Development of amplitude response curves for single-cell and population-level circadian systems

摘要

Circadian rhythms are oscillations in biological systems that help organisms anticipate changes in the day/night cycle. These oscillations are typically coordinated by intricate genetic regulatory networks that generate tunable oscillations through time-delayed negative feedback loops. In addition to serving as an excellent example of a functional genetic circuit [1], circadian rhythms form an integral part of the mammalian metabolic regulatory network. Consequently, disruptions to the circadian clock often manifest in metabolic disease [2]. Since circadian rhythms are damped by factors such as age [3], diet [4], and shift work, an understanding of the forces that regulate clock amplitudes is essential. However, such an understanding is obstructed by the multi-scale nature of the circadian system. In mammals, locomotor rhythms are governed by the suprachiasmatic nucleus (SCN), which serves as the body’s master pacemaker. Metabolic rhythms and other physiological outputs of the circadian clock are mediated by oscillating cells in peripheral tissues. Unlike the SCN, cells in tissues such as the liver and pancreas lack the coupling mechanisms necessary for spontaneous synchronization. As a result, cultured peripheral tissues display rhythms which damp appreciably in only a few days, as stochastic effects cause an initially entrained population of cells to desynchronize. The amplitude of circadian rhythms in metabolic tissues is therefore determined both by the genetic oscillator within each cell and the synchrony of the overall population.