Abstract
Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber).
Highlights
The circadian rhythm of organisms ranging from cyanobacteria to humans beats at the cellular level; it is a remarkable manifestation of celestial mechanics mirrored in molecular biology
We report here that the circadian clock in both wild-type single dissociated SCN neurons and in fibroblasts is well approximated as a damped oscillator driven by biochemical noise
The circadian clock is constructed as a negative feedback loop, in which clock proteins inhibit their own synthesis
Summary
The circadian rhythm of organisms ranging from cyanobacteria to humans beats at the cellular level; it is a remarkable manifestation of celestial mechanics mirrored in molecular biology. The standard view is that the mammalian circadian clock is a hierarchically organized system, governed by the suprachiasmatic nuclei (SCN, consisting of about 20,000 neurons) in the hypothalamus. The SCN neurons are coupled to each other and are entrained by light to oscillate in synchrony to the 24 h earth rotation, and in turn entrain cells and organs in the rest of the body. In studies of dissociated SCN neurons, typically most of the cells are classified as being self-sustained oscillators [1,2,3,4]. At the SCN tissue level, mutant neurons that are arrhythmic when dissociated from each other can interact to generate a collective coordinated self-sustained rhythm [10]
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