Written by 丨Duoduo (School of Neuroscience, Chinese Academy of Sciences)
Editor丨Danny
Typesetting丨Summer otter
As the saying goes: Spring is sleepy, autumn is exhausted, hibernate, and nap in summer. But when you ask which season is the most difficult to get up, winter must be the only way to take charge. In order to ask for leave, some people in China wrote a fake note that "The winter in Changsha is too cold and I can't get up in bed in the morning." Foreign countries need winter time systems to benefit many households with difficulty in getting up... It seems that it is the consensus of the people of the world that don't think about it in winter.
Regarding the reasons behind it, everyone has their own thoughts in their hearts:
"The temperature is too low, so it takes us longer to start, just like driving in winter"
"It's late in winter, and our bodies also need to start working later"
...
What is the fact? Hope this article will tell you the answer.
01 What is circadian rhythm? —Biological phenomenon
To answer this question, we first introduce a word that sounds high-sounding "circadian rhythm". Simply put, circadian rhythm is the change in our life activities in a cycle of about 24 hours: within 24 hours, various life activities proceed in an orderly manner, and the next 24 hours are repeated again. In fact, we are not unfamiliar with this: if you forgot to turn on the alarm clock yesterday and nothing unexpected happens, you will still wake up at about the same time this morning and will not sleep until the afternoon or even tomorrow morning. "Fish at sunrise and rest at sunset" "Can bend at day and out at night"... These are actually examples of circadian rhythms.
Careful you may have noticed the word "day and night", which seems to imply that we are: this rhythm is related to light. In fact, this is indeed the case. But let’s first open this idea: If there is no light in , what changes will happen to our circadian rhythm?
Figure 1 Working from sunrise and setting
The first scientist in human history to study this problem is French geologist Michel Siffre. He has lived alone in Scarasson's cave for 63 days since July 1962, and has recorded his various physiological indicators every day. There is no clue in the cave that can prompt him outside time, but his circadian rhythm remains regular [1]. This shows that the circadian rhythm of does not necessarily require external light to be maintained.
Figure 2 Michel Siffre reads in caves
To more accurately measure circadian cycles, scholars from Harvard University measured a larger population in 1999, and the results showed that the intrinsic circadian cycles of humans were 24.18 hours, and there was no significant difference between young and old people [2]. These results show that the clock outside of is not a necessary condition to ensure individual rhythm .
Figure 3 Histogram of internal circadian rhythm distribution: horizontal axis indicates the length of circadian rhythm, and the vertical axis indicates the number of subjects
02 Why can circadian rhythm be maintained? - Intrinsic mechanism
The results of these research points to a very interesting question: Since we can maintain the circadian rhythm without the need for an external clock, then there must be an internal "clock" in our body. How does this clock work?
Let us open another idea: If you were God, how would you design this "inner clock"?
First consider the characteristics of this "clock":
1. Its time accuracy requirements are not high . We do not need to wake up at the same time of day, the deviation may be minutes or even more than an hour, so this clock does not need to be counted one second or one second;
2. This "clock" and do not necessarily require the existence of the hour hand and minute hand. Imagine a clock with only a second hand, with the scale above from 0 to 86400 (24 hours × 60 minutes × 60 seconds), which can also accurately indicate the time, but it is not presented in the way we are used to.
I don’t know what you have to do with your own ideas, but I know that the real God must be a mathematician. He designed an negative feedback loop , and solved this problem with just two rows of equations.
"What are you talking about? What negative feedback? What loop? What equation?"
Don't worry, let's first use an example of dynamic balance between predators and prey to explain what a negative feedback loop is:
1. The number of prey (# of prey) increases, and predators have more food sources, which will cause the number of predators to rise;
2. The number of predators increases, and more prey needs to be prey, which will cause the number of prey to decline;
3. The number of prey decreases, the food shortage of prey, and the number of predators decreases;
4. The number of prey decreases, the survival pressure of prey becomes smaller, and the number of prey increases.
Figure 4 Negative feedback balance between predators and prey
In the above figure, "+" means that the number of prey is positively correlated with the change in prey number, and "-" means that the number of prey is negatively correlated with the change in prey number. Such a negative feedback system has two important characteristics:
1. Circle: Changes in prey count ultimately affect the prey itself by affecting the number of prey, and the same is true for the number of prey.
2. Negative feedback: Changes in the number of prey (or predators) will cause them to change in the opposite direction through the loop. If there is too much prey, the system will make it fall. If there is too much down, it will make it rise, and so will predators.
Why do we say this is a dynamic balance? From the above description we will find that the number of prey and predators changes in similar patterns: first decrease and then rise, then decrease and then rise... in this cycle. The result is that the number of both floats up and down a certain equilibrium value, but this "balance" is not static, but changes dynamically over time.
"Okay, the negative feedback loop has been finished, so what do you mean by the two-row equation?"
In fact, in mathematics, such a negative feedback system can be portrayed by an ordinary differential equation system:
In order to prove that I am not talking nonsense, let me show you the results obtained by my numerical simulation. Have you noticed that the two lines are rising and falling regularly? We call this phenomenon oscillation.
Figure 5 Numerical simulation of predation equilibrium: blue represents prey, red represents predator. The value is simulated data and does not represent the real situation. Determine time using a negative feedback system: only the results of the first cycle are presented.
In fact, the oscillation of this negative feedback loop system is very accurate and can be fully qualified for the work of the circadian rhythm timer.
See Figure 5: On the premise that we already know that the number of prey changes periodically between 8-12 thousand, in order to determine which time of the cycle is now (i.e. the horizontal axis), we can measure how many prey is now (i.e. the vertical axis). Assuming that the measured prey value is 11k, we can go back to the figure to find the point where the number of prey (vertical axis) is equal to 11k, and we can read which time in this cycle is corresponding.
"But there are obviously two points on the picture, what's going on?" In fact, when we measure how many prey there is, we measure not only the value of a time point, but also the value of for a period of time around . In this way, we not only know how many prey there are, but also how the changes in the number of prey (i.e., whether it becomes more or less). Let’s look back on the figure. Is it true that one of the two points becomes more (A) and the other becomes less (B). Doesn’t this correspond to it?
If there is a dynamic balance similar to prey and predator in the human body - a negative feedback loop "clock", we can know the current time. This "clock" does not have an hour, minute, second hand, but only uses a periodic change in a certain amount (such as the number of prey above). At the same time, it won't be very precise. If a predator is happy today and catches two more preys and goes home, the time indicated by this clock will have some deviation, but for a system with thousands of preys, the impact of this deviation will not be very large.
"Okay OK, you're right, what you said is right, then what you're talking about is theory, do you have practical evidence?" There is really, scientists have discovered the negative feedback loop in the body from the molecular level.The oscillation cycles of specific molecules in this loop determine the rhythm of cells and even organisms [3].
Figure 6 Biological rhythm: molecular mechanism of negative feedback loop
We regard "period mRNA (period mRNA)" as prey and "PER (periodin)" as predator. Increased period mRNA leads to an increase in PER, which inhibits the formation of period mRNA and reduces the number of period mRNA, which forms a negative feedback loop. Moreover, their concentration in the body oscillates periodically, and the period is exactly 24 hours. Did you think it is a coincidence? (You ask me what the TIM in the picture is? Let's keep it a secret first, and we'll talk about it later.)
study shows that the periodic oscillation of period gene-related products (period mRNA, PER) is the molecular basis of the circadian rhythm. Because of the discovery of the molecular mechanism of circadian rhythm, three scientists, Jeffrey C. Hall, Michael Rosbash and Michael W. Young, won the 2017 Nobel Prize in Physiology or Medicine [3].
Figure 7 The 2017 Nobel Prize was awarded to scientists who discovered the molecular mechanism of circadian rhythm
03 What is affecting circadian rhythm? —Is the rhythm of external regulation of
remains unchanged? If you reverse the jet lag, you will definitely answer firmly: Of course not, the circadian rhythm will change with the environment. So, what factors in the environment affect the circadian rhythm? The two hypotheses we proposed at the beginning were supported by experiments, but light seemed to be the main reason [4].
study found that the impact of light on circadian rhythm is very significant. Under light-induced conditions, mice can even produce a rhythm of 22 or 26 hours [8]. If a newborn is unable to receive light for some reason (such as blindness), the probability of circadian rhythm abnormality will increase significantly [10]. In addition to the existence or absence of light, whether light is regular also has a great impact: for newborns, regular light helps them establish the correct circadian rhythm faster [9]. However, irregular external lighting (including improper use of electronic products) can also cause abnormal circadian rhythms [11,12]. This abnormality can lead to illnesses including sleep disorders, which is particularly evident in those who require frequent jet lag or shifts [13].
So, how does light affect the circadian rhythm? First, we need to know where the light goes after it enters the eyes. The answer to this question is the suprachiasmatic nucleus (SCN), whose key area is a group of light-sensitive neurons [5], who can transmit light signals to the pineal gland to regulate rhythmic changes in hormone levels [6], further regulating the circadian rhythm of the entire body, and therefore is also considered the center of the rhythm.
Figure 8 SCN diagram
So in SCN, how does light regulate circadian rhythm? Simply put, it changes the expression level of the relevant genes. For example, TIM in Figure 6, its function is to help PER enter the nucleus . Light will degrade TIM, so:
1. When there is light, the amount of TIM decreases. When PER cannot enter the cell, it cannot inhibit the production of period mRNA, resulting in the accumulation of PER;
2. At night, the amount of TIM increases, and the accumulated large amount of PER enters the nucleus to inhibit the production of period mRNA, causing the amount of PER to decrease.
So the concentration of period mRNA and PER in the body not only maintains its own oscillation, but is also regulated by light. As we mentioned earlier, period gene-related products (period mRNA, PER) are the clock in our body. If light regulates this clock through the above path, it means that it regulates our circadian rhythm. Of course, the actual mechanism is much more complicated than the above description. As for how light affects the expression of related genes (such as the expression level of TIM), scientists are still working to solve them.
So far, we have already known the internal "clock" in the body and the regulation mechanism of external light, but in fact we still have many questions that cannot be answered. Among them, it is very important: the above molecular mechanisms are all for each cell, and the rhythm cycles of different cells vary greatly.If SCN is a circadian center, how do cells in SCN synchronize to produce an individual's circadian rhythm? For example, there are two cells now, their cycles are 23 and 25 hours respectively. How to synchronize into 24 hours? Obviously, the average of 23 and 25 is 24, but how to "average" specifically? "Communication" between cells is very important. There are now some possible models that explain how this "Communication" is completed, but the specific details need to be further studied [7].
Figure 9 Cells achieve synchronization through "communication"
Let's go back to the initial question, why is it so difficult to get up in winter? One important reason is that sunrises later in winter and our circadian rhythms are delayed accordingly. So how to solve this problem?
The first solution is to resign and solve this problem from the source, of course, the premise is that you have money;
The second solution is to pluck this courage to use this article to find your boss, telling that getting up late in winter is human nature, and asking to postpone working hours (of course, you may also be fired by your boss, and the result is the same as the first solution);
The third solution, if you have neither money nor courage, then join the health army of going to bed early and getting up early.
"If I could go to bed early and get up early, I would ask you?" In fact, this is not as difficult as I imagined. Here are some useful methods:
1. Get in touch with more light as soon as possible: let your body start working earlier;
2. After the evening, try to minimize light, especially the blue light of electronic devices, such as dimming indoor lights, turning on eye protection mode, etc.: Let your body feel the arrival of the night in advance, so as to rest earlier;
3. Maintain a regular routine (including weekends): Don't frequently disturb your circadian rhythm, let it work steadily
0 Finally, I wish everyone a happy wake up!
Reference
1. Foer, J. (2008). Caveman: An Interview with Michel Siffre.Cabinet Magazine, (30).
2. Czeisler, C. A., Duffy, J. F., Shanahan, T. L., et al. (1999). Stability, precision, and near-24-hour period of the human circadian pacemaker. Science, 284(5423), 2177-2181.
3. Hall, J. C., Rosbash, M., Young, M. W., Ishiguro, K. (2017). The Nobel Prize in Physiology or Medicine 2017.
4. Baño Otálora, B. (2013). Funcionamiento del sistema circadiano en models fisiológicos y patológicos de cronodisrupción en rodedores: cronopotenciación por melatonina= Circadian system functionality in physical and pathological rodent models of chronodisruption: cronoenhancement by melatonin. Proyecto de investigationación.
5. Yan, L. (2009). Expression of clock genes in the suprachiasmatic nuclearus: effect of environmental lighting conditions. Reviews in Endocrine and Metabolic Disorders, 10(4), 301-310.
6. Borjigin, J., Zhang, L. S., Calinescu, A. A. (2012). Circadian regulation of pineal gland rhythmicity. Molecular and Cellular Endocrinology, 349(1), 13-19.
7. Bell-Pedersen, D., Cassone, V. M., Earnest, D. J., et al. (2005). Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nature Reviews Genetics, 6(7), 544.
8. Azzi, A., Evans, J. A., Leise, T., Myung, J., Takumi, T., Davidson, A. J., Brown, S. A. (2017). Network dynamics mediate circadian clock plasticity. Neuron, 93(2), 441-450.
9. Yates J. (2018). PERSPECTIVE: The Long-Term Effects of Light Exposure on Establishment of Newborn Circadian Rhythm. Journal of Clinical Sleep Medicine, 14(10), 1829–1830.
10. Sack, R. L., Lewy, A. J., Blood, M. L., Keith, L. D., Nakagawa, H. I. R. O. K. I. (1992). Circadian rhythm abnormalities in total blind people: incident and clinical significance. The Journal of Clinical Endocrinology Metabolism, 75(1), 127-134.
11. Blume, C., Garbazza, C., Spitschan, M. (2019). Effects of light on human circadian rhythms, sleep and mood. Somnologie, 1-10.
12. Oh, J. H., Yoo, H., Park, H. K., Do, Y. R. (2015). Analysis of circadian properties and healthy levels of blue light from smartphones at night. Scientific Reports, 5, 11325.
13. Zee, P. C., Attarian, H., Videonovic, A. (2013). Circadian rhythm abnormalities. Continuum: Lifelong Learning in Neurology, 19(1 Sleep Disorders), 132.
Image Source
Cover image https://elpaishml7.com/elpais/2018/10/23/inenglish/1540286443_626629.html
Figure 1 https://new.qq.com/omn/20181020/20181020A0JHIZ.html#p=1
Figure 2 http://www.cabinetmagazine.org/issues/30/foer.php
Figure 3 https://www.scisnack.com/2015/08/04/why-negative-feedback-is-good-for-the-climate/
Figure 8 https://en.wikipedia.org/wiki/Suprachiasmatic_nucleus
Figure 9 https://www.researchgate.net/figure/Synchronization-of-a-population-of-circadian-clocks-A-Illustration-of-two-types-of_fig2_257908100
Original title: "Light, Day and Night and Rhythm"
Source: Brain Renyan
Editor: Be
