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Home , Chronobiology, Circadian clock, Circadian rhythm, Colin Pittendrigh

Overview of Circadian Rhythms

Martha Hotz Vitaterna, Ph.D., Joseph S. Takahashi, Ph.D., and Fred W. Turek, Ph.D.

The daily light-dark governs rhythmic changes in the and/or of most species. Studies have found that these changes are governed by a biological , which in is located in two areas called the suprachiasmatic nuclei. The circadian cycles established by this clock occur throughout and have a of approximately 24 . In addition, these circadian cycles can be synchronized to external 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 products they encode, which regulate various physiological processes throughout the body. Disruptions of the biological rhythms can impair the and well-being of the . KEY WORDS: ; time of ; biological regulation; biological ; temperature; light; ; neural ; ; mutagenesis; 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 , 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- changes in the prey for other . 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 , , 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 , altered hormonal func­ , 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 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 .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- cycles (e.g., 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 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 . 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 forms— that synchronizes the cycle. including , fungi, , fruit Virtually all The persistence of rhythms in the flies, , 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 ) 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 . 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 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 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 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 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. For example, researchers discovered that the organism’s response A representative circadian rhythm is depicted in which the level of a particular measure to light (i.e., whether a cycle advances, (e.g., blood hormone levels and activity levels) varies according to time. The differ­ ence in the level between peak and trough values is the amplitude of the rhythm. is delayed, or remains unchanged) dif­ The timing of a reference point in the cycle (e.g., the peak) relative to a fixed event fers depending on the phase in the (e.g., beginning of the night phase) is the phase. The time interval between phase cycle at which it is presented (Pittendrigh reference points (e.g., two peaks) is called the period. The rhythm shown persists 1960). Thus, exposure to light during even in continuous darkness (i.e., is free running). the early part of the individual’s “nor­ mal” dark period generally results in a B. Resetting the circadian rhythm phase delay, whereas exposure to light Delay during the late part of the individual’s normal dark period generally results in a phase advance. This difference in responses can be represented by a phase- Continuous Darkness response curve (see figure 1 for a schematic Advance Level illustration of a circadian cycle as well as a phase-response curve). Such a curve can predict the manner in which an organism will entrain not only to Continuous Darkness shifts in the light-dark cycles but also Time to unusual light cycles, such as non-24- hour cycles or different light:dark ratios. The effects of a rhythm-resetting signal, such as exposure to light by animals other- The existence of a phase-response curve wise kept in continuous darkness, can shift the rhythm either back (upper panel) or also implies that entrainment is achieved ahead (lower panel), depending on when during the cycle the signal is presented. In by discrete resetting events rather than the case of a phase delay, the peak levels are reached later than they would be had the rhythm not been shifted. In the case of a phase advance, the peak levels are changes in the rate of cycling. reached earlier than they would be had the rhythm not been shifted. The black line In addition to the timing of the light shows how cycling would appear if the rhythm remained unchanged. exposure, the light intensity can modu­ late cycling periods when are C. Changes in circadian rhythm in response to changes in light exposure left in constant light. Thus, exposure to brighter light intensities can lengthen the +6 Subjective Day Subjective Night period in some species and shorten it in Advances other species. This phenomenon has been dubbed “Aschoff’s rule” (Aschoff 1960). 0 Ultimately, both mechanisms of entrain­ ment appear to be aspects of the same

Phase Shift (hours) Delays thing, because the consequences of

-6 Aschoff’s rule can be predicted or explain­ CT 0 CT 12 CT 0 ed by the phase-response curves to light. Circadian Phase of Light Exposure Although the light-dark cycle clearly is the major Zeitgeber for all organisms, Virtually all species show similar phase-dependent-resetting responses to light, which other factors—such as social interactions, can be expressed as a phase-response curve. Exposure to light during the early part of the ’s night causes a phase delay, whereas exposure to light in the latter part activity or exercise, and even tempera­ of the animal’s night causes a phase advance. Light exposure during the animal’s ture—also can modulate a cycle’s phase. usual daytime period produces little or no phase shift. The influence of temperature on circa­ dian rhythms is particularly interesting

Vol. 25, No. 2, 2001 87 in that a change in temperature can in certain invertebrates and vertebrates; et al. 2000). These observations indi­ affect the phase of a cycle without sub­ and the , which is located cate that most cells and tissues of the stantially altering the rate of cycling. within the brain, in nonmammalian verte­ body may be capable of modulating This means that the cycle may start at brates. In mammals, the their activity on a circadian basis. Such an earlier or later-than-normal time but resides in two clusters of nerve cells called findings do not, however, diminish the still have the same length. On the one the suprachiasmatic nuclei (SCN), which central role played by the SCN as the hand, this ability of the internal clock’s are located in a region at the base of the master circadian pacemaker that some- pacemaker to compensate for changes brain called the anterior hypothalamus. how coordinates the entire 24-hour in temperature is critical to its ability temporal organization of cells, tissues, to predict and adapt to environmental and the whole organism. The physio­ changes, because a clock that speeds logical mechanisms underlying this up and slows down as the temperature coordination include signals emitted by changes would not be useful. On the In mammals, the SCN that act on other nerve cells other hand, temperature compensation (i.e., neural signals) or which are also also is rather puzzling, because most the circadian clock distributed through the blood to other kinds of biological processes (e.g., bio­ resides in two organs (i.e., neurohormonal signals). chemical reactions in the body) are accel­ To date, however, the characteristics of erated or slowed by temperature changes. clusters of nerve the circadian signal itself—that is, the Ultimately, this riddle has provided a specific manner in which the SCN clue to the nature of the internal clock— cells called the “talks” to the rest of the body—remain that is, the fact that circadian rhythms suprachiasmatic unknown (see Stokkan et al. 2001). have a genetic basis. Such a program of Although the effects of SCN lesions gene expression would be more resistant nuclei (SCN). on numerous rhythms have been eluci­ to temperature alteration than, for exam­ dated, their effects on sleep are less clear. ple, a simple biochemical reaction. Thus, SCN lesions clearly disrupt the Two final properties of circadian consolidation and pattern of sleep in rhythms also provide important hints The role of the SCN was demon­ rats but have only minimal effects on of the rhythms’ makeup. One of these strated by the landmark discovery in the animals’ amount of sleep or sleep properties is the rhythms’ ubiquity in the early 1970s that by damaging (i.e., need (Mistlberger et al. 1987). For this nature: Circadian rhythms exist in a lesioning) the SCN in rats, researchers and other reasons, researchers have pos­ broad array of biological processes and could disrupt and abolish endocrine tulated that sleep is subject to two organisms, with similar properties and and behavioral circadian rhythms (for a essentially independent control mecha­ even similar phase-response curves to review, see Klein et al. 1991). Further- nisms: (1) the circadian clock that mod­ light. The other property is that circa­ more, by transplanting the SCN from ulates the propensity for sleep and (2) dian rhythms appear to be generated at other animals into the animals with the a homeostatic control that reflects the the cellular level, because the rhythms lesioned SCN, investigators could restore duration of prior waking (i.e., “sleep of unicellular organisms (e.g., algae or some of the circadian rhythms. Finally, debt”). Recently, however, studies in the dinoflagellate Gonyaulax) are much the SCN’s role as a master pacemaker squirrel monkeys found that SCN lesions the same as rhythms of highly complex regulating other rhythmic systems was can affect the amount of sleep. Moreover, mammals. Both of these observations confirmed by similar studies in hamsters, sleep studies in mice carrying changes suggest that a cycle in the activation which demonstrated that the restored (i.e., ) in two of the genes (i.e., expression) of certain genes might rhythms exhibited the clock properties influencing circadian cycles (i.e., the underlie the timekeeping mechanism. (i.e., the period, or phase, of the rhythm) DBP and Clock genes) indicated that of the donor rather than of the host these mutations resulted in changes (Ralph et al. 1990). The discovery that in sleep regulation (Naylor et al. 2000; The Anatomical the SCN is the site of primary regulation Franken et al. 2000). Both of these Organization of of circadian rhythmicity in mammals observations raise the intriguing possi­ the Internal Clock gave researchers a focal point for their bility that the homeostatic and circa­ research: if one wanted to understand dian controls may be more interrelated Although studies of unicellular organisms 24-hour timekeeping, one needed to than researchers previously thought. point to the cellular nature of the system study the clock in the SCN. generating circadian rhythms, the circa­ Recently, however, researchers have dian pacemaker in higher organisms is been surprised to find that circadian Molecular located in cells of specific structures of rhythms could persist in isolated , of Circadian Rhythms the organism. These structures include , and other tissues grown in a cul­ certain regions of the brain (i.e., the optic ture dish (i.e., in vitro) that were not As discussed previously, the properties and cerebral lobes) in insects; the under the control of the SCN (Yamazaki of circadian suggested cyclic

88 Alcohol Research & Health Overview of Circadian Rhythms

changes in the expression of certain mutations into the DNAs of the fruit frustration ensued as researchers sought genes as a possible mechanism underlying fly, melanogaster, and of the to isolate the equivalent genes in mam­ the internal pacemaker. This hypothe­ filamentous Neurospora. The mals (i.e., mammalian homologs). sis was supported by the demonstration resulting mutant organisms then were Finally, in the early 1990s, researchers in a number of species that the expression screened for rhythm abnormalities. This began a similar mutagenesis screening of genes and the production of mutagenesis approach led to the identi­ approach in the mouse and described encoded by those genes were required fication of the first circadian clock the first mouse circadian , called for normal clock function. Nevertheless, mutants, which were called period (per) Clock, in 1994 (see King and Takahashi a completely different experimental and frequency (frq, pronounced “freak”). 2000). In 1997 the gene affected by this approach ultimately led to the identifi­ The genes that carried the mutations mutation became the first mammalian cation of molecular circadian clock in these organisms were cloned in the circadian clock gene to be cloned (King components. Researchers used chemical 1980s (for a review, see Wager-Smith and Takahashi 2000). Like the mutants agents to introduce numerous, random and Kay 2000). However, considerable of the Per and Frq genes, the altered Clock gene both affected the free-running rhythm period (i.e., lengthened the Table 1 Mammalian Circadian Clock Genes; the Corresponding Genes in the Fruit period) and caused a loss of persistence Fly, Drosophila; and the Effects of Changes (i.e., Mutations) in Those of circadian rhythms under constant Genes on the Behavior (i.e., Phenotype) of the Affected Animals environmental conditions. Both the Clock mutant in mice and the Per Mouse Drosophila mutant in flies were the first animals Gene Alias Gene Mutant Phenotype of their respective species identified using such a mutagenesis approach *Clock dClock Lengthened period; loss in which the mutation manifested as of persistent rhythmicity altered behavior rather than an altered in constant conditions physiological process. Since the discovery of the Clock mPer1 period Reduced amplitude, gene in mice, the list of circadian clock shortened period, or loss of rhythm genes identified in mammals has grown in a remarkably short period of time *mPer2 period Shortened period, loss (see table 1). For example, researchers of rhythm have identified not one, but three mam­ malian genes that correspond to the *mPer3 period Modest shortening per gene in both their structure (i.e., of period nucleotide sequence) and their function (King and Takahashi 2000; Lowrey *CKΙε tau Shortened period in and Takahashi 2000). Some of the pro- (hamster) hamster mutants posed circadian clock genes have been *mCry1 dcry Animals lacking the identified solely based on their similarity mCry2 mCry1 gene (i.e., mCry1 in sequence to Drosophila clock genes knockouts) have short­ and have not been confirmed to have clock ened period; mCry2 function based on an examination of the knockouts have length­ behavior of the corresponding mutants. ened period; animals Nevertheless, the findings to date clearly lacking both genes (i.e., indicate the outline of a pacemaker that double knockouts) have is based on a feedback cycle of gene a loss of rhythm expression (see figure 2). *BMAL1 MOP3 cycle Loss of rhythm

?mTim Role in mammals is Importance of the not clear Circadian Clock for Human Health ?DBP Modest lengthening of and Well-Being period Nearly all physiological and behavioral NOTE: Asterisk (*) indicates that a key role for the gene in timekeeping has been demonstrated by the pheno­ type of a mutant. functions in humans occur on a rhythmic basis, which in turn leads to dramatic diurnal rhythms in human performance

Vol. 25, No. 2, 2001 89 capabilities. Regardless of whether it For most animals, the timing of sleep disturbed sleep is a hallmark of many results from voluntary (e.g., shift work and wakefulness under natural condi­ human mental and physiological disorders, or rapid travel across time zones) or tions is in synchrony with the circadian notably affective disorders, it is often involuntary (e.g., illness or advanced age) control of the and all other unclear whether the sleep disturbances circumstances, a disturbed circadian circadian-controlled rhythms. Humans, contribute to or result from the illness. rhythmicity in humans has been associ­ however, have the unique ability to Other circadian rhythm abnormalities ated with a variety of mental and physi­ cognitively override their internal bio­ also are often associated with various dis­ cal disorders and may negatively impact logical clock and its rhythmic outputs. ease states, although again the importance safety, performance, and productivity. When the sleep-wake cycle is out of of these rhythm abnormalities in the Many adverse effects of disrupted circa­ phase with the rhythms that are con- development (i.e., etiology) of the disease dian rhythmicity may, in fact, be linked trolled by the circadian clock (e.g., remains unknown (Brunello et al. 2000). to disturbances in the sleep-wake cycle. during shift work or rapid travel across One important factor contributing Some rhythmic processes are more time zones), adverse effects may ensue. to researchers’ inability to precisely affected by the circadian clock than by In addition to the sleep disturbances define the role of circadian abnormalities the sleep-wake state, whereas other associated with jet lag or shift work, sleep in various disease states may be the lack rhythms are more dependent on the disorders can occur for many other known of knowledge of how circadian signals sleep-wake state. and unknown reasons. And although from the SCN are relayed to target tis-

BMAL1 CK1 Inhibition Clock ? Nucleus

E mPers E mCrys

Transactivation Cytoplasm

P P

Degradation

Figure 2 Schematic representation of the regulation of genes believed to be involved in the circadian clock. BMAL1, Clock, CK1ε, mPer, and mCry all are circadian clock genes identified in mice. (Several variants exist of the mPer and mCry genes.) In the cell’s nucleus, the genetic information encoded in these genes is converted into a carrier called mRNA (black wavy lines), which is transported into the fluid within the cell (i.e., the cytoplasm). There, the mRNA is used to generate the protein products encoded by the circadian clock genes (circles and ovals with colors corre­ sponding to the respective genes). Some of these proteins regulate the activity of certain clock genes by binding to “molecular switches” (i.e., E boxes) located in front of those genes. This is called a feedback cycle. Thus, the BMAL1 and clock proteins promote activation of the Per and mCry genes, whereas Per proteins inhibit activation of those genes. The 24-hour cycling comes about as the BMAL1 and Clock proteins induce increased production of Per and Cry proteins. As Pers and Crys accumulate, they inhibit their own synthesis, and the protein levels decline. CK1ε protein also helps to regulate Clock protein levels by destabilizing Per protein.

NOTE: BMAL1 = brain and muscle ARNT-like 1; CK1ε = caseine kinase 1 epsilon; mPer = mouse period; mCry = mouse .

90 Alcohol Research & Health Overview of Circadian Rhythms

sues. To further elucidate the regulation builds on extensive research carried out This question is addressed in more detail of circadian rhythms, researchers need in many laboratories during the past 50 in this special issue of Alcohol Research a better understanding of the nature of years. Within the same period, other & Health. Drs. Wasielewski and Holloway circadian signal output from the SCN researchers in numerous laboratories review ways in which alcohol and the and of how these output signals may have elucidated the critical role played body’s circadian rhythm interact, using be modified once they reach their target by the SCN in the regulation of circa­ body temperature as an index of circa­ systems. Such an enhanced understanding dian rhythmicity in mammals and per- dian rhythm function. The sleep-wake also would allow for a better delineation haps other vertebrates. (For more infor­ cycle, which constitutes a central aspect of the importance of normal temporal mation on these findings and their rele­ of circadian rhythms in particular, is sub­ organization for human health and dis­ vance, the reader can refer to a variety of ject to modification by alcohol; alcohol’s ease. The finding that two major causes resources on the World Wide Web, effects on the sleep of nonalcoholics and of death—heart attacks and strokes— some of which are listed in table 2.) alcoholics are discussed by Drs. Roehrs show time-of-day variation in their Most animals are content to obey and Roth and by Dr. Brower, respectively. occurrence is a case in point. If scien­ their SCN and let it orchestrate the As indicated in this article, disturbances tists knew more about the mechanisms expression of a multitude of circadian of the normal circadian rhythmicity can responsible for the rhythmicity of these rhythms. Humans, however, have a result in serious health consequences, disorders, they might be able to iden­ of their own and often use this mind including psychiatric disorders, such as tify more rational therapeutic strategies to disobey their “internal clock”—for depression. At the same time, psychoac­ to influence these events. Finally, given example, with an increasing tendency tive drugs, such as antidepressants, also that dramatic changes occur in the cir­ toward 24-hour availability for busi­ have chronobiological effects. Dr. cadian clock system with advanced age, ness. The potential consequences of Rosenwasser explores those associations these changes may underlie, or at least such an increasingly 24-hour on-call and discusses alcohol’s effects in human exacerbate, the age-related deterioration lifestyle are unknown at this point, but and animal models of depression. Other in the physical and mental capabilities the evidence does not bode well. influences of alcohol on the biological of older adults. The challenge for researchers and clock may be even more subtle and clinicians now is to determine not only remain rather speculative, such as the the cause but also the consequences for consequences of prenatal alcohol expo- Conclusions human health and disease of disruptions sure, which is discussed by Drs. Earnest, in the temporal organization of the cir­ Chen, and West. Finally, not only may Although researchers in just the past cadian system. These issues also include alcohol consumption affect circadian few years have made great advances in the question of what role alcohol may rhythms, but circadian factors, such as understanding the molecular basis of play in the disruption of normal circa­ the light-dark cycle, may also influence circadian rhythmicity, this progress dian rhythms and the biological clock. alcohol consumption. This topic is dis­ cussed by Drs. Hiller-Sturmhöfel and Kulkosky. Together, these articles offer Table 2 Chronobiological Resources on the World Wide Web readers insight into the interesting and complex interactions that exist between Web Site Description alcohol and the circadian rhythms that http://www.nwu.edu/ccbm/ Web site of Northwestern University’s govern much of the behavior and well- Center for Sleep and Circadian Biology being of all organisms, including humans. ■ http://www.sleepquest.com/ Information site of William Dement’s Sleep Research Center

http://www.med.stanford.edu/school/ site created by Emmanuel References

Psychiatry/narcolepsy Mignot at ASCHOFF, J. Exogenous and endogenous compo­ nents in circadian rhythms. Cold Spring Harbor http://www.sleepfoundation.org/ Web site of the National Sleep Foundation Symposia on Quantitative Biology: Volume XXV. Biological Clocks. New York: Cold Spring Harbor http://www.srbr.org/ Web site of the Society for Research on Press, 1960. pp. 11–28. Biological Rhythms BRUNELLO, N.; ARMITAGE, R.; FEINBERG, I.; ET AL. Depression and sleep disorders: Clinical relevance, http://www.cbt.virginia.edu/ Web site of the Center for Biological economic burden and pharmacological treatment. Timing at the Neuropsychobiology 42:107–119, 2000.

http://www.hhmi.org/grants/lectures Web site providing Howard Hughes DEMENT, W.C. of sleep physiology and Medical Institute Holiday Lectures medicine. In: Kryer, M.H.; Roth, T.; and Dement, W.C., eds. Principles and Practice of . 3d ed. Philadelphia: W.B. Saunders, 2000.

Vol. 25, No. 2, 2001 91 GLOSSARY

Every scientific field has its specific terminology; the scientific area of biological rhythms and sleep is no exception. This glossary defines some of the terms that readers may encounter in this article and throughout this special issue of Alcohol Research & Health.

Chronobiology: A subdiscipline of biology concerned with the (e.g., in an animal that is unable to entrain because of some timing of biological events, especially repetitive or cyclical defect) is said to be masked by a light cycle. For example, phenomena, in individual organisms. the aversion of a nocturnal rodent to bright light results in Circadian: A term derived from the Latin phrase “circa diem,” its activity onset appearing to coincide with the absence of meaning “about a day”; refers to biological variations or light, or “lights off,” when the animal actually has been rhythms with a cycle of approximately 24 hours. Circadian awake for hours. For comparison, see entrainment. rhythms are self-sustaining (i.e., free running), meaning that Nonrapid movement (NREM) sleep: Sleep stages that they will persist when the organism is placed in an environ­ include the “deeper” stages of sleep in which dreaming typi­ ment devoid of time cues, such as constant light or constant cally does not occur. Also referred to as slow-wave sleep. For darkness. For comparison, see diurnal, infradian, and ultradian. comparison, see . Circadian time (CT): A standardized 24-hour notation of the Phase shift: A change in the phase of a rhythm. This change phase in a circadian cycle that represents an estimation of the organism’s subjective time. CT 0 indicates the begin­ can be measured by observing a change in the timing of a ning of a subjective day, and CT 12 is the beginning of a phase reference point (e.g., activity onset or the nocturnal subjective night. For example, for a nocturnal rodent, the rise in the release of the hormone ) from the tim­ beginning of a subjective night (i.e., CT 12) begins with the ing expected based on previous, free-running cycles. Phase onset of activity, whereas for a diurnal species, CT 0 would shifts may be either advances (i.e., the phase reference point be the beginning of activity. For comparison, see Zeitgeber occurs earlier than normal) or delays (i.e., the phase refer­ time. ence point occurs later than normal). DD: A conventional notation for an environment kept in con­ Phase-response curve (PRC): A graphical summary of the tinuous darkness (as opposed to a light-dark cycle). For phase shifts produced by a particular manipulation, such as comparison, see LD. a light pulse or a pharmacological treatment, as a function Diurnal: Varying with time of day. Diurnal rhythms may per­ of the phase (i.e., circadian time) at which the manipulation sist when the organism is placed in an environment devoid occurs. Defining the PRC to light has enabled researchers of time cues, such as constant light or constant darkness. to understand and predict how entrainment to light cycles Therefore, diurnal variations can be either light driven or is accomplished. clock driven. For comparison, see circadian. Rapid eye movement (REM) sleep: A stage of light sleep char­ Entrainment: The process of synchronization of a timekeeping acterized by rapid eye movements and associated with mechanism to the environment, such as to a light-dark dreaming. Also called paradoxical sleep. For comparison, see cycle, or LD. For comparison, see free running. nonrapid eye movement sleep. Free running: The state of an organism (or rhythm) in the or nuclei (SCN): A cluster of nerve absence of any entraining stimuli. Typically, subjects are cells located in the brain region called the hypothalamus kept in constant dim light or constant darkness to assess that is responsible for generating and coordinating circadian their free-running rhythms. For comparison, see entrainment. rhythmicity in mammals. Infradian: A term derived from the Latin phrase “infra diem,” Ultradian: A term derived from the Latin phrase “ultra diem,” meaning “less than a day”; refers to biological cycles that last meaning “more than a day”; refers to biological cycles that last more than 1 day and, therefore, have a frequency of less than one per day. For comparison, see circadian and less than 1 day and, therefore, have a frequency of more than ultradian. one per day. For comparison, see circadian and infradian. LD: Conventional notation for a light-dark environmental Zeitgeber: A German word literally meaning “time-giver.” A cycle; the numbers of hours of light and dark are typically time cue capable of entraining circadian rhythms. Light rep­ presented separated by a colon. For example, LD 16:8 resents the most important Zeitgeber. denotes a cycle consisting of 16 hours of light and 8 hours Zeitgeber time (ZT): A standardized 24-hour notation of the of dark. For comparison, see DD. phase in an entrained circadian cycle in which ZT 0 indi­ Masking: The obscuring of the “true” state of a rhythm by cates the beginning of day, or the light phase, and ZT 12 is conditions that prevent its usual expression. Usually, the the beginning of night, or the dark phase. For comparison, phase of an entrained rhythm or the absence of entrainment see circadian time.

92 Alcohol Research & Health Overview of Circadian Rhythms

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