Simulation analysis for the effect of light-darkcycle on the entrainment in circadian rhythm
Natsumi Mito1 Yuto Ikegami2Hiroshi Matsuno2 Satoru Miyano3
Shin-ichi T.Inouye4

1 Kyuden Business Solution Co. Inc.
2 Graduate School of Science and Engineering, Yamaguchi University
3 Human Genome Center, Institute of Medical Science, University of Tokyo
4 Research Institute for Time Studies, Yamaguchi University

GIW2008 Gold Coast , Australia, 1- 3 December 2008

Introduction
The topic of this presentation

Simulation for the effects of light in circadian rhythmContents• Circadian rhythm- Gene regulatory network of circadian rhythm• HFPN model for molecular circadian clock- Simulation under free-running conditions• Light induced phase response simulation- Phase Response Curve obtained from simulation• Entrainment to LD cycles- Simulation with the extended HFPN model- Jet lag simulation : Flying from Tokyo to N.Y1

Circadian Rhythm• An approximate daily periodicity• Entrained by external cues,
called Zeitgebers
Daylight

Gene Regulatory Network of Circadian Clock2

Hybrid Functional Petri Net (HFPN)

ContinuousDiscrete

delay

speedMatsuno, H., et al., Biopathways Representation and Simulation on Hybrid
Functional Petri Net., In Silico Biol., 3(3):389-404,2003.
http://www.cellillustrator .org/

Hybrid Functional Petri Net (HFPN)
Circadian Gene Clock

Model of3Hybrid Functional Petri Net (HFPN)
Circadian Gene Clock

Model ofOscillations of mRNAs in the HFPN model
Per, Cry and Rev-Erb
express at day

Clock express constant

Bmal express at night

Generating stable rhythms called free-running rhythms inconstant condition.
How light effect function?

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Per mRNA levels in free-running and induced after lightfrom biological experiment

Biological experiment
3Light pulse

Per mRNA levelmouse

2.5
21.5
10.5
008CT

Subjective day

1624

Subjective night

Miyake et al., Neuroscience Letters 294 (2000)

Simulation of phase shift by light pulse

32.5
21.5

CT 0Per mRNA without light pulse
Per mRNA with light pulse

10.5
008

1624＋1.1
CT 14light pulse－1.4
light pulse

CT 22＋1.3
light pulse

5Phase Response Curve obtained from simulation

Phase response curve obtained fromthe simulation and biological literature
Gene expression

PRC obtained from simulation

Animal locomotor activity

PRC described in biological literature** Pittendrigh, C.S. and Daan, S., J.Comp.Physiol (1976)

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Summary on the way
1. Successfully and quantitatively simulating thebehavioral phase shift of the circadian clock.
(Light induction of one kind of clock gene (Per)was taken into consideration.)

Simulation

2. Suggesting that the five genes feedback
mechanism is essential for phase response
behavior.
Animal experiments

Entrainment to LD Cycles

3Day

2.5
2
1.5

01

10.5

12１008Night

1216１24

Phase-dependent increases in
10 exposuresPer level on light7

Entrainment Simulation in LD 12:12

Mouse free-running period ＜ 24
Per without LDcycle is not lined up LDcycle(24h)Per with LDcycle is entrain LDcycle(24h)

Entrainment Simulation in far from 24h LD cycle

Unable to be entrainedby far from 24h LDcycles.
Confirmed the biological fact

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Jet Lag Simulation: Flying from Tokyo to New York
Travel plan♪
AM6:00

PM6:00

Japan
PM6:00－14h

AM6:00N.Y

・Departure from Tokyo at
11:00
12.5h flight time・Arrival at New York at 9：30

Peaks at day

Peaks at day

Per mRNAN.Y

Summary• Suggesting that the five genes feedback mechanism isessential for phase response behavior.
• Entrainment was found possible only when periodicity ofthe external LD cycle was close to 24hr.
Found in the biological observation strengthens
the usefulness of our HFPN model.

• Our model successfully reproduced unstable transition
period corresponding physiological symptoms of malaise
during the jet lag.

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Thank you for listening !

Actgram Obtained from the Jet Lag Simulation

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