Feb 27, 2008

The study of circadian rhythms

The roots of the study of biological rhythms reach back to the 1700s and the work of the French scientist de Mairan, who published a monograph describing the daily leaf movements of a plant. De Mairan observed that the daily raising and lowering of the leaves continued even when the plant was placed in an interior room and thus was not exposed to sunlight. This finding suggested that the movements represented something more than a simple response to the sun and were controlled by an internal clock.

De Mairan’s apt observations illustrate one critical feature of circadian rhythms- their self-sustained nature. Thus, almost all diurnal rhythms that occur under natural conditions continue to cycle under laboratory conditions devoid of any external time-giving cues from the physical environment (e.g., under constant light or constant darkness). Circadian rhythms that are expressed in the absence of any 24-hour signals from the external environment are called free running.

The persistence of rhythms in the absence of a dark-light cycle or other exogenous time signal (i.e., a Zeitgeber) seems to indicate the existence of some kind of internal timekeeping mechanism, or biological clock. However, some investigators have pointed out that the persistence of rhythmicity does not necessarily exclude the possibility that other, uncontrolled cycles generated by the Earth’s revolution on its axis might be driving the rhythm (see Aschoff 1960).

The hypothesis that such uncontrolled geomagnetic cues might play a role in the persistence of rhythmicity can be refuted by a second characteristic feature of circadian rhythms: These cycles persist with a period of close to, but not exactly, 24 hours. If the rhythms were exogenously driven, they should persist with a period of exactly 24 hours. The seeming imprecision is an important feature of rhythmicity, however.

As Pittendrigh (1960) demonstrated, the deviation from a 24-hour cycle actually provides a means for the internal time-keeping system to be continuously aligned by and aligned to the light-dark environment. This continuous adjustment results in greater precision in controlling the timing, or phase, of the expressed rhythms, because little drift is allowed to occur before the rhythm is “reset” to the correct phase.

A third characteristic property of circadian rhythms is their ability to be synchronized, or entrained, by external time cues, such as the light-dark cycle. Thus, although circadian rhythms can persist in the absence of external time cues (meaning that they are not driven by the environment), normally such cues are present and the rhythms are aligned to them. Accordingly, if a shift in external cues occurs (e.g., following travel across time zones), the rhythms will be aligned to the new cues. This alignment is called entrainment.
Initially, it was unclear whether entrainment was achieved by modulating the rate of cycling (i.e., whether the cycle was shortened or lengthened until it was aligned to the new cues and then reverted to its original length) or whether entrainment was achieved by discrete “resetting” events.

Experiments resulting from this debate led to fundamental discoveries. For example, researchers discovered that the organism’s response to light (i.e., whether a cycle advances, is delayed, or remains unchanged) differs depending on the phase in the cycle at which it is presented (Pittendrigh 1960). Thus, exposure to light during the early part of the individual’s “normal” dark period generally results in a phase delay, whereas exposure to light during the late part of the individual’s normal dark period generally results in a phase advance.

In addition to the timing of the light exposure, the light intensity can modulate cycling periods when organisms are left in constant light. Thus, exposure to brighter light intensities can lengthen the period in some species and shorten it in other species. This phenomenon has been dubbed “Aschoff’s rule”(Aschoff 1960). Ultimately, both mechanisms of entrainment appear to be aspects of the same thing, because the consequences of Aschoff’s rule can be predicted or explained by the phase-response curves to light.

Although the light-dark cycle clearly is the major Zeitgeber for all organisms, other factors-such as social interactions, activity or exercise, and even temperature-also can modulate a cycle’s phase. The influence of temperature on circadian rhythms is particularly interesting in that a change in temperature can affect the phase of a cycle without substantially altering the rate of cycling.
This means that the cycle may start at an earlier or later-than-normal time but still have the same length. On the one hand, this ability of the internal clock’s pacemaker to compensate for changes in temperature is critical to its ability to predict and adapt to environmental changes, because a clock that speeds up and slows down as the temperature changes would not be useful.
On the other hand, temperature compensation also is rather puzzling, because most kinds of biological processes (e.g., biochemical reactions in the body) are accelerated or slowed by temperature changes.

Ultimately, this riddle has provided a clue to the nature of the internal clock- that is, the fact that circadian rhythms have a genetic basis. Such a program of gene expression would be more resistant to temperature alteration than, for example, a simple biochemical reaction. Two final properties of circadian rhythms also provide important hints of the rhythms’ makeup. One of these properties is the rhythms’ ubiquity in nature: Circadian rhythms exist in a broad array of biological processes and organisms, with similar properties and even similar phase-response curves to light.

The other property is that circadian rhythms appear to be generated at the cellular level, because the rhythms of unicellular organisms (e.g., algae or the dinoflagellate Gonyaulax) are much the same as rhythms of highly complex mammals. Both of these observations suggest that a cycle in the activation (i.e., expression) of certain genes might underlie the timekeeping mechanism.

By Martha Hotz Vitaterna, Ph.D., Joseph S. Takahashi, Ph.D., and Fred W. Turek, Ph.D.
MARTHA HOTZ VITATERNA, PH.D., is a senior research associate in the Center for Functional Genomics, Northwestern University, Evanston, Illinois. JOSEPH S. TAKAHASHI, PH.D., is the director of the Center for Functional Genomics, the Walter and Mary E. Glass Professor in the Department of Neurobiology and Physiology, and an investigator at the Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois. FRED W. TUREK, PH.D., is the director of the Center for Sleep and Circadian Biology and is the Charles T. and Emma H. Morrison Professor in the Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois.

Related posts:
* Overview of circadian rhythms
* Glossary of shiftwork terms: shiftwork, sleep, circadian rhythms, and more
* The drivers of human alertness and sleep

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