Circadian Rhythms are amongst the most critical of physiological processes to occur in mammals. This process refers to endogenous phenomena that modulates the sleep–wake cycle. Circadian Rhythms generally have periods of approximately 24 hours. The circadian cycle is effectuated by a molecular circadian clock, which synchronizes the internal biological time relative to the extrinsic environment. Diurnal patterns of light and darkness govern this cycle. The production of various hormones are altered by the absorption of light, through the Suprachiasmatic Nucleus (SCN). This in turn influences numerous physiological processes. Mutations to genes involved in Circadian Rhythms, such as CLOCK and PER2, have severe physiological implications, such as obesity and the proliferation of cancers.
What are Suprachiasmatic Nucleus?
The SCN is the master circadian clock in mammals. Compromising of approximately 20,000 neurons, the bilateral nerve cluster is located in the hypothalamus. It receives light signals, absorbed by specialized photosensitive ganglion cells, through the Retinohypothalamic Tract (RHT). The SCN then signals the pineal gland, through the multi-synaptic pathway, to produce the hormone melatonin. Light inhibits the production of melatonin. It is no surprise therefore, that melatonin production commences at the early hours of night. In humans, melatonin concentrations peak soon after midnight. (Mant, 2018) Figure 1 aptly conveys the melatonin production cycle in humans.
Melatonin is an essential hormone, for it regulates numerous physiological processes. It has antidepressant, anti-inflammation and antioxidant effects, amongst others. It is also a regulator of locomotor activity. Melatonin operates by binding to either receptors, such as Orphan Nuclear Receptors and Melatonin Receptors, or intracellular proteins, such as calmoduline. (Emet et al., 2016)
SCNs also transfer the temporal information to peripheral clocks in the brain and outlying tissue. However, contrary to earlier hypothesis, these peripheral clocks are not solely dependent on neurohumoral modulation by the SCN. When SCNs are not present, these clocks are able to establish circadian rhythms through other factors, such as food and drug sensitive oscillators. (Astiz et al., 2019)
Intracellular molecular clocks are found in SCN cells. These transcriptional feedback loops consist of positive regulators, such as BMAL1 and CLOCK, and negative regulators, PER1 and CRY. (Van Laake et al., 2017)
The Genetics of the Circadian Rhythms
It has been observed that numerous clock genes regulate down streamed “clock-controlled genes”, influencing numerous critical biological processes. This includes cell proliferation, apoptosis and metabolism. For this reason, alterations in the expressions of these genes is the root of numerous physiological disorders including tumours and cardiovascular diseases. The attenuation PER2 gene expression has been observed in numerous forms of cancer, including that of the colon, liver and neck squamous cell carcinomas. (Xiong et al., 2017)
It was found that homozygous CLOCK mutants in mice instigate diet related disorders. In Wild Type Mice, 75% of the feeding occurred at night. Comparatively, nocturnal feeding dropped down to 53% in mutated individuals. The latter group was also observed to consume a more high-fat diet compared to their wild type counterparts. Other than prominent alterations in diurnal feeding patterns, mutated individuals also displayed a 10% reduction in energy expenditure. These factors are attributed for the alleviated incidences of diseases, such as hyperphagic and obesity, amongst mutant individuals. Additionally, the Wild Type Mice slept an additional one to two hours than their mutated counterparts. A single mutation not only disrupts the circadian rhythm, but also causes chronic sleep reduction and obesity (Turek, 2005).
What are the impacts of disturbed Circadian Rhythms?
The influence of a lack of sleep on metabolism has also been observed in humans. A study found that the duration of sleep was inversely proportionate to the Body Mass Index of the samples. Furthermore, individuals who regularly slept for five hours had 15.5% lower leptin levels than those who slept the recommended eight hours. The adipocyte-derived hormone is attributed for repressing appetite. (Taheri et al., 2004) While further studies are required, it is likely that complex molecular mechanisms correlate energy metabolism with sleep patterns and circadian clocks.
Circadian dysfunctions also are known to cause severe cardiovascular disorders, both through genetic mutations and environmental disruptions. In mice, alteration of circadian rhythms have resulted in attenuated ischaemic tolerance. Cardiac hypertrophy has also been observed following circadian dysfunctions. (Martino & Young, 2015)
Circadian rhythms are certainly amongst the most crucial physiological processes regulating mammalians. Disruptions of the cycle, either through genetic mutation or environmental alterations, tend to unleash a plethora of diseases. That being said, the mechanisms of mammalian circadian clocks have been well researched. The significance of light and SCNs in circadian clocks have been well established. Nonetheless, much research is still required to understand the molecular mechanisms of such clocks across vertebrate taxa. It is not surprising therefore, that artificial lighting can significantly hinder the physiology of animals by disrupting their circadian rhythms. This is a major concern about changing landscapes on avian behavior.
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References
Astiz, M., Heyde, I. & Oster, H., 2019. Mechanisms of Communication in the Mammalian Circadian Timing System. International Journal of Molecular Sciences, 20(2), p.343. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359556/ [Accessed May 19, 2021].
Emet, M. et al., 2016. A Review of Melatonin, Its Receptors and Drugs. The Eurasian Journal of Medicine, 48(2), pp.135–141. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970552/ [Accessed May 19, 2021].
Mant, A., 2018. Entrainment of Melatonin Secretion Cycles. BLUblox. Available at: https://www.blublox.com/blogs/news/entrainment-of-melatonin-secretion-cycles [Accessed May 21, 2021].
Martino, T.A. & Young, M.E., 2015. Influence of the Cardiomyocyte Circadian Clock on Cardiac Physiology and Pathophysiology. Journal of Biological Rhythms, 30(3), pp.183–205. Available at: https://pubmed.ncbi.nlm.nih.gov/25800587/ [Accessed May 20, 2021].
Taheri, S. et al., 2004. Short Sleep Duration Is Associated with Reduced Leptin, Elevated Ghrelin, and Increased Body Mass Index. PLoS Medicine, 1(3), pp.211–217. Available at: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0010062 [Accessed May 20, 2021].
Turek, F.W., 2005. Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice. Science, 308(5724), pp.1043–1045. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764501/ [Accessed May 19, 2021].
Van Laake, L.W., Lüscher, T.F. & Young, M.E., 2017. The circadian clock in cardiovascular regulation and disease: Lessons from the Nobel Prize in Physiology or Medicine 2017. European Heart Journal, 39(24), pp.2326–2329. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012474/ [Accessed May 19, 2021].
Xiong, H. et al., 2017. Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. International Journal of Oncology, 52(1), pp.279–287. Available at: https://www.spandidos-publications.com/ijo/52/1/279 [Accessed May 19, 2021].