A period without PER: understanding 24-hour rhythms without classic transcription and translation feedback loops.

Since Ronald Konopka and Seymour Benzer's discovery of the gene Period in the 1970s, the circadian rhythm field has diligently investigated regulatory mechanisms and intracellular transcriptional and translation feedback loops involving Period, and these investigations culminated in a 2017 Nobel Prize in Physiology or Medicine for Michael W. Young, Michael Rosbash, and Jeffrey C. Hall. Although research on 24-hour behavior rhythms started with Period, a series of discoveries in the past decade have shown us that post-transcriptional regulation and protein modification, such as phosphorylation and oxidation, are alternatives ways to building a ticking clock.

Control of Rest:Activity by a Dopaminergic Ultradian Oscillator and the Circadian Clock.

There is long-standing evidence for rhythms in locomotor activity, as well as various other aspects of physiology, with periods substantially shorter than 24 h in organisms ranging from fruit flies to humans. These ultradian oscillations, whose periods frequently fall between 2 and 6 h, are normally well integrated with circadian rhythms; however, they often lack the period stability and expression robustness of the latter. An adaptive advantage of ultradian rhythms has been clearly demonstrated for the common vole, suggesting that they may have evolved to confer social synchrony. The cellular substrate and mechanism of ultradian rhythm generation have remained elusive so far, however recent findings-the subject of this review-now indicate that ultradian locomotor rhythms rely on an oscillator based on dopamine, dubbed the dopaminergic ultradian oscillator (DUO). These findings also reveal that the DUO period can be lengthened from <4 to >48 h by methamphetamine treatment, suggesting that the previously described methamphetamine-sensitive (circadian) oscillator represents a long-period manifestation of the DUO.