Research Article: Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus

Date Published: April 13, 2007

Publisher: Public Library of Science

Author(s): Samuel Bernard, Didier Gonze, Branka Čajavec, Hanspeter Herzel, Achim Kramer, Karl J Friston

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.

Partial Text: 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]. Molecular and physiological rhythms are coordinated with the daily changes in the environment by a dominant circadian pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN neurons endogenously generate circadian rhythm and adapt that rhythm according to light–dark (LD) cycles of the environment (entrainment). The approximately 20,000 neurons in the SCN [2,3] vary (1) in their ability to sense the environmental timing cues, (2) in the neurotransmitters they express or respond to, and (3) in their connectivity properties. A desire to understand how such a heterogeneous network produces a coherent and synchronous circadian output has motivated extensive experimental and theoretical work.