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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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Cytosolic calcium levels regulate circadian behavior.Circadian profiles of Per mRNA (A) and firing rate (B) are shown for the control (black line), 50% reduced cytosolic Ca2+ concentration (red dashed line) and 50% increased cytosolic Ca2+ concentration (blue dotted line) compared to the control. C). Per mRNA (red dashed line) and firing rate (black solid line) amplitudes as a function of the cytosolic calcium concentration. D). The period of the core oscillator as a function of the cytosolic calcium concentration. The circles in 6C and 6D represent nominal values of the model.
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pcbi-1000706-g006: Cytosolic calcium levels regulate circadian behavior.Circadian profiles of Per mRNA (A) and firing rate (B) are shown for the control (black line), 50% reduced cytosolic Ca2+ concentration (red dashed line) and 50% increased cytosolic Ca2+ concentration (blue dotted line) compared to the control. C). Per mRNA (red dashed line) and firing rate (black solid line) amplitudes as a function of the cytosolic calcium concentration. D). The period of the core oscillator as a function of the cytosolic calcium concentration. The circles in 6C and 6D represent nominal values of the model.

Mentions: We varied the intracellular calcium concentration to investigate its effects on the rhythmic output of the circadian clock. Changes in effective Ca2+ levels were achieved by scaling the output of Eq. 12, responsible for the circadian evolution of intracellular calcium, by multiplying with a scaling factor ranging from 0.5 to 1.5. Hence mean levels of calcium were varied by ±50% of their nominal value. Because our model was constructed under the assumption that cytosolic calcium instigates a signaling cascade with Per gene transcription as the final product [19] incrementally increasing Ca2+ concentrations had a positive effect on Per mRNA amplitudes (Figs. 6A, 6C). A similar trend was observed for neural firing, as increasing intracellular calcium increased firing frequency amplitudes (Figs. 6B, 6C). The calcium concentration also affected the periodicity of the model system. Increased Ca2+ levels produced longer periods of the core oscillator, reaching a maximum of 25.6h for a 50% Ca2+ increase (Fig. 6B).


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

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

Cytosolic calcium levels regulate circadian behavior.Circadian profiles of Per mRNA (A) and firing rate (B) are shown for the control (black line), 50% reduced cytosolic Ca2+ concentration (red dashed line) and 50% increased cytosolic Ca2+ concentration (blue dotted line) compared to the control. C). Per mRNA (red dashed line) and firing rate (black solid line) amplitudes as a function of the cytosolic calcium concentration. D). The period of the core oscillator as a function of the cytosolic calcium concentration. The circles in 6C and 6D represent nominal values of the model.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000706-g006: Cytosolic calcium levels regulate circadian behavior.Circadian profiles of Per mRNA (A) and firing rate (B) are shown for the control (black line), 50% reduced cytosolic Ca2+ concentration (red dashed line) and 50% increased cytosolic Ca2+ concentration (blue dotted line) compared to the control. C). Per mRNA (red dashed line) and firing rate (black solid line) amplitudes as a function of the cytosolic calcium concentration. D). The period of the core oscillator as a function of the cytosolic calcium concentration. The circles in 6C and 6D represent nominal values of the model.
Mentions: We varied the intracellular calcium concentration to investigate its effects on the rhythmic output of the circadian clock. Changes in effective Ca2+ levels were achieved by scaling the output of Eq. 12, responsible for the circadian evolution of intracellular calcium, by multiplying with a scaling factor ranging from 0.5 to 1.5. Hence mean levels of calcium were varied by ±50% of their nominal value. Because our model was constructed under the assumption that cytosolic calcium instigates a signaling cascade with Per gene transcription as the final product [19] incrementally increasing Ca2+ concentrations had a positive effect on Per mRNA amplitudes (Figs. 6A, 6C). A similar trend was observed for neural firing, as increasing intracellular calcium increased firing frequency amplitudes (Figs. 6B, 6C). The calcium concentration also affected the periodicity of the model system. Increased Ca2+ levels produced longer periods of the core oscillator, reaching a maximum of 25.6h for a 50% Ca2+ increase (Fig. 6B).

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