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Coupling governs entrainment
range of circadian clocks
Abril 2015
Introduction
Circadian clocks are endogenous oscillators that
synchronize an organism to periodically recurring
environmental conditions
How?
1. periodic light detected by the eyes entrains (i.e.
synchronizes) neurons in the bilateral SCN (the master
clock in mammals) of the hypothalamus via neuronal
signals
2. Within SCN tissue, individual neurons synchronize
each other, generating self-sustained oscillations
3. SCN synchronizes other peripheral tissues
Goals
Theoretical and experimental study of which properties of
circadian clocks influence the entrainment range (period,
relaxation rate, coupling strength and ratio between zeitgeber
strength and amplitude)
This study will be made for the central circadian clock (SCN)
and for a peripheral clock (lung)
Amplitude and zeitgeber strength
determine the entrainment range
Figure1 A: Schematic representation
of a circadian rhythm entrained by
24h temperature cycles
Figure1 B: Schematic representation
of entrainment region
Oscillator characterized by its amplitude, intrinsic period and
its stability with respect to amplitude perturbations (relaxation
rate)
Poincaré oscillator:
A0: amplitude of oscillation
\tau: intrinsic period
\lambda: relaxation of amplitudes to the stable oscillation
Relaxation rate affects range of entrainment,
entrained amplitude and phase shifting properties
Figure2 A: Numerically calculated
entrainment region for Poincaré
oscillator
Figure2 B: Entrained amplitude of
weak and rigid oscillators within the
entrainment range
The ratio of zeitgeber strength to oscillator
amplitude detemines the range of entrainment
Dots are numerically simulated lower
limits of entrainment for a Poincaré
oscillator with \lambda=1 h-1
Figure 3:The lower limit of
entrainment (LLE) is plotted as a
function of the ratio of zeitgeber
strength to oscillator amplitude
Conclusion: ratio between the zeitgeber
strength and oscillator amplitude
indeed determines the entrainment
range for a given oscillator period and
relaxation rate \lambda
Lung tissue behaves as a weak oscillator and SCN
as a rigid oscillator
Weak, small-amplitude oscillators exhibit larger range of
entrainment compared with rigid, high-amplitude oscillators
Test these predictions experimentally: investigate entrainment of
circadian oscillators using temperature as a zeitgeber (quasisquare-wave temperature profile ranging from 35.5ºC - cold - to
37ºC -warm)
Two different cycles: 10h of cold and 10h of warm and 14h of
cold and 14h of warm
Tissue explants from PER2::LUC mice were subjected to temperature cycles
and simultaneously monitored for bioluminescence rhythms
Applied extreme temperature cycle (T=20h) but with
increasing strength (0.75, 1.5, 3 and 6ºC temperature
variation)
Still no entrainment of SCN
Repeat experience (T=22ºC) with even
strengths (4, 6 and 8ºC temperature variation)
stronger
Entrainment of SCN for the two stronger strengths
Coupling makes oscillators more rigid
What is the fundamental difference between lung and SCN tissue
that so profoundly affects entrainment behavior?
Coupling of circadian rhythms can have a huge effect on the
properties of oscillators
Study two coupled Poincaré oscillators
Coupling makes the synchronized oscillatory state more rigid in two
aspects:
(i) resonance increases the amplitude (Figure A);
(ii) coupling leads to faster relaxation (Figure B)
Coupling makes the system harder to entrain
Reducing coupling faciltates entrainment of SCN
tissues
Test experimentally predictions (attenuating coupling makes the coupled
system weaker and so enlarges entrainment range) - reduce
pharmacologically coupling in SCN slices taken from PER2-LUC mice
(drug: MDL)
MDL reduces cellular
coupling
with
no
detectable effect on
relative amplitude
MDL treated SCN slices entrain to temperature cycle in a MDL dosedependent manner.
Conclusion: subjecting SCN slices to decoupling agents leads to
expanded entrainment range
Lung is probably a weak oscillator, likely because a lack of coupling leads
to a slow amplitude relaxation and SCN is a rigid oscillator, whereby
coupling probably are the main causes for this rigidity.
Why is the SCN designed to be a stronger circadian oscillator
than peripheral organs?