Peripheral Circadian Oscillators

Circadian rhythms are ~24-hour cycles of physiology and behavior that are synchronized to environmental cycles, such as the light-dark cycle. During the 20th century, most research focused on establishing the fundamental properties of circadian rhythms and discovering circadian pacemakers that were believed to reside in the nervous system of animals. During this time, studies that suggested the existence of circadian oscillators in peripheral organs in mammals were largely dismissed. The discovery of a single-locus circadian pacemaker in the nervous system of several animals affirmed the single-oscillator model of the circadian system. However, the discovery of the genes that constituted the molecular timekeeping system provided the tools for demonstrating the existence of bona fide circadian oscillators in nearly every peripheral tissue in animals, including rodents, in the late 1990s and early 2000s. These studies led to our current understanding that the circadian system in animals is a hierarchical multi-oscillatory network, composed of master pacemaker(s) in the brain and oscillators in peripheral organs. Further studies showed that altering the temporal relationship between these oscillators by simulating jet-lag and metabolic challenges in rodents caused adverse physiological outcomes. Herein we review the studies that led to our current understanding of the function and pathology of the hierarchical multi-oscillator circadian system.