Circadian rhythms
Neuroscientist Russell Foster on the sleep–wake cycle, photosensitive retinal ganglion cells and circadian rhythm disorders
Circadian rhythm is an endogenous biological rhythm with a period of about 24 hours. The simplest example is our sleep–wake cycle.
Circadian rhythm is needed to accurately adjust all aspects of physiology and behavior to the requirements of the 24-hour world. It anticipates daily changes in daylight hours, temperature, food availability and even predator behavior and prepares the body in advance for changes in the environment so that it is fully adapted.
Clock Cells
Circadian rhythms are characteristic of almost all forms of life, including unicellular life and bacteria. The circadian clock works in the body at the molecular level, which controls the internal oscillation, the period of which is about 24 hours. This oscillation adjusts the internal physiological rhythm to the external 24-hour cycle. We know what makes the internal clock work: there are several important clock genes that produce clock proteins. They interact with each other, forming a molecular feedback loop that generates vibrations in clock proteins with a period close to 24 hours; then the proteins tell the cell when to do what and what time of day it is. Initially, we thought that circadian rhythms occur when many different cells work together to form a single network, but now it is believed that this is a property of individual cells.
In order for the circadian clock to benefit the body, it must be adjusted to the outside world. The most obvious example of the discrepancy between the internal clock and the outside world is jetlag: when we fly through several time zones, we need to adjust our internal clock to the local time, which is determined by the cycle of sunrise and sunset. Photoreceptors register the duration of the phases of light and darkness in the cycle and send signals to the molecular clock mechanism to adjust the internal clock to the outside world. Humans are most sensitive to diurnal changes in the amount of light and darkness, but some animals, such as reptiles, also focus on daily temperature changes to establish their biological rhythm. Adjusting to the outside world, no matter how it happens, guarantees that at any hour all the cells of the body will perform the necessary processes at the right time of day.
Complex multicellular life forms often have a central, or "guiding", clock that coordinates all the others. In mammals, the control clock is located inside the brain and is called the suprachiasmatic nucleus. It receives information about the light level from the eyes and adjusts the work of its 50,000 neurons according to it, which then send a lot of signals, coordinating the work of the rest of the body. To generate a circadian rhythm, the clock cells of the suprachiasmatic nucleus use more than 14 different genes and their protein products.
The main properties of circadian rhythms
Circadian rhythm is a special type of biological rhythm. Biological rhythm is a general term describing any rhythmic process. Some rhythms are generated by the internal clock, while others depend on the environment. The biological rhythm generated by the clock will remain constant at a constant level of light and temperature. In addition to 24-hour circadian rhythms, there are clocks that run with a period of a year or 360 days and are called circadian rhythms, or "tidal clocks", which have been found in organisms living on the seashore ― their biological clocks have a period of about 12.8 hours.
We have known about 24-hour rhythms for a very long time: even the ancient Greeks talked about daily changes in the body, but they thought that they were caused only by changes in the amount of light and temperature in the outside world. The first scientific experiment to identify circadian rhythms was conducted in 1729 by the French scientist and astronomer Jean-Jacques Dort de Meran: when he put the plant in a dark place, he noticed that in constant darkness the leaves open and close with a rhythm close to 24 hours. This observation was the first fixed indication that biological rhythms can be set from within. After that, there were very few experiments, and this continued until the 1950s and 1960s, when the real properties of circadian rhythms were discovered.
The first property of the circadian rhythm is that under constant light conditions it remains unchanged. In different species, the rhythm period may be slightly longer or shorter than 24 hours: in humans, the clock is slightly longer, whereas in mice it is slightly shorter.
The second key property is that these rhythms have temperature compensation. This means that even if the outside temperature changes radically, the 24-hour rhythm does not accelerate or slow down very much. This is extremely important, because if there was no temperature compensation, then the circadian clock could not accurately indicate the time.
The third key feature is that circadian rhythms are closed to an external 24–hour day. The main signal for adjusting the rhythm is light, although there are other signals, for example, temperature.
Some organisms can adjust their clocks based on the circadian behavior of other animals. For example, baby mice establish their circadian rhythms before and after birth based on their mother's hormonal signals: in the uterus, signals enter the blood through the placenta, and after birth – with milk. Later, when the axons between the eyes and the suprachiasmatic nucleus are already formed, the mice can rely on the light level. Whether it happens in humans the same way or not – we don't know for sure. Another example: malaria parasites can determine the time of day by signals in the blood, and this prompts them to move at night to blood vessels very close to the skin, where mosquitoes pick them up along with the blood. The mosquito then bites another person and infects another victim.
The Importance of routine
The main advantage of having a watch is that it allows the body to anticipate predictable changes in the environment and adjust physiology and behavior in advance to changing conditions. For example, if you know that dawn will be in three hours, you can start increasing your metabolic rate, body temperature, muscle strength and blood flow and generally tune in to activity. All this prepares you so that when the morning comes, you will be active and able to fully use the new environment. If we were just waiting for the morning to do this, we would spend a lot of time adjusting to the new environment, and during this time we would not be able to fully use the "new" conditions.
In the same way, at the end of the day, when we begin to fall asleep, the physiology of the body begins to decline and turn off, preparing the brain and the rest of the body for sleep. During sleep, the brain is very busy: creating memories, processing information to find new solutions to complex problems, entrusting the rest of the body to repair damaged tissues, restore metabolic pathways and organize energy reserves. Some parts of the brain are more active during sleep than during wakefulness, so even though we don't move, the brain is incredibly active, performing extremely important actions necessary for the next day. The ability to predict and anticipate, and not just react, gives the body a huge selective advantage in the struggle for existence.
Some animals and plants also use circadian clocks to determine the season: if the body measures daily changes in the amount of darkness and light and if the duration of darkness increases or decreases, then it can very accurately determine the time of year. In the Northern Hemisphere, some mammals use the autumn increase in the length of the night as a signal that they need to prepare for hibernation, and in other animals, such as deer and sheep, this can encourage mating: autumn mating means that the cub will develop during the winter and be born in the spring, when the weather is usually good and there are many new plants for food. There are mammals that change the thickness and color of their fur to prepare for winter: for example, Arctic foxes grow thicker and whiter fur for winter, which helps them camouflage and survive.
Humans also have seasonal biology. For most of us, it is not very noticeable, but in general, people in the winter months often report changes in appetite and weight gain, and some people become more depressed at this time. How these changes occur is still unclear. It is likely that in the past we were more dependent on the seasons than we are now. This may partly be due to the fact that we now live in houses and are thus protected from the outside world and that the seasonal rhythms of the Earth are no longer so sharply defined.
How to set up a watch
The big question is: how does the eye detect light, with which it corrects circadian rhythms? Our team recently discovered the fact that the eye contains a special set of light-sensitive cells called "photosensitive retinal ganglion cells" (pRGC). These cells are very different from cones and rods, which detect light and create an image. They are formed from ganglion cells, the axons of which come out of the eye, gather in the optic nerve and are sent to the brain. About 1-2% of these cells have a light-sensitive blue photopigment called OPN4. Photosensitive ganglion cells register sunrise and sunset, and then set the molecular clock to the correct time of day.
Another key discovery was that blind people, as well as those whose cones and rods are damaged due to genetic diseases, can have completely normal and functional photosensitive ganglion cells. So these people are blind, but from the point of view of the clockwork, they see. This has important implications for medical practice, and ophthalmologists should recommend that blind patients with intact photosensitive cells receive enough light to properly adjust circadian rhythms. Ophthalmologists now understand that the eye is an organ that gives us both a sense of space (vision) and a sense of time (circadian regulation). This understanding has changed our definition of blindness and methods of treating eye diseases.
It is important to emphasize that if you do not have eyes at all, then the whole adjustment based on light is lost. Previously, some people claimed that we have photoreceptors in the brain and even behind the knee, but such claims have never been confirmed by scientific research. Without eyes, most of us will go to bed every day about 30 minutes later than the previous one, since our internal rhythm is about 24 and a half, not exactly 24 hours. There are tragic situations when people are born without eyes or lose them as a result of an accident, and work is currently underway to provide a "pharmacological replacement" of light ― these are pills that trick the molecular mechanism into thinking that it sees light, and as a result, the clock adjusts to the right time.
There is also another problem related to light: we don't get enough of it at the right time. Most of the time we spend in a room where the light is not bright enough for us to adjust the clock according to it. For the elderly, this is a particularly serious problem, regardless of where they live ― in their home or in a nursing home. However, when the amount of light received increases, it is possible to restore internal circadian rhythms and the sleep―wake model, resulting in improved brain functioning. It has also been proven that eating at the same time and even morning exercises help people maintain a good sleep regime.
Circadian rhythms and sleep
In developed and increasingly developing countries, where society lives 24/7, we urgently need to restore proper sleep patterns. Our 24-hour sleep rhythm is the most obvious circadian rhythm that is observed in humans and many animals, but sleep is more than just part of the circadian system. Sleep is a very complex state created by several brain regions, neurotransmitter systems and modulators. Because of this complexity, sleep is very vulnerable to disorders. Recent work has shown that sleep and circadian rhythm disorders (SCRD) are common for various neurodegenerative and neuropsychiatric diseases in which neurotransmitter pathways are disrupted. For example, SCRD is observed in more than 80% of patients with depression or schizophrenia. Feeling sleepy at the wrong time is, of course, uncomfortable, but this is just the tip of the iceberg. SCRD is also associated with a wide range of interrelated pathologies, such as poor attention and memory, decreased speed of mental and physical reactions, decreased motivation, depression, insomnia, metabolic disorders, obesity, immune disorders and even an increased risk of cancer. All of them are often observed in both mental and neurodegenerative diseases.
Some indicators of human circadian rhythm // wikimedia.org
We have made great progress in understanding the mechanisms that generate and regulate circadian rhythms and sleep, as well as in understanding the broad health problems associated with SCRD. All this provides us with a truly wonderful opportunity to work so that society understands the importance of sleep for human health. Sleep is truly our best medicine, and working at the wrong time can be disastrous–literally. Our level of attention reaches its lowest point in the early morning: it is no coincidence that such disasters as Chernobyl and the Exxon Valdez tanker accident occurred during the night shift. Even taking into account fatigue and traffic intensity, there are disproportionately many accidents at 4 a.m. – more than at other times of the day.
Even if we cannot help all people realize that it is necessary to pay attention to sleep and prioritize taking into account its importance, understanding the mechanisms and ways that generate and regulate sleep will allow us to develop new treatments and medicines that would be evidence-based and could improve health and the quality of life of many people with various diseases throughout society. The potential effect of helping people solve their sleep problems is huge, and we can do it. And it is very important to change the fact that at the moment in most five-year training programs in the field of medicine, sleep and circadian rhythms are considered only in one or two lectures.
This is a translation of an article from our English-language publication Serious Science. You can read the original version of the text by following the link.
About the author:
Russel Foster – PhD, Head of the Nuffield Laboratory of Ophthalmology and the Sleep and Circadian Neuroscience Institute, Chair of Circadian Neuroscience, Nicholas Kurti Senior Fellow, Brasenose College, University of Oxford
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01.06.2017