What are circadian rhythms?

Introduction

Circadian rhythms are a fundamental characteristic of life. The term circadian was coined by Franz Halberg and refers to rhythms that are about a day in length (from the Latin circa, “about,” and dies, “day”). Although historically many of the early observations were made on plants and animals, later research has shown a remarkable similarity in the structure and functioning of the circadian clock across different species. Circadian rhythms are ubiquitous and are exhibited by most physiological, biochemical, and molecular events that occur in organisms and share common mechanisms of operation.

The most obvious rhythm of human activity is the sleep-wake cycle. Human beings are most active during the daylight hours and sleep for much of the dark period. A species with this schedule is called diurnal (animals active during the dark period are termed nocturnal). Human beings are essentially diurnal except for the adaptations that come with work, travel, and other circumstances.

It is known that the sleep-wake cycle is not determined as rigidly as many other physiological rhythms. For example, one can choose not to sleep for several days and thereby temporarily abolish the pattern. A more fundamental and less easily modified rhythm is the circadian rhythm of core body temperature. In this case, there is a daily fluctuation of slightly more than 1 degree Celsius over the course of twenty-four hours, with the lowest body temperature occurring between 4:00 and 5:00 a.m., when a person is deep in sleep. The temperature rhythm continues its fluctuation, although somewhat dampened, even if a person stays awake for several days. This condition is called desynchronization of rhythms—in this case, the temperature rhythm and the sleep-wake rhythm are desynchronized from each other.

One of the first discoveries made on circadian rhythms is that they are endogenous in nature—the rhythmic activities are engendered and controlled from within the organism rather than being influenced or controlled by external agents such as the changing light and dark cycles or changes in temperature. Isolating human beings under constant conditions, where natural changes to day and night or fluctuations in temperature are absent, do not lead to abolition of rhythmicity. Even in the absence of external time cues, human beings are able to tell time because of the presence of an endogenous clock. The daily rhythmic occurrence of events (such as the time interval between the onset of sleep or the time interval between the occurrences of temperature minima) is measured by period. Under normal conditions, the period is close to twenty-four hours because the rhythms are synchronized or “entrained” by the light-dark cycles and other cues afforded by nature. However, if human beings are kept under constant conditions, they exhibit a period called a free-running rhythm that deviates slightly from twenty-four hours.

Free-running rhythms are observed in humans if the individual lives for many days or weeks in an isolated cave or bunker, where possible time cues such as the light-dark cycle or other factors have been eliminated. The famous cave explorer Michel Siffre found that he had a sleep-wake cycle of twenty-four hours and thirty-one minutes when he lived alone in a cave for two months without time cues. Similar studies in the more controlled environments of World War II bunkers were carried out by the German scientist Jürgen Aschoff. In each case, it was found that the body’s rhythms gradually drifted out of phase with the actual time of day when watches and the natural cycle of light changes were eliminated. Aschoff termed factors that maintain a circadian periodicity Zeitgebers, or time givers. Individual subjects were found to have their own unique period, or length, for their free-running rhythms—for example, 24.3, 24.5, 24.7, or 24.9 hours. It has been well documented that various rhythms such as the sleep-wake cycle, body temperature, blood pressure, respiration rate, and urinary excretion of sodium, under constant conditions, will show slightly different period lengths and will therefore become desynchronized. Desynchronization, which may occur in the elderly under normal living conditions, is thought by some scientists to lead to various disease states. For example, episodes of mania in people with bipolar disorder can be triggered by travel to a geographical zone with increased sunlight.

Various mental abilities in humans have been shown to be subject to circadian variations. A person’s ability to estimate time duration varies during the day inversely to the daily change in temperature. The ability to memorize numbers is better in the morning than in the afternoon, and the ability to add random numbers is better in the morning than in the afternoon. Eye-hand coordination changes with a circadian rhythm, with skills better during the day and performance reduced at night. The existence of these rhythms has many implications, and the further study of such rhythmic factors remains a vital common ground between physiology and psychology.

Two small nuclei, suprachiasmatic nuclei (SCN), situated just below the optic chiasma in the hypothalamus of the brain, are implicated to be crucial for the generation and sustenance of rhythmic behavior. They are called the core circadian clock, and their removal abolishes an array of rhythmic activities, including sleep-wake and temperature cycles. The hypothalamus, located just above the pituitary gland in the brain, is thought to regulate many human rhythms. Its cell clusters, or nuclei, receive input from various sense organs and brain areas. In response, they secrete releasing hormones, which travel to glands in the body and stimulate the release of second and third downstream hormonal systems that modulate body processes. These hypothalamic nuclei and secondary hormones are active in many cyclical patterns. For example, female sex hormones from the pituitary gland follow characteristic circadian patterns—monthly patterns that develop the female ovum (egg) and regulate each menstrual cycle—and lifetime patterns that initiate sexual maturation and menopause.

Genetic and Molecular Basis

In 1971, Ronald J. Konopka and Seymour Benzer isolated mutations in the fruit fly, Drosophila melanogaster, with consistent differences in their periods (such as short-period mutants and long-period mutants) and identified three alleles of the Period gene (PER) as being responsible for the changes.
Understanding of the components and the functioning of circadian clocks at the molecular level has increased tremendously. More than ten genes have been shown to be responsible for proper functioning of the circadian clock (core clock genes) and several others have been indicated as clock-controlled genes. At least three period genes (PER1, PER2, and PER3) have been identified in mammals as components of the core clock. These, along with other identified circadian clock genes such as Cryptochrome 1 and 2 (CRY 1, CRY 2), CLOCK, BMAL1, and REV-ERB alpha, generate the twenty-four-hour rhythmicity of the circadian clock through a series of transcriptional and translational events. The mechanism of their action involves an interlocking positive and negative feedback loop (turning the expression of certain genes on and off at given intervals of time, while having their own expression turned on and off at given intervals of time). Such molecular oscillations are observed in the SCN as well as in several other peripheral organs like the liver and the brain. The molecular mechanism of the circadian clock function is remarkably similar among different species, including fungi, insects, rodents, and humans.

Manipulating Circadian Rhythms

The most familiar way humans apply their understanding of body clocks is to adjust to external changes in the sleep-wake cycle. A person can willfully avoid sleep for hours without a parallel increase in fatigue, as is attested by students who get a “second wind” once they study past 3:00 or 4:00 a.m. Some researchers envision an underlying circadian rhythm of alertness and fatigue that enhances a person’s ability to awaken in the morning and to fall asleep in the late evening. In general, it is easier to awaken in the morning when the body temperature is increasing, and it is easier to fall asleep in the late evening when body temperature is falling. So-called owls and larks do exist in the human population; people who fall into these two groups differ as to when their body temperature peaks, with larks peaking earlier.

In human beings, such manipulations are a bit tricky because the sleep-wake cycle can be modified by alcohol, drugs, and social interactions, among other factors. However, studies on a specific population in Utah found people who have an inherently shifted period. Individuals in this population had their sleep phase advanced by about four to six hours a day. This is called familial advanced sleep phase syndrome (FASPS). FASPS manifests itself in early childhood as a dramatic advance in the sleep schedule, and with advances in age it gets even worse. This syndrome is in contrast to the delayed sleep phase syndrome (DSPS) observed in many adolescents. Extensive genetic studies identified alterations in hPER2, (human period 2), a critical core circadian clock gene, in the affected population. Several clock genes, including hPER3, arylalkylamine N-acetyltransferase, and hCLOCK have been linked to DSPS.

The detailed makeup of sleep also shows periodicity. Brain waves measured with an electroencephalograph (EEG) record four distinct waves, each associated with a type and depth of sleep that repeats two to five times each night. The pattern changes with age; children sleep most deeply on initiation of sleep, while adults sleep most deeply just before waking. Rapid eye movement (REM) sleep, associated with dreaming, occurs more frequently later during the sleep period. Most major cities now have sleep laboratories in which scientists monitor the sleep of patients and apply theories involving circadian rhythms to improve the type and timing of medications.

Shift Work and Jet Lag

When people are forced to change their sleep-wake schedule for either work or travel, shift-work problems and jet lag can result. Shift work is required in circumstances in which around-the-clock services are either essential or economically beneficial. These include medical, police, military, utility, transportation, and other essential services, as well as tasks in the chemical, steel, petroleum, and various other manufacturing industries. Work is done and days off are given according to many different schedules. A number of catastrophic events, such as the Three Mile Island nuclear accident (1979), the chemical explosion in Bhopal, India (1984), and the Chernobyl nuclear accident (1986) happened during the late-evening or night shift, when fatigue of ill-adapted workers may have been a factor. Within the population, there are owls who can adapt to night shift work without the physical problems experienced by their peers. It is known that physiological and behavioral rhythms will shift to a new schedule only if the schedule is kept the same for a period of weeks. Shift workers who stay on their schedule of night work and day sleep will quickly shift their sleep-wake cycle and eventually shift their various behavioral and more fundamental physiological rhythms such as body temperature. Because the body’s circadian rhythms are more than twenty-four hours in length, it is easier to start work later on successive days than it is to start work earlier.

What later became known as jet lag was first experienced by Wiley Post and Harold Gatty on their 1931 around-the-world airplane trip. By the 1950s, increasing numbers of tourists, diplomats, flight crews, and pilots were suffering from the general malaise, headaches, fatigue, disruptions of the sleep-wake cycle, and gastrointestinal disorders that can occur when people cross several time zones within a few hours. The effects are worse on eastward flights than on westward flights, perhaps because the circadian rhythms can undergo an adjustment to a lengthening in timing better than to a shortening. A night flight from New York to Paris results in a six-hour time shift, with breakfast coming six hours early according to nonshifted circadian rhythms. Within a few days, the sleep-wake cycle adjusts, but deeper physiological rhythms may take two or more weeks to shift to the new time zone.

There is mounting evidence to suggest that jet lag and shift-work sleep disorders are due to disturbances in the circadian phase of plasma melatonin levels. Melatonin, the so-called hormone of sleep, is available for shifting the phase of sleep (phase shifting) and to synchronize sleep patterns. Melatonin is widely used for treating problems related to jet lag and shift work. The hormone melatonin binds to its receptors—melatonin receptors 1 and 2, called MT1 and MT2. Both of these receptors are located in the SCN region of the brain. The administered dose of melatonin changes depending on the duration of the travel time. Longer travel requires starting of the treatment regimen a few days in advance of the travel, while shorter travel can bypass this step. Drugs that bind to the melatonin receptor and activate it are being tested in clinical settings.

Seasonal Affective Disorder

Another application of chronobiology is in the study and treatment of seasonal affective disorder (SAD). People with SAD typically experience clinical depression in March and April, at the end of the winter months of shorter daylight. This depression is unlike the more common melancholic depression, which is characterized by loss of sleep and appetite, in that it is accompanied by increased eating, particularly of carbohydrates, and increased sleep, up to sixteen hours per day. It is also distinguished from the winter blues, which occur in one of four individuals, usually earlier in the winter. Although SAD is not considered a variant of bipolar disorder, it resembles bipolar disorder in the type of depressive symptoms and its relationship to sunlight. Many highly creative individuals, such as artist Vincent Van Gogh, writers Tennessee Williams and Edgar Allan Poe, President Abraham Lincoln, and many others have suffered either bipolar illness or SAD, describing the “seasons of the mind” in their work.

Circadian rhythms are fundamental to the pathophysiology and treatment of SAD. Response to daylight is modulated by the pineal gland, a pea-sized organ midline under the cerebral hemispheres of the brain. In darkness, the pineal gland secretes melatonin and possibly other substances. Information about light, transmitted along specific nerve pathways from the eyes, inhibits release of melatonin. Although it is not clear exactly how loss of daylight leads to seasonal depression, bright light therapy can reverse or prevent it, possibly by altering circadian rhythms such as those influencing mood, sleep, and appetite via secondary effects of melatonin. The standard light therapy involves exposure to approximately 1,500 lux (the unit of measurement for light) at a frequency that mimics sunlight. For mood disorders, patients are exposed to 10,000 lux light intensity daily for twenty to thirty minutes, preferably in the morning as nighttime treatments have been known to cause insomnia. Although the majority of light therapy products filter or completely block harmful UV light, individuals should not look directly at the light but instead have it nearby so that the light is absorbed through peripheral vision.

The severity of other illnesses also follows a circadian rhythm. Stomach acid secretion peaks in the late afternoon and just after midnight, leading to worsened symptoms of peptic ulcers at these times. Drugs that inhibit acid secretion are given at night to take advantage of this phenomenon. Similarly, asthma exacerbations tend to occur at night; predictably, oral medications for asthma produce better results if given before bedtime. Some types of high blood pressure peak at night, others in the morning; again, drugs should be given so that peak drug levels coincide with peak blood pressure readings.

There has been tremendous progress in the understanding of the cellular and molecular mechanisms dictating the functioning of a normal circadian clock. Associations of pathophysiology of diseases to disruptions in circadian clock functions are being investigated. Many clock genes have been implicated in complex mental illnesses such as major depression, bipolar, and schizophrenia, in addition to insomnia and SAD. Modifications of treatments based on the understanding of circadian rhythms have become a reality. For example, chemotherapy is given for cancer at more exact times to coincide with the most vulnerable period of cancer cell division, allowing for lower doses, fewer side effects, and better treatment results. As circadian rhythms are better understood, many aspects of health and daily life may be managed with greater ease.

Circadian Rhythm Research

In 1729, French astronomer Jean Jacques d’Ortous de Mairan reported his observations on the leaf movements of a “sensitive” heliotrope plant that continued to open and close its leaves approximately every twenty-four hours even when it was kept in continuous dark. This was the first demonstration of a free-running rhythm. Studies on humans included those by Sanctorius, who in the seventeenth century constructed a huge balance on which he was seated in a chair and studied circadian rhythms in body weight. Julian-Joseph Virey, a Parisian pharmacist, postulated endogenous biological clocks modified by environmental input in his 1814 doctoral thesis and is credited with formally establishing the field of chronobiology. Yet despite these early studies, it was the 1950’s before circadian rhythms were more widely studied and research on humans began to be more common.

In psychology, Nathaniel Kleitman and Eugene Aserinsky in the 1940’s discovered rapid eye movement, or REM, sleep. The rhythmic patterns in REM sleep and their relation to the circadian sleep-wake cycle have remained an active area for research. The psychobiologist Curt Richter carried out work on the activity rhythms in rats. Richter also identified the general area in which the suprachiasmatic nuclei are found as a region of the hypothalamus important in controlling circadian rhythms. Simon Folkard and colleagues have studied various human performance tests and have found numerous circadian rhythms. They found that the circadian rhythms in memory tests peaked at different times, depending on the complexity of the number to be memorized. There remains a need for more research by psychologists who incorporate variation due to circadian rhythm into their research design.

The research on the genetics of circadian rhythms was initiated by Konopka and Benzer in 1971, using a forward genetic approach. The Period gene was first identified in Drosophila, and its orthologs in mammals were identified in 1997. Another important clock gene, Clock was identified through genetic studies in 1994 and was subsequently cloned in 1997. Two other important genes, the cryptochromes, CRY1 and CRY2 were identified in the same year, and the molecular mechanism involving the positive and negative feedback loops was uncovered subsequently. Research on this field focuses not only on further details and missing elements of the circadian clock, but also on how alterations in these identified genes could be related to various disease states.

Bibliography

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Toh, K. L., et al. “An hPER2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome.” Science 291 (2001): 1040-1043. This article showed that mutations in a single gene (hPER2) caused alterations in sleep behavior. The study was conducted in a small population in Utah. This is the first identification in humans of a single gene mutation affecting as complex a behavior as sleep.