Overview of Circadian Rhythms Martha Hotz Vitaterna, Ph.D., Joseph S. Takahashi, Ph.D., and Fred W. Turek, Ph.D. The daily light-dark cycle governs rhythmic changes in the behavior and/or physiology of most species. Studies have found that these changes are governed by a biological clock, which in mammals is located in two brain areas called the suprachiasmatic nuclei. The circadian cycles established by this clock occur throughout nature and have a period of approximately 24 hours. In addition, these circadian cycles can be synchronized to external time signals but also can persist in the absence of such signals. Studies have found that the internal clock consists of an array of genes and the protein products they encode, which regulate various physiological processes throughout the body. Disruptions of the biological rhythms can impair the health and well-being of the organism. KEY WORDS: circadian rhythm; time of day; biological regulation; biological adaptation; temperature; light; hypothalamus; neural cell; gene expression; mutagenesis; sleep disorder; physiological AODE (effects of alcohol or other drug use, abuse, and dependence) ne of the most dramatic features between the organism and the external of the world in which we live is environment may lead to the individ­ MARTHA HOTZ VITATERNA, PH.D., is a the cycle of day and night. Cor­ ual’s immediate demise. For example, if senior research associate in the Center for O Functional Genomics, Northwestern respondingly, almost all species exhibit daily a nocturnal rodent were to venture from changes in their behavior and/or physiol­ its burrow during broad daylight, the University, Evanston, Illinois. ogy. These daily rhythms are not simply a rodent would be exceptionally easy response to the 24-hour changes in the prey for other animals. Similarly, a lack JOSEPH S. TAKAHASHI, PH.D., is the director physical environment imposed by the earth of synchrony within the internal envi­ of the Center for Functional Genomics, turning on its axis but, instead, arise from ronment might lead to health problems the Walter and Mary E. Glass Professor a timekeeping system within the organism. in the individual, such as those associated in the Department of Neurobiology and This timekeeping system, or biological with jet lag, shift work, and the accom­ Physiology, and an investigator at the “clock,” allows the organism to anticipate panying sleep loss (e.g., impaired cog­ Howard Hughes Medical Institute, and prepare for the changes in the physi­ nitive function, altered hormonal func­ Northwestern University, Evanston, Illinois. cal environment that are associated with tion, and gastrointestinal complaints). day and night, thereby ensuring that the The mechanisms underlying the FRED W. TUREK, PH.D., is the director of organism will “do the right thing” at the biological timekeeping systems and the the Center for Sleep and Circadian Biology right time of the day. The biological clock potential consequences of their failure and is the Charles T. and Emma H. also provides internal temporal organiza­ are among the issues addressed by Morrison Professor in the Department of tion and ensures that internal changes take researchers in the field of chronobiology.1 Neurobiology and Physiology, Northwestern place in coordination with one another. In its broadest sense, chronobiology University, Evanston, Illinois. The synchrony of an organism with encompasses all research areas focusing both its external and internal environ­ on biological timing, including high- 1For a definition of this and other technical terms used in ments is critical to the organism’s well- frequency cycles (e.g., hormone secre­ this article and throughout this issue of the journal, please being and survival; a lack of synchrony tion occurring in distinct pulses through- see glossary, p. 92. Vol. 25, No. 2, 2001 85 out the day), daily cycles (e.g., activity The roots of the study of biological that are simply a response to 24-hour and rest cycles), and monthly or annual rhythms, however, reach back even fur­ environmental changes. For practical cycles (e.g., reproductive cycles in some ther, to the 1700s and the work of the purposes, however, there is little reason species). Among these interrelated areas French scientist de Mairan, who pub­ to distinguish between diurnal and cir­ of chronobiology, this article focuses on lished a monograph describing the daily cadian rhythms, because almost all one frequency domain—the daily cycles leaf movements of a plant. De Mairan diurnal rhythms are found to be circa­ known as circadian rhythms. (The term observed that the daily raising and low- dian. Nor is a terminology distinction “circadian” derives from the Latin phrase made among circadian rhythms based “circa diem,” which means “about a on the type of environmental stimulus day.”) Although virtually all life forms— that synchronizes the cycle. including bacteria, fungi, plants, fruit Virtually all The persistence of rhythms in the flies, fish, mice, and humans—exhibit absence of a dark-light cycle or other circadian rhythms, this review is primar­ life forms— exogenous time signal (i.e., a Zeitgeber) ily limited to the mammalian system. including bacteria, clearly seems to indicate the existence Other animals are discussed only in of some kind of internal timekeeping cases in which they have contributed to fungi, plants, fruit mechanism, or biological clock. How- the understanding of the mammalian ever, some investigators have pointed out system, particularly in studies of the flies, fish, mice, that the persistence of rhythmicity does molecular genetic makeup of the time- and humans— not necessarily exclude the possibility keeping system. (For comparative dis­ that other, uncontrolled cycles gener­ cussions of other nonmammalian model exhibit circadian ated by the Earth’s revolution on its systems that have contributed to the rhythms. axis might be driving the rhythm (see depth of understanding of circadian Aschoff 1960). rhythmicity in mammals, the reader is The hypothesis that such uncon­ referred to Wager-Smith and Kay 2000.) trolled geomagnetic cues might play a Overall, this article has the following ering of the leaves continued even when role in the persistence of rhythmicity major objectives: (1) to provide a highly the plant was placed in an interior room can be refuted by a second characteris­ selective historical overview of the field, and thus was not exposed to sunlight. tic feature of circadian rhythms: These (2) to review characteristic properties of This finding suggested that the move­ cycles persist with a period of close to, circadian rhythms, (3) to define the ments represented something more but not exactly, 24 hours. If the rhythms structural components and the molecu­ than a simple response to the sun and were exogenously driven, they should lar genetic mechanisms comprising the were controlled by an internal clock. persist with a period of exactly 24 hours. biological clock, and (4) to explore the The seeming imprecision is an impor­ health effects of biological rhythms. tant feature of rhythmicity, however. As Characteristic Properties Pittendrigh (1960) demonstrated, the of Circadian Rhythms deviation from a 24-hour cycle actually Historical Overview provides a means for the internal time- of Chronobiology De Mairan’s apt observations illustrate one keeping system to be continuously critical feature of circadian rhythms— aligned by and aligned to the light-dark Researchers began studying biological their self-sustained nature. Thus, almost environment. This continuous adjust­ rhythms approximately 50 years ago. all diurnal rhythms that occur under ment results in greater precision in Although no single experiment serves natural conditions continue to cycle controlling the timing, or phase, of the as the defining event from which to under laboratory conditions devoid expressed rhythms, because little drift date the beginning of modern research of any external time-giving cues from is allowed to occur before the rhythm in chronobiology, studies conducted in the physical environment (e.g., under is “reset” to the correct phase. the 1950s on circadian rhythmicity in constant light or constant darkness). A third characteristic property of fruit flies by Colin Pittendrigh and in Circadian rhythms that are expressed circadian rhythms is their ability to be humans by Jürgen Aschoff can be con­ in the absence of any 24-hour signals synchronized, or entrained, by external sidered its foundation. The area of sleep from the external environment are called time cues, such as the light-dark cycle. research, which also is subsumed under free running. This means that the rhythm Thus, although circadian rhythms can the field of chronobiology, evolved some- is not synchronized by any cyclic change persist in the absence of external time what independently, with the identifi­ in the physical environment. Strictly cues (meaning that they are not driven cation of various sleep stages by Nathaniel speaking, a diurnal rhythm should not by the environment), normally such Kleitman around the same time (Dement be called circadian until it has been cues are present and the rhythms are 2000). The legacies of these pioneers shown to persist under constant envi­ aligned to them. Accordingly, if a shift continue today with the advancement ronmental conditions and thereby can in external cues occurs (e.g., following of the fields they founded. be distinguished from those rhythms travel across time zones), the rhythms 86 Alcohol Research & Health Overview of Circadian Rhythms will be aligned to the new cues. This Figure 1 Circadian rhythm responses to light. alignment is called entrainment. Initially, it was unclear whether A. Parameters of circadian rhythm entrainment was achieved by modulat­ ing the rate of cycling (i.e., whether the Amplitude Phase Period cycle was shortened or lengthened until it was aligned to the new cues and then reverted to its original length) or whether Level entrainment was achieved by discrete “resetting” events. Experiments result­ Night Day Night Day Continuous Darkness ing from this debate led to fundamen­ Time tal discoveries.