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A multiscale model to investigate circadian rhythmicity of pacemaker neurons in the suprachiasmatic nucleus.

Vasalou C, Henson MA - PLoS Comput. Biol. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, United States of America.

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.

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Schematic representation of the SCN neuron model.The gene expression model was obtained from a published study by Leloup and Goldbeter (2003), whereas the intracellular calcium model was adapted from Goldbeter et. al (1990). VIP expressed as a function of firing frequency was responsible for the rhythmic release of GABA. Because our model describes a single SCN cell, we assumed that the VIP and GABA concentrations acting on the cell membrane were the same as the released concentrations. In that sense our model assumes autocrine responses. The signaling cascade that activates Per transcription was adapted from To et. al (2007) to include the effects of intracellular calcium. Extracellular post-synaptic currents involve AMPA and NMDA receptors activated in a constant phase relationship to the Na+ and Ca2+ concentrations, respectively.
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pcbi-1000706-g001: Schematic representation of the SCN neuron model.The gene expression model was obtained from a published study by Leloup and Goldbeter (2003), whereas the intracellular calcium model was adapted from Goldbeter et. al (1990). VIP expressed as a function of firing frequency was responsible for the rhythmic release of GABA. Because our model describes a single SCN cell, we assumed that the VIP and GABA concentrations acting on the cell membrane were the same as the released concentrations. In that sense our model assumes autocrine responses. The signaling cascade that activates Per transcription was adapted from To et. al (2007) to include the effects of intracellular calcium. Extracellular post-synaptic currents involve AMPA and NMDA receptors activated in a constant phase relationship to the Na+ and Ca2+ concentrations, respectively.

Mentions: In this work we developed a firing rate code model to capture the circadian fluctuations of relevant ion channels as well as 24 hour trends in core-clock gene expression. Individual currents (IK, INa, ICa, IKCa, Iex and Iinhib) were assumed to interact with the circadian gene regulatory network via signaling pathways that included VIP and Ca2+ contributions (Fig. 1). Our model produced daily oscillations in constant darkness with 23.6 hour periodicity in the ionic and synaptic currents (Figs. 2A–2F), intracellular calcium concentration (Fig. 2G), Per mRNA expression (Fig. 2H) and neural firing rate (Fig. 2I). These rhythmic profiles constitute the nominal output of our model and will be referred to as the “control.”


A multiscale model to investigate circadian rhythmicity of pacemaker neurons in the suprachiasmatic nucleus.

Vasalou C, Henson MA - PLoS Comput. Biol. (2010)

Schematic representation of the SCN neuron model.The gene expression model was obtained from a published study by Leloup and Goldbeter (2003), whereas the intracellular calcium model was adapted from Goldbeter et. al (1990). VIP expressed as a function of firing frequency was responsible for the rhythmic release of GABA. Because our model describes a single SCN cell, we assumed that the VIP and GABA concentrations acting on the cell membrane were the same as the released concentrations. In that sense our model assumes autocrine responses. The signaling cascade that activates Per transcription was adapted from To et. al (2007) to include the effects of intracellular calcium. Extracellular post-synaptic currents involve AMPA and NMDA receptors activated in a constant phase relationship to the Na+ and Ca2+ concentrations, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837390&req=5

pcbi-1000706-g001: Schematic representation of the SCN neuron model.The gene expression model was obtained from a published study by Leloup and Goldbeter (2003), whereas the intracellular calcium model was adapted from Goldbeter et. al (1990). VIP expressed as a function of firing frequency was responsible for the rhythmic release of GABA. Because our model describes a single SCN cell, we assumed that the VIP and GABA concentrations acting on the cell membrane were the same as the released concentrations. In that sense our model assumes autocrine responses. The signaling cascade that activates Per transcription was adapted from To et. al (2007) to include the effects of intracellular calcium. Extracellular post-synaptic currents involve AMPA and NMDA receptors activated in a constant phase relationship to the Na+ and Ca2+ concentrations, respectively.
Mentions: In this work we developed a firing rate code model to capture the circadian fluctuations of relevant ion channels as well as 24 hour trends in core-clock gene expression. Individual currents (IK, INa, ICa, IKCa, Iex and Iinhib) were assumed to interact with the circadian gene regulatory network via signaling pathways that included VIP and Ca2+ contributions (Fig. 1). Our model produced daily oscillations in constant darkness with 23.6 hour periodicity in the ionic and synaptic currents (Figs. 2A–2F), intracellular calcium concentration (Fig. 2G), Per mRNA expression (Fig. 2H) and neural firing rate (Fig. 2I). These rhythmic profiles constitute the nominal output of our model and will be referred to as the “control.”

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus