932564

DiFrancesco, D

1995-01-01

402

Clinical assessment of pacemaker power sources  

SciTech Connect

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.

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

1980-01-01

403

Steroid treatment of the painful pacemaker pocket.  

PubMed

Chronic pain about a pacemaker secondary to sterile fibrotic contracture of the capsule is an uncommon but frustrating complication for both the physician and the patient. Three cases of this complication controlled by the late injection of triamcinolone are reported. PMID:6199773

Kratz, J M; Campbell, W C; Leman, R B; Harvin, J S

1984-01-01

404

Common indications of permanent pacemaker insertion.  

PubMed

Approximately one million people in the US have permanent pacemakers. These patients are usually seen in general practice and referred to a cardiologist. Therefore, it is important for the internists and hospitalists to be aware of the indications and complications of cardiac pacing. PMID:18681108

Ahmed, Syed Mashood; Ansari, Muhammad Jaffer

2008-01-01

405

Veela defines a molecular link between Cryptochrome and Timeless in the light-input pathway to Drosophila's circadian clock  

PubMed Central

Organisms use the daily cycles of light and darkness to synchronize their internal circadian clocks with the environment. Because they optimize physiological processes and behavior, properly synchronized circadian clocks are thought to be important for the overall fitness. In Drosophila melanogaster, the circadian clock is synchronized with the natural environment by light-dependent degradation of the clock protein Timeless, mediated by the blue-light photoreceptor Cryptochrome (Cry). Here we report identification of a genetic variant, Veela, which severely disrupts this process, because these genetically altered flies maintain behavioral and molecular rhythmicity under constant-light conditions that usually stop the clock. We show that the Veela strain carries a natural timeless allele (ls-tim), which encodes a less-light-sensitive form of Timeless in combination with a mutant variant of the F-box protein Jetlag. However, neither the ls-tim nor the jetlag genetic variant alone is sufficient to disrupt light input into the central pacemaker. We show a strong interaction between Veela and cryptochrome genetic variants, demonstrating that the Jetlag, Timeless, and Cry proteins function in the same pathway. Veela also reveals a function for the two natural variants of timeless, which differ in their sensitivity to light. In combination with the complex array of retinal and extraretinal photoreceptors known to signal light to the pacemaker, this previously undescribed molecular component of photic sensitivity mediated by the two Timeless proteins reveals that an unexpectedly rich complexity underlies modulation of this process.

Peschel, Nicolai; Veleri, Shobi; Stanewsky, Ralf

2006-01-01

406

Wake-related activity of tuberomammillary neurons in rats  

Microsoft Academic Search

Histaminergic neurons of the tuberomammillary nucleus (TMN) are hypothesized to promote wakefulness, but little is known about the activity of these cells during spontaneous behavior. We measured histaminergic neuron activity in the dorsomedial, ventrolateral, and caudal TMN at four different times using Fos and adenosine deaminase immunohistochemistry and recordings of sleep\\/wake behavior. Because circadian factors could influence neuronal activity, we

Emily M. Ko; Ivy V. Estabrooke; Marie McCarthy; Thomas E. Scammell

2003-01-01

407

Measuring pacemaker dose: A clinical perspective  

SciTech Connect

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.

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

2012-07-01

408

Measuring pacemaker dose: a clinical perspective.  

PubMed

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

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

2011-08-27

409

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

Microsoft Academic Search

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

Jianqing Wang; Osamu Fujiwara; Toshio Nojima

2000-01-01

410

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

NASA Astrophysics Data System (ADS)

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

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

2010-04-01

411

Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia  

PubMed Central

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythmin humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain–behaviour relationships in the human.

Harper, David G.; Stopa, Edward G.; Kuo-Leblanc, Victoria; McKee, Ann C.; Asayama, Kentaro; Volicer, Ladislav; Kowall, Neil; Satlin, Andrew

2012-01-01

412

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

PubMed

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. PMID:22351107

Huddle, Thomas S; Amos Bailey, F

2012-12-01

413

[Two cases of depressive disorder after pacemaker implantation].  

PubMed

We report 2 patients who showed psychological symptoms after pacemaker implantation. Pacemaker syndrome was excluded, and a diagnosis of depressive disorder not otherwise specified was made in both patients. Patient 1 complained of discomfort early after pacemaker implantation but became unaware of the pacemaker after 1 year. However, after 3 years, lack of activity, general fatigue, and unaccountable sensations developed. These symptoms improved with symbiosis with the pacemaker. Patient 2 developed many complications after pacemaker implantation. Therefore, he was markedly aware of the pacemaker as not-self and wanted to remove it. One month after implantation, unaccountable sensations and irritations began to occur. He did not return to work, and the symptoms improved with progression of "mourning for the loss of the perfection of the own body". In both patients, their symptoms improved after "acceptance that their own body depended on the pacemaker" and "symbiosis with the pacemaker as not-self", not complete integration of the pacemaker. Therefore, the psychological process after pacemaker implantation consisted of the establishment of "mourning for the loss of the perfection of the own body" and "symbiosis with not-self". In these patients, this process was impaired, causing depressive symptoms. This process resembled the integration process in patients undergoing dialysis or renal transplantation. As, compared with renal transplantation, it is more difficult to integrate the pacemaker to the own body, so, it seems better to aim for "symbiosis with the pacemaker" to promote the adjustment process. To promote the adjustment process and decrease depression, support after understanding of this psychological process is needed. PMID:8552727

Tanaka, K

1995-01-01

414

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

PubMed Central

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

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

2013-01-01

415

Circadian Variations in Time Perception in Rats.  

National Technical Information Service (NTIS)

Circadian variations in time perception in rats. The hypothesis that time perception is determined by an internal clock's rate, which is sensitive to physioligical circadian changes was examined. This hypothesis suggests that when body temperature and act...

D. Shurtleff T. G. Raslear L. Simmons

1990-01-01

416

Melatonin, the Pineal Gland and Circadian Rhythms.  

National Technical Information Service (NTIS)

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

V. M. Cassone

1995-01-01

417

Circadian rhythm of melatonin release in pineal gland culture: arg-vasopressin inhibits melatonin release  

Microsoft Academic Search

The mammalian pineal gland is known to receive a noradrenergic sympathetic efferent signal from the suprachiasmatic nucleus (SCN) via the superior cervical ganglion. Arg-vasopressin (AVP) containing neurons in the SCN is one of the output paths of circadian information to the other brain areas. AVP release from the SCN is suppressed by melatonin. In turn, we determined the direct effect

Yoshiaki Isobe; Junko Fujioi; Hitoo Nishino

2001-01-01

418

Multiple Amidated Neuropeptides Are Required for Normal Circadian Locomotor Rhythms in Drosophila  

Microsoft Academic Search

In Drosophila, the amidated neuropeptide pigment dispersing factor (PDF) is expressed by the ventral subset of lateral pace- maker neurons and is required for circadian locomotor rhythms. Residual rhythmicity in pdf mutants likely reflects the activity of other neurotransmitters. We asked whether other neuropep- tides contribute to such auxiliary mechanisms. We used the gal4\\/UAS system to create mosaics for the

Paul H. Taghert; Randall S. Hewes; Jae H. Park; Martha A. O'Brien; Mei Han; Molly E. Peck

2001-01-01

419

Circadian Rhythms in Drinking Behavior and Locomotor Activity of Rats are Eliminated by Hypothalamic Lesions  

Microsoft Academic Search

Bilateral electrolytic lesions in the suprachiasmatic nuclei permanently eliminated nocturnal and circadian rhythms in drinking behavior and locomotor activity of albino rats. The generation of 24-hr behavioral rhythms and the entrainment of these rhythms to the light-dark cycle of environmental illumination may be coordinated by neurons in the suprachiasmatic region of the rat brain. Destruction of the medial preoptic area

Friedrich K. Stephan; Irving Zucker

1972-01-01

420

Diurnal regulation of the gastrin-releasing peptide receptor in the mouse circadian clock  

Microsoft Academic Search

In mammals, circadian rhythms are generated by the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN neurons are heterogeneous and can be classified according to their function, anatomical connections, morphology and ?or peptidergic identity. We focus here on gastrin-releasing peptide- (GRP) and on GRP receptor- (GRPr) expressing cells of the SCN. Pharmacological application of GRP in vivo or in vitro can

Ilia N. Karatsoreos; Russell D. Romeo; Bruce S. McEwen; Rae Silver

2006-01-01

421

The circadian control of calling song and walking activity patterns in male crickets (Teleogryllus commodus).  

PubMed

Calling song and walking activity patterns of the Australian field cricket Teleogryllus commodus were simultaneously recorded in LD and LL at constant temperature. The results were analysed with respect to their circadian structure: (1) Circadian properties were expressed more clearly in singing than in walking, with cases approaching arrhythmicity in the latter. Still, (independent) circadian control was proven for walking as in most cases the phase response of the recorded data was different from tha