The circadian cycle: daily rhythms from behaviour to genes

Abstract

The daily recurrence of activity and rest are so common as to seem trivial. However, they reflect a ubiquitous temporal programme called the circadian clock. In the absence of either anatomical clock structures or clock genes, the timing of sleep and wakefulness is disrupted. The complex nature of circadian behaviour is evident in the fact that phasing of the cycle during the day varies widely for individuals, resulting in extremes colloquially called 'larks' and 'owls'. These behavioural oscillations are mirrored in the levels of physiology and gene expression. Deciphering the underlying mechanisms will provide important insights into how the circadian clock affects health and disease.

Figure 1

Cartoon of a circadian rhythm in free-running and entrained conditions. The width of the panels is 24 h, except for (G), which represents 20 h. Each bar exemplifies a bout of activity (in this case, the 'activity' of spore formation in Neurospora crassa). (A) In constant darkness and temperature (25 °C), spores develop once per 22 h. The period changes only slightly with ambient temperature, lengthening when it is colder (20 °C; B), and shortening when warmer (30 °C; C). The phase of the rhythm is not changed significantly when a light pulse (flash) is delivered in the subjective mid-day (D), whereas large phase shifts are induced when light is given in the subjective night (E). The rhythm is entrained to a period of exactly 24 h in appropriate zeitgeber cycles of light and darkness (F). Entrainment to non-24-h T cycles is also possible, as shown in (G), in which the phase settles later in the short, 20-h cycle of warm and cold than it would in a 24-h cycle. If an entraining cycle is about one-half of the free-running period, a frequency demultiplication occurs, whereby one bout occurs per two cycles (H, showing 12-h temperature cycles).

Figure 2

The circadian system in animals is organized hierarchically. Molecular oscillations are generated at the cellular level, in which clock components include transcription–translation feedback loops and possibly metabolic regulatory pathways (left). Organ or peripheral clocks develop a coordinated rhythm that is synchronized relative to a pacemaker in the brain. The most obvious manifestation of this timing system is the sleep–wake cycle, but hundreds of parameters—from cognitive functions to circulating hormone levels—are also changing over the 24-h day. Coupling between the brain and oscillators in the periphery has been shown, and it can be disrupted (Damiola et al, 2000), but feedback from peripheral clocks to the brain has yet to be formally demonstrated.