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

Abstract

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.

Keywords: biological rhythms; circadian clock; dopamine transporter; dopaminergic ultradian oscillator; rest:activity.

Figure 1

Ultradian rhythms and their manipulation from voles to humans. (A) Locomotor activity (LA) rhythms in the common vole in the presence of a running wheel; red bar indicates days when the wheel was blocked; bar on top indicates periods of lights on (white) and off (black); adapted from Ref. (16) with permission. (B) Activity record of a preterm infant based on ankle-actigraphy; arrow indicates day of hospital discharge; adapted from Ref. (8) with permission. (C) Recording of ambulatory activity in the mouse by telemetry implants; right, average daily activity based on primary data shown on the left; yellow shading indicates lights on. (D) Running wheel activity of a DAT^−/− mouse; yellow area, lights on; red bar indicates the emergence of a second rhythmic component, supported by periodogram analysis (right). (E) Gradual ultradian locomotor period lengthening by increasing methamphetamine concentration in the drinking water of Bmal1^−/− mice in constant darkness. (F) Extracellular dopamine measured by microdialysis in the striatum fluctuates synchronously with ultradian LA in Bmal1^−/− under constant dim red light. Graphs shown in D, E, F are adapted from Ref. (20).

Figure 2

Dopaminergic ultradian oscillator (DUO) make up and output integration. (A) Structural basis of the DUO: ultradian rhythm generation may be cell autonomous (a), require a cell ensemble (b), or rely on a network of cell ensembles (c). (B) Possible DUO/circadian clock [suprachiasmatic nucleus (SCN)] interaction and output integration. LA, locomotor activity. (C) Schematic representation of typical LA patterns found in mice with and without dopamine system interference. The periodicities of the SCN and DUO oscillators suggested to underlie the activity patterns are illustrated below each actogram.