Circadian Rhythms

CIRCADIAN RHYTHMS

Circadian rhythms (from circa [approximately] and dies (day)) are internally generated, near-24-hour fluctuations in physiology, performance, and behavior. Circadian rhythms have been identified in nearly every species in which they have been examined, from unicells to plants to mammals. Circadian rhythms are thought to provide an adaptive advantage to the organism by providing it a means to anticipate regular periodic changes in the environment, and such daily oscillations are thought to have arisen through the process of natural selection that took place in the presence of a regular 24-hour environmental alteration of day and night.

In the early 1970s, the neural structure responsible for synchronizing circadian rhythms in mammals was localized to the suprachiasmatic nucleus (SCN), a small structure located in the brain's hypothalamus. This structure was first identified in studies in which the SCN was lesioned. SCN lesions, resulted in behavior that no longer occurred at regular, near-24-hour intervals but instead was arrhythmic. After the SCN was identified, additional studies in which the electrical activity of the SCN was recorded revealed that part of the brain has a 24-hour cyclicity in electrical activity. A series of elegant studies in which the SCN from mutant animals was transplanted into SCN-lesioned wild-type animals, and vice versa, resulted in the host animals exhibiting the circadian characteristics of the donor animals, further evidence of the role of the SCN as the circadian pacemaker. Since that time, further studies have demonstrated that the near-24-hour pattern of electrical activity is a property of individual SCN neurons.

In the 1990s, great progress in understanding the molecular and cellular basis for near-24-hour rhythmicity was made. The production of 24-hour rhythms from much shorter biochemical events within the cell results from the interaction of several genes and their protein products. Rising levels of proteins interact and then bind to DNA to halt further protein production. As the levels of these clock component proteins fall, the genes are no longer inhibited, and begin production of these proteins again. In some cases, levels of particular proteins are suppressed by exposure to light, adding another feature to the variation of gene and protein levels between day and night that might be related to the mechanism of photic resetting of the circadian clock. The genes and proteins involved in generating circadian rhythmicity have now been identified for a number of species, and while some details differ from species to species, the general mechanism of transcriptional-translational feedback loops is highly conserved—meaning that the general mechanism of having a transcription-translation feedback loop to produce near-24-hour rhythms is quite similar across a wide array of species, from lower to higher organisms.

The primary source of environmental information to this internal pacemaker is the light-dark cycle, which is transmitted along a mono-synaptic pathway (the retinohypothalamic tract, or RHT) from the retina to the SCN. There are other, non-photic, rhythmic factors from the environment that have been shown to provide information to the circadian pacemaker in some species, including cycles in environmental temperature or food availability. Rhythmic alterations in behavior can also provide timing information to the circadian system in certain situations.

Circadian rhythms are endogenously generated, and not simply a reflection of daily changes in light and darkness, ambient temperature, or patterns of rest and activity. As such, circadian rhythms continue to be expressed when the organism is studied in constant conditions, although the exact period (cycle length) of the rhythm is usually no longer precisely 24 hours, but instead is slightly shorter or longer than 24 hours. The actual cycle length of a circadian rhythm when studied under constant environmental conditions is termed the free-running period. Under normal conditions, these non-24-hour rhythms are synchronized to the 24-hour day by periodic exposure to signals from the environment, a process called entrainment. For most mammals, regular exposure to the light-dark (LD) cycle entrains the circadian timing system to the 24-hour solar day. In order to maintain entrainment, an organism with a slightly shorter than 24-hour circadian period must have its circadian system reset slightly later each day, while an organism with a longer than 24-hour period must have its circadian system reset earlier each day.

The time of a particular event within the circadian cycle is referred to as the phase of that event. For example, the nadir of the endogenous circadian rhythm of core body temperature is often used as a circadian phase marker. The time at which the core body temperature phase occurs can then be compared with respect to the timing of the sleep-wake cycle, can be compared between individuals, or can be compared before and after an intervention. Thus, the term phase refers to a reference point within the near-24-hour rhythm.

Another key feature of the circadian timing system is that it typically has a phase-dependent response to many types of stimuli. This means that the time within the circadian cycle that a stimulus is applied will affect the magnitude and direction of the response to that stimulus. For example, the resetting response of the circadian system of most organisms to light is phase-dependent. A light stimulus applied in the early night will cause a phase delay shift of the animal's circadian rhythms (the timing will be shifted to a later hour), a light stimulus applied in the late night will cause a phase advance shift (to an earlier hour), and a light stimulus applied in the middle of the day will cause a very small change in phase. The phase-dependent response of the circadian system to a stimulus is typically summarized in a phase-response curve (PRC).

Under entrained conditions, the phase of a circadian rhythm has a fixed relationship to the signal from the environment (in most cases, the light-dark cycle) that synchronizes, or entrains, the circadian timing system to the 24-hour day. This phase relationship is termed the phase-angle of entrainment.

Another feature of a circadian rhythm is its amplitude, or the size (magnitude) of the oscillation.

The study of circadian rhythms in the laboratory

While circadian rhythms are endogenously (internally) generated, they can also be directly affected by changes in the environment or by changes in behavior. For example, nocturnal rodents typically are inactive during the light portion of the light-dark cycle. If bright lights were turned on during the animal's normal dark time (when it would typically be active), the animal may cease activity. Thus, the endogenous component of the animal's circadian activity rhythm is acutely altered by exposure to light. This can also occur when human circadian rhythms are studied, and the endogenous circadian component of many physiologic and behavioral rhythms can be affected by things such as ambient light, activity, sleep-wake state, food intake, postural change, and emotional state. Thus, it is important that studies of circadian rhythmicity be conducted under controlled conditions in which the endogenous component of circadian rhythms can be measured.

Studies of circadian rhythms in humans began as early as the 1930s. Nathaniel Kleitman studied human subjects in Mammoth Cave in Kentucky, an environment where temperature, humidity, and darkness were constant. While the experimental subjects in those studies were allowed access to artificial lighting, Kleitman's studies revealed that humans, like other organisms, continue to exhibit near-24-hour physiological rhythms even when living in constant conditions. In the 1960s, JÎrgen Aschoff and colleagues began a series of circadian rhythm studies in Germany. They studied their subjects in underground bunkers, which, like the cave used by Kleitman, were shielded from information from the external environment. In the 1970s and later, special laboratories were developed for the study of circadian rhythms in humans. Those laboratory study rooms were typically shielded from outdoor light, were soundproof, and contained no obvious means of telling the time of day (e.g., they did not have clocks, radios, televisions).

Results of studies from humans living in those special laboratory conditions have revealed that there are circadian rhythms in many aspects of human behavior and physiology. Those rhythms include daily oscillations of hormone levels (including such hormones as cortisol, melatonin, thyroid stimulating hormone, and prolactin); core body temperature; EEG activity; alertness and vigilance; sleep tendency; and many aspects of performance. Neuroanatomical studies have also found that the same structures that comprise the circadian timing system in mammals, the SCN and RHT, are present in the human brain.

The particular methods used for studying human circadian rhythms depend on the aspect of circadian physiology that is of interest. The constant routine is an effective protocol to assess phase, amplitude, or the effect of a particular stimulus on the endogenous output of the human circadian system. In this protocol, subjects' circadian rhythms are measured for at least one complete circadian cycle while they remain awake, in a constant posture, in constant dim light, and with food and fluid intake distributed across day and night. In constant routine studies, often multiple variables controlled by the circadian timing system are measured simultaneously, so the phase and amplitude of each of those rhythms can be assessed. In studies in which the influence on the circadian timing system of a particular stimulus is of interest, an initial assessment of circadian phase and amplitude is made, the stimulus is applied, and then a reassessment of phase is done. Thus, the change in phase and amplitude as a result of the stimulus can be estimated.

Initial studies attempting to measure the period of the human circadian system used the free-running protocol. This protocol required subjects to live in an environment without time-of-day information, but allowed them to self-select their light exposure. As described above, it is now understood that light is the primary signal from the environment that affects the human circadian system, and light has phase-dependent effects on circadian timing. Experts also know that when subjects are allowed to choose when to go to sleep and wake without knowledge of what time it is, they prefer to go to sleep several hours later than they do under normal, entrained conditions. In doing so, they remain awake, exposed to light, throughout much of the time in the circadian cycle when light causes phase delay shifts. In addition, they remain asleep several hours beyond when they would wake up under normal entrained conditions, shielding themselves from light exposure during the time when light causes phase advance shifts. Thus, in free-running studies, allowing subjects to self-select their own light-dark exposure leads to cumulative phase delay shifts each day, and an observed free-running period that is consequently longer. It was widely reported based on results from free-running studies that the period of the human circadian system was near 25 hours, substantially longer and much more variable than the periods reported from most other species.

In more recent studies carried out in the 1990s, the forced desynchrony protocol was used to assess circadian period in humans under conditions that minimizes the influence of the light-dark cycle on the observed period. In this protocol, subjects are scheduled to live on a sleep-wake cycle length that is much shorter (typically ü20 hours) or longer (ü28 hours) than 24 hours. Furthermore, ambient light levels during the entire time one is awake are kept to a low level to minimize the phase-shifting effect of such light exposure. Using such protocols, it has been reported that the period emanating from the human circadian pacemaker is very close to 24 hours, with much less interindividual variability, similar to that found in most other mammalian species.

Relationship of sleep to circadian rhythmicity

The circadian timing system is a major determinant of daily variations in subjective alertness, neurobehavioral performance, and sleep. The early evidence for this was derived from longterm sleep deprivation experiments carried out in the 1970s. In those experiments, alertness and performance exhibited rhythmic variations over the course of the sleep deprivation, with a period close to 24 hours, superimposed on a steady deterioration of alertness and performance, attributable to sleep loss. The notion that sleep, alertness, and neurobehavioral performance are determined by the interaction of two processes, a circadian and a sleep-wake dependent process (sometimes referred to as a homeostat), is now widespread.

Studies carried out in the late 1970s found that spontaneous sleep duration depends primarily on the phase of the circadian timing system at bedtime, rather than on the length of prior wakefulness. Those studies involved young subjects free-running in temporal isolation, with the subjects allowed to self-select their bed and wake times. Results from such studies consistently documented that spontaneous sleep duration was longest when bedtime occurred near the circadian phase at which temperature peaks, and spontaneous sleep duration was shortest when bedtime occurred closer to the circadian phase of the temperature nadir (which under normal entrained conditions occurs 2-3 hours before usual wake time). Thus, the spontaneous self-selected duration of sleep episodes begun at the peak of circadian sleep tendency (at or after the temperature nadir) were actually cut short by the rising portion of the wake propensity rhythm (the variation in the likeliness of waking up or of remaining awake), whereas those begun at the nadir of circadian sleep tendency (near the temperature crest) were extended by the rising portion of the sleep propensity rhythm. Ironically, this occurred because sleep propensity was greatest just after the endogenous circadian temperature nadir and minimal near the endogenous circadian temperature peak. In fact, results from forced desynchrony studies carried out on young adults during the 1990s suggest that proper alignment between the timing of sleep and the timing of circadian rhythms is even more important for sleep consolidation than previously thought.

Circadian rhythms in older subjects.

One prominent age-related change in the organization of daily behavior is the advance of bed and wake times to an earlier hour. Associated with this is an age-related increase in two specific sleep complaints, early morning awakening and difficulty maintaining sleep. Early morning awakening and difficulty maintaining sleep in the latter part of the night have been shown in a number of studies to affect up to 40% of the older population. It has also been reported that age-related sleep disturbances are associated with increased mortality and with increased usage of sleeping pills.

Given the role played by the circadian system in sleep-wake timing, age-related changes in circadian rhythms have been hypothesized to underlie the shift of sleep-wake timing and the increase in circadian rhythm sleep disorders in older people. Numerous reports that daily physiologic rhythms occur at an earlier hour in older people than in young adults seem to support the idea that there is a change in the circadian timing system with age. In fact, circadian entrainment theory predicts that a shortening of the period of the circadian pacemaker would result in a phase advance of circadian rhythms with respect to the light-dark cycle, the main environmental signal synchronizing circadian rhythms to the 24-hour day. Studies of animal circadian rhythms carried out in the 1970s and 1980s supported the idea that the period of the circadian system shortened with age. Those studies compared separate groups of young and older animals. In the 1990s, studies were carried out in which the circadian period of animals was monitored throughout their entire life span. Those more recent studies found that the average period in when the animals were old was not significantly different from when the same animals were young, thus refuting the idea that circadian period shortens with age.

Early studies of human circadian rhythms had also suggested that circadian period shortened with age, but those studies were confounded by allowing the subjects to self-select their sleep-wake and light-dark times. During the 1990s, a series of forced desynchrony studies were carried out in very healthy young and older human subjects to compare circadian period lengths between the two age groups. Those studies found no significant difference in circadian period with age. Thus, a key feature of the circadian timing system, its intrinsic period, does not appear to change with age.

Interaction of sleep and circadian rhythmicity in aging

Despite consensus on the significance of both the rhythmic circadian and the sleep-wake dependent processes in the regulation of sleep in young adults, attempts to quantify the extent to which each process contributes to sleep in older people are scarce. The forced desynchrony studies of human circadian rhythms described above, in which it was found that circadian period is not significantly different with age, revealed several new findings about the relationship between the circadian timing system and the sleep-wake cycle in aging. Despite the fact that the older subjects in that type of study were extremely healthy, had no sleep complaints, and were screened to rule out the presence of sleep disorders, they slept much more poorly than did the young subjects. On the baseline nights in that study when all subjects were sleeping at their habitual times, the older subjects had a sleep efficiency of only 77 percent compared with a greater than 90 percent sleep efficiency in the young subjects. During the forced desynchrony segment of the study when sleep episodes were scheduled at all different circadian phases, even small changes in the timing of sleep with respect to the phase of the circadian pacemaker resulted in substantial self-perceived and objectively-measured sleep disruption. This sleep disruption was greater in the older subjects, especially when the latter part of the sleep episode was scheduled to occur after the temperature minimum, which occurred on average in those same subjects at 5:15 a.m. Finally, there was a much narrower range of circadian phases when older subjects could maintain high sleep efficiency at the end of their scheduled sleep episodes. It therefore seems that the circadian drive for sleep is reduced in the early morning hours in even very healthy older individuals. This finding suggests that there is a crucial relationship between the circadian timing system and the timing of the sleep episode, and that if the alignment between these two regulatory systems is altered, the sleep of older individuals is much more vulnerable to disruption. Two additional studies support the notion that the alignment between the circadian timing system and the timing of the sleep-wake cycle may be altered in aging. Those studies used different experimental designs, but both found that the relative timing of the habitual sleep-wake cycle with respect to the timing of circadian rhythms is significantly different in older subjects.

Melatonin, sleep, and aging

Melatonin is a hormone produced by the pineal gland at night in both nocturnal and diurnal mammals. The circadian pacemaker imposes rhythmicity onto the pineal gland through a well-characterized neural pathway, thus driving the rhythm of melatonin secretion. In addition to this control by the circadian pacemaker, melatonin production can be suppressed by light. In seasonally breeding mammals, the nightly duration of melatonin secretion is used as an endocrine signal of day length, and seasonal changes in the duration of melatonin secretion times reproduction to the optimal time of year.

Because melatonin is produced at night, it was thought to be causally related to sleep in humans (although it should be noted that melatonin is produced at night in nocturnal animals, who sleep during the day). In fact, studies of exogenous melatonin administration have shown that melatonin can facilitate sleep onset at certain times of day, although not at all times of day.

Because there is increased sleep disruption with age and because of reports of exogenous melatonin's sleep promoting effects, there have been suggestions that an age-related reduction in melatonin level or a decrease in the duration of melatonin secretion might be associated with the age-related decrease in sleep quality. While some older people may secrete less melatonin, a study published in 1999 reported that nocturnal plasma melatonin concentrations in most very healthy older subjects was not significantly reduced when compared to those of healthy young men and women, nor was there a significant difference in the duration of the nightly melatonin secretion time between young and older subjects. Thus, neither decreased plasma melatonin levels nor a shorter duration of melatonin secretion can fully explain the age-related changes in sleep timing and consolidation that have been observed in even healthy older individuals.

There have been conflicting reports of whether exogenous melatonin administered to older individuals with insomnia improves sleep quality. In one study in which sleep (brain waves, eye movements, muscle activity) was recorded, of older insomniacs, exogenous melatonin administration did not affect total sleep time, sleep efficiency, or subjective sleep quality, and there was no correlation between endogenous melatonin level and sleep quality. However, another similar study reported that older insomniacs had low endogenous melatonin levels. That same study also reported that a low dose (0.3 mg) of melatonin improved sleep efficiency in those older insomniacs with low melatonin levels, although it did not affect the sleep in older control subjects. Thus, there is conflicting information about how endogenous melatonin levels in aging are related to sleep quality and whether melatonin replacement will improve sleep.

Summary

The circadian timing system is a major organizing feature of human physiology and behavior. Great progress in understanding the molecular and genetic basis of circadian rhythmicity in mammals was made in the 1990s. While it was once hypothesized that age-related changes in the circadian timing system led to an increase in disorders of sleep timing with age, recent studies have indicated that many aspects of circadian rhythmicity are not significantly different between young and healthy older individuals. There are, however, age-related changes in sleep, and also age-related changes in the interaction between the timing of sleep and the output of the circadian pacemaker, resulting in age-related sleep disruption in the latter half of the night. While the neurobiological basis of age-related changes in the interaction between sleep and circadian rhythmicity are not yet known, continued research promises better understanding of how these systems change with age and how knowledge of such changes can lead to development of chronobiological treatment for age-related sleep disruption.

Figure legend

(A basic description of Figure 1 on page 233 is listed with the figure. This is a more detailed description.)

Filled symbols refer to the older subjects; open symbols to the young subjects; means = standard errors. Data are double plotted and shown with respect to circadian phase (lower axis) derived from core body temperature data (nadir temperature waveform = 0¤). The corresponding time of day under normal conditions for the older subjects is shown in the upper axis. Lower panel: percent of wakefulness during scheduled sleep. Middle panel: subjective early awakening. Upper panel: normalized cognitive performance.

There are prominent circadian variations in objective and subjective sleep quality and performance, with all showing a nadir at the circadian phases corresponding to the early morning hours. Older subjects show greater objective and subjective sleep disruption at all circadian phases, and there is a much narrower range of circadian phases when older subjects can remain asleep; young subjects can maintain high sleep quality for many hours after their typical wake time, while older subjects experience increasing levels sleep disruption when scheduled to sleep at or just after the time of their circadian temperature nadir (0¤, on average at 5:15 a.m.). This is also reflected in the circadian performance rhythm, where young subjects show impaired performance at and just after the circadian phases corresponding to their usual wake time, while the performance of the older subjects is improving at these phases.

These measures of sleep and wake indicate that there is a change in the interaction between the circadian timing system and sleep with age, and that there appears to be a decreased drive for sleep in older subjects in the early morning hours.

The figure was adapted from the following sources: Duffy, J. F.; D. F. Dijk; E. B. Klerman; and C. A. Czeisler. "Later Endogenous Circadian Temperature Nadir Relative to an Earlier Wake Time in Older People." American Journal of Physiology 275 (1998): R1478–R1487; and Dijk, D. J.; J. F. Duffy; E. Riel; T. L. Shanahan; and C. A. Czeisler. "Ageing and the Circadian and Homeostatic Regulation of Human Sleep During Forced Desynchrony of Rest, Melatonin and Temperature Rhythms. Journal of Physiology (London) 516 2 (1999): 611–627.

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Jeanne F. Duffy Charles A. Czeisler

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