Abstract
The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides coordinating cells, the synchronization factors play a crucial role in the sustenance of intrinsic cellular rhythmicity. Disruption of intercellular signaling abolishes sustained rhythmicity in a majority of neurons and desynchronizes the remaining rhythmic neurons. Based on these observations, the authors propose a model for the synchronization of circadian oscillators that combines intracellular and intercellular dynamics at the single-cell level. The model is a heterogeneous network of circadian neuronal oscillators where individual oscillators are damped rather than self-sustained. The authors simulated different experimental conditions and found that: (1) in normal, constant conditions, coupled circadian oscillators quickly synchronize and produce a coherent output; (2) in large populations, such oscillators either synchronize or gradually lose rhythmicity, but do not run out of phase, demonstrating that rhythmicity and synchrony are codependent; (3) the number of oscillators and connectivity are important for these synchronization properties; (4) slow oscillators have a higher impact on the period in mixed populations; and (5) coupled circadian oscillators can be efficiently entrained by light–dark cycles. Based on these results, it is predicted that: (1) a majority of SCN neurons needs periodic synchronization signal to be rhythmic; (2) a small number of neurons or a low connectivity results in desynchrony; and (3) amplitudes and phases of neurons are negatively correlated. The authors conclude that to understand the orchestration of timekeeping in the SCN, intracellular circadian clocks cannot be isolated from their intercellular communication components.
Highlights
IntroductionA set of ‘‘clock’’ genes and proteins forms a regulatory network that produces oscillations with a circadian period (’24 h) [1]
In most mammalian cells, a set of ‘‘clock’’ genes and proteins forms a regulatory network that produces oscillations with a circadian period (’24 h) [1]
The central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where it receives light signals from the retina
Summary
A set of ‘‘clock’’ genes and proteins forms a regulatory network that produces oscillations with a circadian period (’24 h) [1]. SCN neurons in low-density dispersal cultures, do not show a coordinated activity but express a large variation in their free-running periods [4,5]. This has led to the conclusion that SCN neurons are self-sustained circadian oscillators that need a synchronization signal to produce a coherent output. Even before this experimental evidence, it had been hypothesized that the coupling of ‘‘sloppy’’ clocks improves the reliability of the output [6]. All published mathematical models of the synchronization of the SCN rest on the coupling of self-sustained circadian oscillators
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