Circadian rhythm

from Wikipedia, the free encyclopedia

In chronobiology , the term circadian rhythm (also: circadian rhythm ) is a summary of the endogenous (internal) rhythms that have a period length of about 24 hours and, in many living beings, have a great influence on the functions of the organism. They were created as an adaptation to the changing daily rhythm of environmental conditions.

The most obvious consequence in many animal species and in humans is the sleep-wake rhythm . However, in addition to activity, innumerable other physiological parameters show a rhythmicity with a 24-hour period. The circadian rhythm can also be demonstrated at the level of individual cells . The Nobel Prize for Medicine / Physiology was awarded in 2017 to three chronobiologists who were able to decipher the molecular mechanisms of circadian rhythms while studying the fruit fly Drosophila melanogaster .

There are also biological rhythms whose period is significantly shorter or longer than a day (see ultradian rhythms or infradian rhythms ).

terminology

The adjective circadian - or with Germanized spelling circadian - can be understood as "around the day" ( Latin about "around ...", this "day"). Franz Halberg , who introduced the term in 1959, primarily associated the meaning “approximately” with approximately , so that circadian in his sense would translate as “approximately one day long”.

Halberg later stated that he had become aware of the word circadian before 1951 when his friend Henry Nash Smith used it. In the 1950s, Halberg was looking for an alternative for the ambiguous word diurnal , which on the one hand can mean "in daylight" and on the other hand "24 hours". Halberg also wanted to be able to differentiate between “24 hours” and “approximately 24 hours”, since daily rhythms in organisms only have a period length of approximately 24 hours, especially when they are not synchronized by daylight. In 1955 he first proposed the word creations diel for "24 hours long" and dieloid for "about 24 hours long", which, however, did not meet with approval. In 1959 Halberg used the terms dian for "24 hours long" and circadian for "about 24 hours long". Critical colleagues then objected that the juxtaposition of the two names was confusing. Halberg did without dian - and the term circadian caught on.

Colloquially, the entirety of circadian rhythms is also referred to as the "internal clock".

Basics

function

Due to the rotation of the earth around its own axis, environmental conditions such as the amount of light, the temperature, the availability of food and the threat from predators change rhythmically with a period of 24 hours. When living things adapt to such profound changes, they have an advantage in survival.

At the cellular level, too, innumerable chemical reactions are subject to a circadian rhythm. In multicellular organisms, the internal clock is used to synchronize the clocks present in practically every cell in order to give important functions of the entire organism a time frame. It is believed that all eukaryotes have circadian rhythms in virtually every cell of theirs. In particular, incompatible chemical reactions must be separated from one another in time.

In a study in mice has been shown that 43% of all of proteins coding genes in the mouse organism with a rhythm 24 hours transcribed be. Insects also depend on a functioning circadian clock. For example, a bee that uses a waggle dance to communicate information about food sources to its conspecifics adjusts the angle about every 5 minutes because the sun, which serves as an orientation point for the location, has moved on in the meantime. Circadian rhythms and their inter-individual synchronization are also of great importance for the organization of the social system of the beehive.

Plants adapt their activity to the change of day and night. Before sunrise, they activate their photosynthetic apparatus and thus prepare for the start of photosynthesis , which takes place in daylight. Open many plants and close their petals and stomata at certain times of the day (see the flower clock of Linnaeus ). Other plants, whose flowers are open for several days in a row, only produce fragrances and nectar at certain times of the day. Pollinating insects such as bees adjust their visits accordingly.

In the mushroom kingdom , too, circadian rhythms have evolved as an adaptation to a regularly changing environment. The reproduction of the fungus Neurospora crassa , for example, is controlled by an internal clock.

The simplest organism in which a circadian clock could be detected is Synechococcus elongatus from the genus Synechococcus of the cyanobacteria . How widespread circadian clocks are in other prokaryotes is still largely open.

Properties of the circadian rhythm

Although the biological background and mechanisms for circadian rhythms differ between different organisms, circadian rhythms have certain properties that are common to many species . The exact period length can vary between different species, but is usually 22 to 25 hours. The inner rhythm does not need any signals from the outside world in order to follow its rhythm, which however is not always exactly 24 hours long. However, the process can adapt to an exact 24-hour cycle by correcting itself with the help of external stimuli called timers . This process is called synchronization or entrainment . The external stimuli that can serve as timers are different for different species, but the most important is often light. Other timers in some species are, for example, the ambient temperature and social stimuli (e.g. the alarm clock).

Features of real biological clocks are:

  • their endogenous character, which means that the rhythm is maintained even under constant environmental conditions ( free running ).
  • the fact that they are "entrainable", which means that despite their own rhythm, they can adjust their period within certain limits to the rhythm of the surrounding conditions (ability to entrain ).
  • the relative insensitivity to non-rhythmic temperature changes (temperature compensation), which is unusual in that almost all other (bio) chemical reactions depend very strongly on the temperature in their speed. In ordinary chemical reactions, it is assumed that the reaction rate doubles for every 10 ° C increase in temperature ( RGT rule ).

Period length (τ)

A circadian rhythm is characterized by a certain period length, which means that each repetition lasts a certain time. The period length is often referred to with the Greek letter Tau (τ) and lasts around 24 hours for most organisms. If an organism is kept in a constant environment, that is, with a constant amount of light and temperature around the clock, it will follow a daily cycle, the length of which depends on its internal clock. Over time, the internal clock can deviate more and more from the course of real time.

The period length of the internal clock depends on the genetic makeup, and it is possible to breed organisms that have an internal clock with a longer or shorter period length. One can also manipulate the τ of an organism with drugs or hormones or change it by manipulating the environment of the organism. The age of the organism also influences the period length of the internal clock. In some organisms, such as humans, τ decreases with age, while τ in other organisms, e.g. B. mice, increases with age. It is also possible to change τ using artificial light. Cockroaches exposed in a 22 hour cycle developed a shorter period length than cockroaches exposed in a 26 hour cycle. These effects persist long after the experiment is over.

Phase (Φ) and phase angle (ψ)

The time according to the internal clock when the organism “expects” that a certain event will take place (e.g. sunrise or sunset) is called the phase . The phase is denoted by the Greek symbol Phi (Φ).

Jet lag is an example of how the subjective (circadian) time of the internal clock and the objective time can differ . The difference between circadian and objective time is denoted by the Greek letter Psi (ψ). It can be expressed either in hours or as a phase angle , i.e. as a degree . A phase angle of 180 ° corresponds to a difference of 12 hours.

Phase shift

Four examples of the shifting of the internal clock by the action of a timer, each for three consecutive days. The numbers are times.
Phases of the internal clock:
Blue: The internal clock is set to "Night".
Yellow: The internal clock is set to "day".
Effect of the dark / light timer:
Blue arrow: Darkness signals "night".
Yellow arrow: light signals "day".
Top left: At 6 a.m. the internal clock is already calculating with day (yellow route), but it is still dark at 7 a.m. (blue arrow). The organism adapts and then expects a later daybreak.
Above right: The internal clock does not expect until 6 p.m., but it is already dark at 5 p.m. The organism adapts and then expects the night earlier.
Bottom left: At 5 a.m. the internal clock is still set to night, but it's already light.
Bottom right: At 7 p.m., the internal clock is already set to night, but it is still light.

Since the period length of the internal clock is not exactly 24 hours and the time for sunrise and sunset varies over the course of the year, the internal clock must be able to correct itself with the help of external clock signals.

There are two types of phase shifts in the internal clock:

  • The weak phase shift (type 1 reaction): The reaction to a timer is relatively small, at most a few hours. The figure on the right illustrates type 1 reactions with a phase shift of one hour each.
  • The strong phase shift (type 0 reaction): Somewhere in the cycle there is a certain point at which a timer can shift the internal clock forward or backward by up to 12 hours.

Whether an organism exhibits a type 1 response or a type 0 response depends on the type of organism and the intensity of the stimulus. When the stimulus is intense, an organism that normally has a weak Type 1 response may respond with a strong Type 0 response. One study has shown that people exposed to strong light in the morning for three days in a row can react with a large phase shift.

synchronization

Light as a timer

Since the external cause of the circadian rhythm is the natural rotation of our planet , the most obvious external rhythm generator is the change in the lighting intensity of the earth. This pacemaker is recognized in the visual system , in some cases also the changing position of the sun .

Light is probably the timer whose effect is most universal. In humans, light in the subjective evening and night slows down the period of the internal clock, while light in the early morning hours causes it to accelerate. Light acts as a timer in almost all of the organisms studied, including those that live in constant darkness. The organism reacts to light in the environment with a light-sensitive pigment that is either in the retina (in vertebrates) or in other cells (in insects and plants).

Synchronization in animals

The continued existence of a free-running circadian rhythm under constant conditions shows that there must be an oscillator , a rhythm-generating internal unit. As long as it is not known how this oscillator works, measurements can only be carried out on the perceived rhythm, with the greatest possible exclusion of external rhythm generators. Properties of the oscillator must then be derived from the behavior: the classic "black box" method of behavioral research . In the meantime, at least parts of the black box in the central nervous system ( CNS ) have been localized for a number of animal groups .

The central pacemaker can be influenced by external effects, especially light. In all the organisms examined, cryptochrome seems to play a decisive role in readjusting the internal clock:

In fish , amphibians , reptiles and many birds , however, the epiphysis is still sensitive to light. In some amphibians, a so-called parietal eye is observed: an opening in the skull that is only covered by the meninges and skin, allowing light to pass into the brain (“third eye”). In reptiles and some birds, the epiphysis controls not only the circadian melatonin production but also other circadian rhythms, for example in body temperature and food intake. In terms of evolution, it is older than the suprachiasmatic nucleus (SCN).

Mammalian molecular biology

In mammals, the central circadian pacemaker is found in the suprachiasmatic nucleus of the hypothalamus , which coordinates other peripheral pacemakers. The molecular clock runs through a transcription - translation feedback, in that the protein translation inhibits the transcription of the gene of this protein. Several proteins are involved, of which CLOCK, BMAL1, PER, CRY and NPAS2 are considered key proteins. The circadian molecular clock (CMC = circadian molecular clock ) has a positive arm with a CLOCK-BMAL1 heterodimer, which stimulates the negative arm with a PER-CRY heterodimer, which inhibits the positive arm. A feedback sequence lasts about 24 hours, with an oscillation in protein expression. This is controlled for the two proteins BMAL1 and CLOCK by two cell nucleus receptors (REV-ERB-α and REV-ERB-β) and thereby modulates the circadian rhythm. Peripheral tissues have a similar cycle, but are synchronized by the central pacemaker through indirect neuronal and hormonal signals and temperature changes.

The synthetically developed agonists SR9009 and SR9011 of the nuclear receptors REV-ERB-α and REV-ERB-β can reduce the strength of the circadian oscillations by inhibiting BMAL1 expression. In mice, the injection of the agonists led to an increased basal oxygen demand and a loss of adipose tissue. Furthermore, decreased lipogenesis in the liver, increased glucose and lipid oxidation in muscle cells and decreased triglyceride synthesis and storage in white fat cells were found.

Sensitivity to light in plants

"Sleeping tree" by day and by night

In addition to chlorophyll, plants have three other classes of light-sensitive pigments:

  • Phytochromes are particularly sensitive to red light, and to a lesser extent also to blue light.
  • Cryptochromes are particularly sensitive to blue light. They are also used as signal molecules when the phytochromes “catch” light.
  • Phototropins are not involved in regulating the circadian rhythm. They control the phototropism of the plants, which means that the plant grows towards a light source.

The plant regulates its sensitivity to light through the production of phytochromes and cryptochromes, reinforced in the morning. During this time the plant is most sensitive to light.

Circadian rhythms in humans

In humans, the circadian rhythm controls or influences, among other things, the sleep-wake rhythm, heart rate , blood pressure , body temperature , hormone levels (e.g. cortisone and insulin ), the concentration of immune cells in the blood and their migration into other tissues . The gluconeogenesis , fat absorption in the intestines and many other metabolic functions are influenced by the circadian clock, as well as the cognitive performance.

Chronotypes

The dependence of middle sleep on age

Between different individuals there are certain differences in the phase of the internal clocks relative to the outside world, which is expressed in different chronotypes . This is seen as the reason why some people go to sleep early and wake up early (“larks”), while others go to sleep late and wake up late (“owls”). At a middle age (around 15 to 50 years) there are greater differences between the sexes in this regard.

The differences in chronotype are most likely due to genetic predisposition . A different expression of the PER2 gene is discussed as the cause. A person's chronotype can be determined quite precisely using questionnaires such as the MCTQ.

Changes also occur within an individual in the course of life, which can be determined based on the average time they sleep and wake up. Children are usually very early chronotypes, then become later and later in the course of their teenage years, until the trend reverses again around the age of 20.

In studies on adolescents, most of whom can be characterized as “owls” during puberty , it has been shown that delaying the start of day-to-day activities by an hour - especially in winter - led to a general improvement in performance and better health. These and other scientific findings have important implications for the optimal time to start school.

The individual chronotype is less clear in small children and old people because the circadian rhythm is not yet clearly dominant or no longer has such a strong effect. In babies, the ultradian system still predominates - short phases of activity alternate with short phases of sleep of sometimes less than half an hour. Only the rhythm of the toddler is increasingly controlled by the circadian system. In old age it loses its influence again.

Disorders of the sleep-wake cycle

People often live contrary to their inner rhythm or at least disturb it. The proportion of shift work is increasing . In addition, less time is spent in daylight, especially in winter, where indoor light radiation is rarely higher than 500 lux . Even an overcast sky outdoors can generate more than 20,000 lux horizontal illuminance, direct sunlight even up to 100,000 lux. On the other hand, humans are also exposed to artificial light stimuli at night. The internal clock, which needs to be “adjusted” every day, has to struggle with problems due to this “blurred” timer structure. With modern alternating shift plans , one works with "interspersed night shifts", i.e. short night shift blocks that ideally only comprise one to two, but a maximum of three nights.

When changing to other time zones , your own circadian rhythm only adapts to the time zone after you have got used to it. This adjustment takes place much more slowly than the flight and can make itself felt through so-called jet lag in fatigue and poor performance.

In regions very far from the equator (such as Norway ), the sleep-wake cycle can be disturbed by the fact that in winter the light yield per day tends to zero. The lack of daylight and the disturbed daily routine can lead to a so-called winter depression . In the meantime, light therapy has been recognized as an effective treatment for winter depression (“light showers” ​​are bright lights attached to the front of special headgear).

Connection with diseases

The internal clock influences the course of cardiovascular diseases such as atherosclerosis . Furthermore, epidemiological studies as well as experimental work show that circadian rhythms have an influence on the development or prevention of cancer. Shift workers suffer from metabolic stress due to the disturbance of the daily rhythm - a risk factor for the development of diabetes mellitus and obesity, among other things .

Neurodegenerative diseases such as Alzheimer's , Parkinson's , ALS and Huntington's chorea are often associated with disruptions in circadian rhythms early in the course of the disease. The sleep-wake rhythm is also disturbed in many psychiatric illnesses, and disorders of the circadian system are a risk factor for psychiatric illnesses. A permanently disturbed sleep-wake rhythm, for example when working shifts, can lead to sleep and eating disorders , lack of energy and depression .

A study in mice found that more than half of the 100 best-selling drugs in the US act on proteins that (in mice) are subject to circadian control.

See also

literature

Understandably introductory
  • Till Roenneberg: How we tick: The importance of chronobiology for our lives. 2nd Edition. DuMont, Cologne 2010, ISBN 978-3-8321-6188-0
Further publications
  • Jürgen Aschoff (Ed.): Circadian Clocks. North Holland Press, Amsterdam 1965.
  • Joseph S. Takahashi and Martin Zatz: Regulation of circadian rhythmicity. In: Science . Volume 217, No. 4565, 1982, pp. 1104-1111, doi: 10.1126 / science.6287576
  • Jürgen Zulley , Barbara Knab: Our internal clock. Herder, Freiburg im Breisgau 2003.
  • Peter Spork : The clockwork of nature. Chronobiology - living with the times. Rowohlt, Reinbek near Hamburg 2004.
  • Wolfgang Deppert , K. Köther, B. Kralemann, C. Lattmann, N. Martens, J. Schaefer (Eds.): Self-organized system times. An interdisciplinary discourse on the modeling of living systems based on internal rhythms. Volume I of the series: Fundamental Problems of Our Time. Leipziger Universitätsverlag, Leipzig 2002.

Web links

Commons : Circadian rhythm  - collection of images, videos and audio files

Individual evidence

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