Emergence of Noise-Induced Oscillations in the Central Circadian Pacemaker

Abstract

Author SummaryThe suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals that controls and coordinates physiological processes in a daily manner. The SCN is composed of a network of cells, with each cell acting as an autonomous oscillator. In isolated individual cells, timekeeping is not precise because of the inherent randomness in the biochemical reactions within each cell, involving its core clock components. However, in the SCN network, precise rhythms can emerge because of intercellular coupling. In this article, we study a loss-of-function mutation of BMAL1, a core clock component, which eliminates timekeeping in isolated cells. Surprisingly, in both experiments and mathematical simulations, we find that noisy rhythms emerge from the SCN network even in the presence of this BMAL1 mutation. This random yet coordinated timekeeping has not been observed in previous modeling and experimental work and indicates that a network of cells can utilize noise to help compensate for loss of a physiological function. In normal function, the SCN network mitigates any variability observed in individual cellular rhythms and produces a precise and rhythmic network timekeeping signal. When the individual cells are no longer rhythmic, the coupling pathways within the SCN network can propagate stochastic rhythms that are a reflection of both feed-forward coupling mechanisms and intracellular noise. Thus, in a manner analogous to central pattern generators in neural circuits, rhythmicity can arise as an emergent property of the network in the absence of component pacemaker or oscillator cells.