Introduction to Chronobiology

Abstract

A diverse range of species, from cyanobacteria to humans, evolved endogenous biological clocks that allow for the anticipation of daily variations in light and temperature. The ability to anticipate regular environmental rhythms promotes optimal performance and survival. Herein we present a brief historical timeline of how circadian concepts and terminology have emerged since the early observation of daily leaf movement in plants made by an astronomer in the 1700s.

Figure 1.

Transcription–translation regulatory feedback loops: a common theme in the generation of eukaryotic circadian rhythms. Many circadian systems are composed of positive and negative elements that are involved in feedback loops. Positive elements (ovals) interact and bind to upstream elements (white rectangles) in the promoter regions (bent arrows) of genes that encode negative elements to activate their expression. These negative components (tetrahedrons) interact to inhibit the activity of the positive elements, which ultimately leads to a decrease in expression of the negative elements. Progressive phosphorylation (P) of negative elements leads to their degradation and a relief of the inhibition of the positive effectors to allow the cycle to start again. Other components (diamonds) may be present that bind to the promoters of genes that encode the positive elements to comprise an additional feedback loop. Arrows and perpendicular lines indicate positive and negative regulation, respectively (see also Bell-Pedersen et al. 2005).

Figure 2.

Properties of a circadian rhythm. (A) Behavioral circadian rhythms can be entrained by external stimuli, such as a light–dark cycle, and will persist with a near 24-h period in the absence of environmental cues, such as constant darkness. Properties of the rhythm that are commonly measured are period, phase, and amplitude. Period is the duration of time to complete one cycle. It is typically measured from peak to peak, but it can be measured from any specific position on the curve. Phase is the relative position on the curve (e.g., the peak) in reference to a particular time, such as time placed in constant darkness. Amplitude is the measurement of the recorded output from the midline of the curve to either the peak or trough. (B) The phase of a circadian rhythm can be reset by the stimuli to which it entrains. In this case, exposure to a stimulus (input) rapidly lowers the level of the rhythmic variable (dashed line), which recovers to a rhythm with a shifted phase as compared with the curve that did not receive the input (solid line). On the x-axis time in the light–dark cycle is depicted by alternating white and black bars, and time under constant conditions is depicted by alternating hatched and black bars. Level of clock-controlled output is displayed on the y-axis. (C) Phase-response curves measure the magnitude and direction of phase-dependent responses to brief exposures of an external stimulus. The x-axis represents the circadian time at which a light pulse is applied to an organism; the y-axis shows the change in phase of the circadian-controlled output in response to the light pulse. Positive shifts are indicated as advances and negative phase shifts are delays. A brief light pulse given to an organism during the subjective day (the organism’s own internal day) produces little to no phase response, light in the early subjective night (the organism’s own internal early night) produces phase-delay shifts, and light in the late subjective night produces phase-advance shifts.

Figure 3.

Importance of assaying rhythms at a single-cell resolution. To be considered circadian, a rhythm must be maintained under constant conditions. When examining rhythms at the tissue level in which the tissue is composed of multiple cells, it is important to realize that the absence of rhythmicity under constant conditions could be attributable to two possibilities: either the loss of rhythmicity (indicating the rhythm is not circadian) or desynchrony among oscillators. In the latter case, individual rhythms may actually be circadian; however, the assay has insufficient resolution to show the presence of rhythmicity. To distinguish between the two possibilities, assays sensitive to the functional unit of rhythms generation must be used.

Figure 4.

Representation of circadian clock divisions. A circadian clock can be depicted as having input pathways, a central oscillator (or pacemaker), and output pathways. The central oscillator produces the endogenous biological rhythm and can be synchronized with the environment via input pathways through cues such as light or temperature. Output pathways convey the clock’s rhythms to downstream targets and drive overtly rhythmic activities. Some circadian systems consist of more elaborate pathways (shown as dashed lines) that include multiple, interlocking oscillators and positive or negative feedback from clock-controlled activities to oscillator and/or input components. (Figure based on data in Gardner et al. 2006.)

Figure 5.

Schematic representation of the overlap between circadian genes and those with important medical relevance. The figure shows the overlap between genes that have a circadian oscillation (red), those known to be associated with disease (tan), and those that are targets of the 100 top-selling drugs in the United States (blue). Few of the drugs are prescribed with specific timing information, representing potential targets for development of chronopharmacology to improve efficacy and/or reduce side effects. (Panel A from Zhang et al. 2014; reprinted, with permission, from the National Academy of Sciences © 2014.)