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A Multiscale Model to Investigate Circadian Rhythmicity of Pacemaker Neurons in the Suprachiasmatic Nucleus  [PDF]
Christina Vasalou,Michael A. Henson
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000706
Abstract: The suprachiasmatic nucleus (SCN) of the hypothalamus is a multicellular system that drives daily rhythms in mammalian behavior and physiology. Although the gene regulatory network that produces daily oscillations within individual neurons is well characterized, less is known about the electrophysiology of the SCN cells and how firing rate correlates with circadian gene expression. We developed a firing rate code model to incorporate known electrophysiological properties of SCN pacemaker cells, including circadian dependent changes in membrane voltage and ion conductances. Calcium dynamics were included in the model as the putative link between electrical firing and gene expression. Individual ion currents exhibited oscillatory patterns matching experimental data both in current levels and phase relationships. VIP and GABA neurotransmitters, which encode synaptic signals across the SCN, were found to play critical roles in daily oscillations of membrane excitability and gene expression. Blocking various mechanisms of intracellular calcium accumulation by simulated pharmacological agents (nimodipine, IP3- and ryanodine-blockers) reproduced experimentally observed trends in firing rate dynamics and core-clock gene transcription. The intracellular calcium concentration was shown to regulate diverse circadian processes such as firing frequency, gene expression and system periodicity. The model predicted a direct relationship between firing frequency and gene expression amplitudes, demonstrated the importance of intracellular pathways for single cell behavior and provided a novel multiscale framework which captured characteristics of the SCN at both the electrophysiological and gene regulatory levels.
Phase Resetting of the Mammalian Circadian Clock Relies on a Rapid Shift of a Small Population of Pacemaker Neurons  [PDF]
Jos H. T. Rohling, Henk Tjebbe vanderLeest, Stephan Michel, Mariska J. Vansteensel, Johanna H. Meijer
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025437
Abstract: The circadian pacemaker of the suprachiasmatic nuclei (SCN) contains a major pacemaker for 24 h rhythms that is synchronized to the external light-dark cycle. In response to a shift in the external cycle, neurons of the SCN resynchronize with different pace. We performed electrical activity recordings of the SCN of rats in vitro following a 6 hour delay of the light-dark cycle and observed a bimodal electrical activity pattern with a shifted and an unshifted component. The shifted component was relatively narrow as compared to the unshifted component (2.2 h and 5.7 h, respectively). Curve fitting and simulations predicted that less than 30% of the neurons contribute to the shifted component and that their phase distribution is small. This prediction was confirmed by electrophysiological recordings of neuronal subpopulations. Only 25% of the neurons exhibited an immediate shift in the phase of the electrical activity rhythms, and the phases of the shifted subpopulations appeared significantly more synchronized as compared to the phases of the unshifted subpopulations (p<0.05). We also performed electrical activity recordings of the SCN following a 9 hour advance of the light-dark cycle. The phase advances induced a large desynchrony among the neurons, but consistent with the delays, only 19% of the neurons peaked at the mid of the new light phase. The data suggest that resetting of the central circadian pacemaker to both delays and advances is brought about by an initial shift of a relatively small group of neurons that becomes highly synchronized following a shift in the external cycle. The high degree of synchronization of the shifted neurons may add to the ability of this group to reset the pacemaker. The large desynchronization observed following advances may contribute to the relative difficulty of the circadian system to respond to advanced light cycles.
Lmo Mutants Reveal a Novel Role for Circadian Pacemaker Neurons in Cocaine-Induced Behaviors  [PDF]
Linus T.-Y Tsai,Roland J. Bainton,Justin Blau,Ulrike Heberlein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020408
Abstract: Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LNvs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LNv function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LNvs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LNvs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LNvs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug.
Lmo Mutants Reveal a Novel Role for Circadian Pacemaker Neurons in Cocaine-Induced Behaviors  [PDF]
Linus T.-Y Tsai,Roland J Bainton,Justin Blau,Ulrike Heberlein
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020408
Abstract: Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LNvs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LNv function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LNvs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LNvs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LNvs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug.
The Neuropeptide PDF Acts Directly on Evening Pacemaker Neurons to Regulate Multiple Features of Circadian Behavior  [PDF]
Bridget C. Lear,Luoying Zhang,Ravi Allada
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000154
Abstract: Discrete clusters of circadian clock neurons temporally organize daily behaviors such as sleep and wake. In Drosophila, a network of just 150 neurons drives two peaks of timed activity in the morning and evening. A subset of these neurons expresses the neuropeptide pigment dispersing factor (PDF), which is important for promoting morning behavior as well as maintaining robust free-running rhythmicity in constant conditions. Yet, how PDF acts on downstream circuits to mediate rhythmic behavior is unknown. Using circuit-directed rescue of PDF receptor mutants, we show that PDF targeting of just ~30 non-PDF evening circadian neurons is sufficient to drive morning behavior. This function is not accompanied by large changes in core molecular oscillators in light-dark, indicating that PDF RECEPTOR likely regulates the output of these cells under these conditions. We find that PDF also acts on this focused set of non-PDF neurons to regulate both evening activity phase and period length, consistent with modest resetting effects on core oscillators. PDF likely acts on more distributed pacemaker neuron targets, including the PDF neurons themselves, to regulate rhythmic strength. Here we reveal defining features of the circuit-diagram for PDF peptide function in circadian behavior, revealing the direct neuronal targets of PDF as well as its behavioral functions at those sites. These studies define a key direct output circuit sufficient for multiple PDF dependent behaviors.
The Neuropeptide PDF Acts Directly on Evening Pacemaker Neurons to Regulate Multiple Features of Circadian Behavior  [PDF]
Bridget C. Lear,Luoying Zhang,Ravi Allada
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000154
Abstract: Discrete clusters of circadian clock neurons temporally organize daily behaviors such as sleep and wake. In Drosophila, a network of just 150 neurons drives two peaks of timed activity in the morning and evening. A subset of these neurons expresses the neuropeptide pigment dispersing factor (PDF), which is important for promoting morning behavior as well as maintaining robust free-running rhythmicity in constant conditions. Yet, how PDF acts on downstream circuits to mediate rhythmic behavior is unknown. Using circuit-directed rescue of PDF receptor mutants, we show that PDF targeting of just ~30 non-PDF evening circadian neurons is sufficient to drive morning behavior. This function is not accompanied by large changes in core molecular oscillators in light-dark, indicating that PDF RECEPTOR likely regulates the output of these cells under these conditions. We find that PDF also acts on this focused set of non-PDF neurons to regulate both evening activity phase and period length, consistent with modest resetting effects on core oscillators. PDF likely acts on more distributed pacemaker neuron targets, including the PDF neurons themselves, to regulate rhythmic strength. Here we reveal defining features of the circuit-diagram for PDF peptide function in circadian behavior, revealing the direct neuronal targets of PDF as well as its behavioral functions at those sites. These studies define a key direct output circuit sufficient for multiple PDF dependent behaviors.
PDFR and CRY Signaling Converge in a Subset of Clock Neurons to Modulate the Amplitude and Phase of Circadian Behavior in Drosophila  [PDF]
Seol Hee Im,Weihua Li,Paul H. Taghert
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018974
Abstract: To synchronize their molecular rhythms, circadian pacemaker neurons must input both external and internal timing cues and, therefore, signal integration between sensory information and internal clock status is fundamental to normal circadian physiology.
Modeling the Emergence of Circadian Rhythms in a Clock Neuron Network  [PDF]
Luis Diambra, Coraci P. Malta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033912
Abstract: 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.
Emergence of Noise-Induced Oscillations in the Central Circadian Pacemaker  [PDF]
Caroline H. Ko,Yujiro R. Yamada,David K. Welsh,Ethan D. Buhr,Andrew C. Liu,Eric E. Zhang,Martin R. Ralph,Steve A. Kay,Daniel B. Forger,Joseph S. Takahashi
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000513
Abstract: 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.
Emergence of Noise-Induced Oscillations in the Central Circadian Pacemaker  [PDF]
Caroline H. Ko equal contributor,Yujiro R. Yamada equal contributor,David K. Welsh equal contributor,Ethan D. Buhr,Andrew C. Liu,Eric E. Zhang,Martin R. Ralph,Steve A. Kay,Daniel B. Forger,Joseph S. Takahashi
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000513
Abstract: 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.
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