22/02/2023 - Journal Club

Are you a morning person? – Chronotypes, Circadian Rhythms, and Questionnaires

by Prajwal DSouza and Carlo De Nart

Life as we know it has been shaped by the constraints of the environment. The aerodynamic shape of leaves to prevent the tree from toppling at high winds, or gravity that affects heights of organisms (extraterrestrial humanoids on the fictional pandora in Avatar), or the color of a polar bear. The environment is a critical factor that shapes life. For us humans, along with our living companions on earth, this includes revolving and rotating around a single star, with a single moon. This has enabled us to develop several rhythms, such as circadian cycle (24 hours), ultradian cycle (less than 24 hours), and infradian rhythms such as the human menstrual cycle have periods longer than a day. There are clocks within us, in every organ, every cell. At the cellular level, these are just chemical clocks that play with protein concentrations.

Circadian rhythm is not only important to understand better human pathologies or to find new potential therapeutic candidates, but may also help in personalized medicine. Knowing that the immune system and hepatic metabolism change throughout the day, it is possible to study at which moment a specific drug can be given to a specific patient in order to maximize its effect or reduce its toxicity. Unfortunately the inner clock’s timing can not be generalized, each individual has a different rhythm that depends both on the lifestyle and genetic predisposition [1]. Moreover the rhythm can be totally disrupted, causing each organ’s clock not to be in phase with the body’s one and/or with the day-night cycle. Several factors, especially now with humans’ modern lifestyle, may induce such disruption: examples are the jet-lag, jobs that require frequent night shifts or any kind of stress that precludes a person from having a constant resting-active state cycle [2].

One possible way to investigate a person’s circadian rhythm is through the use of questionnaires. They are used to categorize patients in chronotypes through questions about normal day habits like at what time the subject wakes up, has meals, goes to sleep and how they affect his/her life [3]. Through such data it is possible to determine if the person is an early bird or a night owl (which are called chronotypes) and with this information it is possible to say that, for example, the last type will have its active phase shifted towards the evening. As it is understandable there are several limitations: this approach must rely on what the subject says and do not allow to say with certainty if there is a circadian rhythm disruption.

In this month’s journal club, we decided to take a dive into the circadian rhythm, chronotypes, and the molecules that affect them. We also took the opportunity to develop a web app that helps you figure out your chronotype and what it means for your health, personality, etc. We turned to literature for connections between chronotypes and health, and we zeroed in on a paper by Fabbian et al., 2016 [5]. 

We decided to create an online questionnaire that with simple questions and a nice interface is able to predict the user’s chronotype. The idea of such a questionnaire is to find a way to make data gathering more interesting for those who have to respond to questions, translating a simple questionnaire into a game that in the end may give some information. Such information about chronotypes is given using simple terms in order to be understandable even without any scientific knowledge.

The questions used are from the Horne and Östberg Questionnaire [4] and information about the chronotypes were obtained from the paper F. Fabbian et al. 2016 [5]. There were many other papers that were referenced for this journal club, but these two were instrumental to informing the application design.

Chronotypes

There are several chronotypes that have been theorized by scientists, but for ease we decided to select only three. The selected ones are:

Early Birds/Lack. People having this chronotype tends to go to sleep early in the evening (between 9/10 PM) and wake up very early in the morning (7 AM or before). The peak of activity and energy is reached at the morning, while during the rest of the day they will become more and more tired.

Eagles. This chronotype is a mixture of the other two: peak of activity is reached after noon and they usually go to sleep between 10 and 11 PM and wake up between 8 and 9 AM.

Night Owls. Such chronotype describes people that usually stay awake at night until 12PM or later and wake up in the morning after 9 AM. The peak of activity is reached at the late afternoon, making these people feel less energetic when they wake up while becoming more active and efficient as the day progresses.

Circadian rhythm regulation

To understand better what a chronotype means it is necessary to explain before how the circadian rhythm is regulated, both at the systemic and molecular level.

At the systemic level the main center of regulation is situated in the brain, in particular is a region called the suprachiasmatic nucleus (SNC) in the amygdala. These neurons receive inputs from the whole brain and in particular from eyes and through them they are able to determine if it is day or night [6]. The SNC uses this information to regulate several body functions like animal’s behavior and psychology, body temperature, metabolism and body temperature. All such functions oscillate during the day and do not need inputs from the SNC to do so, although its main function is to reset the whole body circadian clock to ensure that all functions are in phase together and with the environment [7]. To ensure that each organ and tissue is synchronized, there are several genes embedded in the genome that regulate the rhythm in each cell at the molecular level. CLOCK and BMAL1 are the two core genes coding for the two homonym transcription factors, which form a complex that enhances transcription of several other genes [8].

Simple representation of how BMAL1-CLOCK regulate themselves through other transcriptional factors (Courtesy of Pickel L. et Sung H. K. 2020)

CLOCK-BMAL1 complex promotes CRY-PER factors production, which then acts on CLOCK and BMAL1 promoters suppressing their expression, suppressing then indirectly also their own expression and restarting the cycle again. This negative feedback loop is the main mechanism that allows CLOCK-BMAL1 expression to be cyclical with a period of around 24 hours [9]. Other genes promoted by CLOCK-BMAL1 complex are those coding for the nuclear receptors REV-ERB and ROR, which then regulate the expression of several genes involved in cell metabolism and other vital functions. Moreover, REV-ERBα acts also as a suppressor for BMAL1, while RORα enhances it, showing redundancy in the system that regulates core clock genes [10]. An interesting fact is those core clock genes are the same for each cell type, although they regulate a wide number of genes that are different for each tissue. This is in line with the fact that during specific phases of the day organs and tissues may be more or less active, so CLOCK-BMAL1’s effect can not be the same for each cell population. It is although not clear how this exactly happens: some studies found that CLOCK-BMAL1 activates different transcription factors for each cell type, while others suggest that clock genes can activate different promoters thanks to complexes with tissue-specific transcription factors [11, 12].

Considering what said so far, it is possible to reconsider each chronotype as the moment in which a person has the peak of CLOCK-BMAL1: for early birds it will be between late morning and noon while for late owls will be more shifted toward the afternoon. It is not clear although how much a chronotype is determined by genetic predisposition or environmental factor, probably a mixture of both. 

Several studies found strong correlation between night owls and detrimental behaviors, at the point that the chronotype can be considered a risk factor for several pathologies. One important thing to point out is that such correlation may be caused by other factors, like for example circadian rhythm disruption, since night owls’ life-style may conflict with modern world working hours and everyday life [13]. Moreover psychiatric disorders such as depression commonly cause difficulties in falling asleep and waking up early in the morning. This obviously does not mean that such people have an evening-type chronotype, even though through a questionnaire it may seem so.

References
1. Vitaterna MH, Takahashi JS, Turek FW. Overview of circadian rhythms. Alcohol Res Health. 2001;25(2):85-93. PMID: 11584554; PMCID: PMC6707128.
2. Eastman, C. I., Tomaka, V. A., & Crowley, S. J. (2016). Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work. Scientific Reports, 6(1), 36716.
3. Zavada, A., Gordijn, M. C. M., Beersma, D. G. M., Daan, S., & Roenneberg, T. (2005). Comparison of the Munich Chronotype Questionnaire with the Horne‐Östberg’s Morningness‐Eveningness score. Chronobiology International, 22(2), 267–278.
4. Horne, J. A., & Östberg, O. (1976). A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. In International Journal of Chronobiology (Vol. 4, pp. 97–110). Gordon and Breach Science Pub Ltd.
5. Fabbian, F., Zucchi, B., De Giorgi, A., Tiseo, R., Boari, B., Salmi, R., Cappadona, R., Gianesini, G., Bassi, E., Signani, F., Raparelli, V., Basili, S., & Manfredini, R. (2016). Chronotype, gender and general health. Chronobiology International, 33(7), 863–882.
6. Hastings, M. (1998). The brain, circadian rhythms, and clock genes. BMJ, 317(7174), 1704–1707.
7. Moore, R. Y. (2007). Suprachiasmatic nucleus in sleep–wake regulation. Sleep Medicine, 8, 27–33.
8. Trott, A. J., & Menet, J. S. (2018). Regulation of circadian clock transcriptional output by CLOCK:BMAL1. PLOS Genetics, 14(1), 1–34.
9. Yu, W., Nomura, M., & Ikeda, M. (2002). Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2. Biochemical and Biophysical Research Communications, 290(3), 933–941.
10. Guillaumond F, Dardente H, Giguère V, Cermakian N. Differential Control of Bmal1 Circadian Transcription by REV-ERB and ROR Nuclear Receptors. Journal of Biological Rhythms. 2005;20(5):391-403.
11. Kondratov, R. V, Shamanna, R. K., Kondratova, A. A., Gorbacheva, V. Y., & Antoch, M. P. (2006). Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation. The FASEB Journal, 20(3), 530–532.
12. Qu, M., Duffy, T., Hirota, T., & Kay, S. A. (2018). Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proceedings of the National Academy of Sciences, 115(52), E12305–E12312.
13. Togo, F., Yoshizaki, T., & Komatsu, T. (2022). Interactive effects of job stressor and chronotype on depressive symptoms in day shift and rotating shift workers. Journal of Affective Disorders Reports, 9, 100352.

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