How the Circadian Rhythm Affects Sleep, Wakefulness, and Overall Health: Background for Understanding Shift Work Disorder

Andrew D. Krystal, MD, MS
Listen to Audio Introduction
Properties of the Circadian Rhythm

The field of circadian rhythm research was launched in the early 18th century (AV 1).1 The circadian rhythm entrains an organism’s functions to the environmental cycle of light and dark. This rhythm is seen in nearly all species and plays an important role in synchronizing organ systems to optimal phase relationships with each other. Variations in many biological processes occur over roughly a 24-hour period (AV 2).

AV 1. Discovery of Circadian Rhythm (00:45)


This type of endogenous rhythmicity is also seen in many other biological measures. For example, levels of plasma melatonin increase in the evening and early part of the night, while levels of plasma cortisol increase over the course of the night, peak at waking, and diminish throughout the day.2

AV 2. Circadian Rhythm (0:29)


Our innate circadian rhythm can be modified by a number of factors, especially light. For example, when you travel to a new time zone, your body is on a different schedule from the new environment, because it continues to function for some time on the circadian rhythm you developed in your previous location. The longer you stay in the new environment, the more your body aligns with its new environmental clock. This process is driven by cues, especially exposure to light, which tells us when it is day or night.

Light has different effects on the circadian rhythm depending on when we are exposed to it.1 Thus, if we are exposed to light late during the night, this shifts our rhythm so that we tend to go to bed and wake up earlier. If we are exposed to light in the early part of the night, this shifts our rhythm so that we tend to stay up and sleep later. Exposure to light during the period when we are usually awake has no effect at all.

Other factors that can affect our internal clock include when we eat, our activity level, and caffeine intake.3,4 Thus we often have gastrointestinal upsets in a new time zone because we are eating when our body does not expect to eat (ie, our digestive hormones are out of synch with our meal time).5 Our innate circadian rhythm also affects how our autonomic nervous system and our brain function.6

Anatomy of the Circadian Rhythm

The important role of the suprachiasmatic nucleus (SCN) in regulating periodic behavior7 has been confirmed by a number of findings in animal studies (AV 3).

  1. When the SCN is lesioned, circadian rhythmicity goes away because the SCN is no longer able to stimulate the production of melatonin and other substances that modulate the sleep-wake pattern.8
  2. If cells are removed from the SCN and grown in vitro, they continue to show self-sustaining circadian rhythmicity.9
  3. If the SCN is transplanted from one animal to another, the recipient manifests the circadian rhythm of the donor, showing that the SCN can entrain biological activity and drive a circadian process on its own.10

AV 3. Suprachiasmatic Nucleus (00:35)

Genetics of the Circadian Rhythm

Although researchers had been able to breed for changes such as different eye or hair color for a long time, it was not until the 1960s that Benzer first demonstrated that behavior could be modified genetically by breeding circadian behavioral patterns into fruit flies.11 This demonstrated that the chemical clock in the SCN is under genetic control. A relatively small number of genes and proteins regulate this biological clock. The critical components of this genetic system are the Period, Clock, and Cryptochrome (Cry) genes, and these can be manipulated to alter the circadian cycle.12

The role of genetic factors in our circadian rhythm is supported by the observation that preferred sleep/wake schedules (eg, being a “night owl” or a “ morning lark”) tend to run in families. The tendency to go to bed and get up very early (sleep phase advance), is linked to a mutation in the human Period-2 (hPer2) gene that is an autosomal dominant trait.13 The tendency to stay up late and sleep late (sleep phase delay) is associated with several genes, including the human Period-3 (hPer3) gene.14

Effects on Sleep/Wake Function

The SCN regulates our sleeping and waking through its effect on 3 brain regions7:

  • Ventrolateral preoptic area: releases γ-aminobutyric acid (GABA) and promotes sleep
  • Lateral hypothalamic area: releases the transmitter hypocretin/orexin that promotes wakefulness
  • Paraventricular hypothalamus: involved in the release of melatonin

The interaction shown in the sleep/wake model15 produces a consolidated period of wakefulness, driven by the circadian rhythm, and a consolidated period of sleep that occurs when the homeostatic drive to sleep has built up and the wake-promoting systems have shut down (AV 4).16 The circadian rhythm system enables us to stay awake for extended periods, despite a growing homeostatic drive for sleep. It does this by modulating the release of neurotransmitters, in particular hypocretin/orexin, that maintain wakefulness. Otherwise, we would have great difficulty functioning, since we would fall asleep as soon as a great enough drive to sleep had built. This is what happens in narcolepsy, which involves abnormalities in the hypocretin/orexin system.17

AV 4. Model of the Sleep-Wake Cycle (01:04)

Problems in Sleep/Wake Function

Problems can occur when the drive for wakefulness and the drive for sleep are not correctly synchronized. Thus, if you try to sleep when your body doesn’t normally sleep, you will sleep less and you will not sleep as well because your circadian processes are fighting the sleep drive. Individuals with circadian rhythm sleep disorders often experience at least partial sleep loss on a long-term basis. This is because they are trying to sleep at an unfavorable time for extended periods. Even modest prolonged sleep deprivation can produce 4 types of serious physiological abnormalities18-23:

  • Metabolic dysfunction (increased appetite, metabolism, or oxygen consumption; sympathetic nervous system activation; decreased cerebral glucose utilization in certain subcortical structures)
  • Neuroendocrine abnormalities (low thyroid-stimulating hormone; decreased levels of growth hormone, prolactin, or leptin)
  • Decreased resistance to infectious disease
  • Oxidative stress

Humans who experience prolonged sleep deprivation also demonstrate higher rates of obesity and type 2 diabetes and neurobehavioral impairment, including a shortening of voluntary and involuntary sleep latency resulting in daytime sleepiness, microsleeps (intrusion of sleep into wakefulness), and errors of omission and commission on cognitive testing.24,25

Role of the Circadian Rhythm in Health and Disease

By synchronizing the body’s biological clocks, the SCN has extensive influence on peripheral tissues through the autonomic nervous system.26 For example, glucose is released in a gradual, oscillating, sinusoidal-like pattern over a 24-hour period. If animals are fed at times other than their natural feeding times, the original cycle continues. However, if you cut out the SCN, glucose release becomes entrained to feeding times and is no longer linked to other physiologic processes related to eating and digestion.27

Phase dyssynchrony occurs when the rhythms of organs are out of synch with the SCN. Research in animals and humans has shown that such disruptions can have negative effects on health. For example, one study found that disrupting the normal circadian rhythmicity of hamsters with cardiomyopathy reduced their median life span by 11%.28 In the next report, Dr Roth will discuss the types of negative effects that can occur in humans who experience such phase dyssynchrony, as occurs when someone has Shift Work Disorder.


The circadian rhythm, a self-sustained rhythm of biological processes observed in nearly all species, is determined by both genetic and behavioral factors. It plays an important role in coordinating and modulating sleep/wake function and in many other biological processes. Disturbances of the circadian rhythm cause misalignment among biological and behavioral processes that can lead to disturbances in sleep/wake function and other types of impaired functioning and may affect our capacity to fight off disease.

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Andrew D. Krystal, MD, MS

Andrew D. Krystal, MD, MS

Department of Psychiatry and Behavioral Sciences, and Director of the Insomnia and Sleep Research Program,

Duke University School of Medicine, Durham, North Carolina


Supported by an educational grant from Cephalon, Inc.
J Clin Psychiatry 2011;72:e05

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