?Biological Clocks
Avery Volz
BIO 219
September 20, 2018
Without an internal system inside the body ensuring that each individual cell in an organism is functioning correctly, organisms could not survive. Biological clocks are the fundamental mechanisms that control an organism’s physiological activities and regulate homeostasis through the production of circadian rhythms. This concept of biological clocks was first discovered in the 18th century in the plant Mimosa pudica by Jean-Jacques d’Ortous De Mairan. The biological clock can be observed in almost all living organisms and has been found to have similarities in differing species. The most crucial role of the biological clock is the production of the circadian rhythms, which is the 24-hour cycle of the body that controls all homeostatic functions such as temperature regulation or blood glucose level. To ensure that these circadian rhythms are properly functioning, specific genes are designated to these processes.
To understand the importance of the biological clock, it is necessary to understand how the biological clock functions. In the hypothalamus, the biological clock sends signals to regions in the brain, which are then transmitted to target cells throughout the body. The hypothalamus contains a small bundle of nerve cells known as the superchiasmatic nucleus, SCN. “By regulating day-to-day oscillations of the internal milieu and synchronizing them to the changing cycles of day and night and of body state” the superchiasmatic nucleus can regulate the daily functions of an organism (Gillette, Tischkau). Specific genes have been found that control the biological clock. “CLOCK and BMAL1 are transcription factors that act as positive regulators of circadian gene expression and activate the expression of the negative regulators of circadian gene expression: cryptochrome (CRY1 and CRY2) and period (PER1, PER2, PER3) families. CRY and PER proteins feedback and inhibit their own expression as well as the expression of other clock-controlled genes” (Kalsbeek). Without these genes, the body would not be able to regulate the circadian rhythms, therefore the biological clock would not serve a purpose in individuals.
Circadian rhythms are commonly associated and mostly known to have a role in the sleep wake cycle. Light enters the eye through the cornea, through the pupil’s opening, through the lens and then is focused onto the retina and received by the rods and cones, which send a signal to the occipital lobe of the brain through the optic nerve. When light enters the eye, it triggers the circadian rhythm into the wake section of the sleep wake cycle. As less light enters the eye, “it triggers the production of melatonin” which sends the body into the sleep phase of the sleep wake cycle” (NIH). Having the sleep wake cycle in a regulated manner, directly relates to “homeostasis, which is the capacity of a living structure not only to withstand and adapt its internal conditions to progressive or sudden changes of the environment but also to anticipate the occurrence of reoccurring events” (Kaeffer). If the sleep wake cycle is not in a proper homeostatic state, the rest of the physiological processes controlled by the circadian rhythms are likely to have negative effects and cause imbalances in the body.

Blood glucose level is controlled through circadian rhythms. The blood glucose level has a negative feedback loop that controls it. As glucose is released into the blood, insulin is released by the pancreas and sent to target cell receptors to allow glucose to enter the cells for cellular respiration. Some of the glucose is sent to the liver to be stored as glycogen. On the other hand, if the glucose level is too low in the blood, glucagon is released by the pancreas and sent to the liver to breakdown the stored glycogen into glucose that is released back into the blood. It has been found “that a disruption of biological rhythms increases the risk of developing obesity” (Kalsbeek). Obesity is linked with type 2 diabetes, which is where the body inefficiently produces insulin, or the cells resist the insulin. Both type one and type two diabetes are related to the blood glucose level. There are two main phases during the day, rest/fasting and feeding/activity, which influence where the body retrieves its energy. Another factor that influences the blood glucose level is the “hypothalamus controls a vast array of these alternating behavioral and physiological processes, including food and water intake, but also sleep and arousal, thermoregulation, and energy expenditure” (Kalsbeek). A phenotypic Clock mutant led mice to “severely disturbed daily feeding rhythms, they were also hyperphagic, obese, hyperleptinemic, hyperlipidemic, hyperglycemic and hypoinsulinemic” (Kalsbeek).
Besides melatonin and insulin, there are multiple other hormones regulated by the biological clock through circadian rhythms. These hormones include vasopressin, acetylcholine, glucocorticoids, cortisol, and multiple others. Vasopressin “is produced in paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and transported to the posterior pituitary, whence it is released in the system circulation, reducing water elimination from kidneys to prevent dehydration” (Gnocchi). Acetylcholine, a neurotransmitter, has been found to be increased during the wake part of the sleep wake cycle, and levels of acetylcholine are decreased during the sleep phase. Glucocorticoids released from the adrenal cortex has “maximal production in the early morning for diurnal animals, and in the early evening for nocturnal ones” (Gnocchi). Cortisol is one of the most known examples of hormone control by the circadian rhythms. “In humans, cortisol production usually increases during the night and shows a peak of secretion in the morning, around 07:00–08:00, in this way setting the endocrine balance for the stress associated with waking” (Gnocchi). Cortisol also has relations to jet lag and other circadian rhythm disruptions.

Another factor maintained through the circadian rhythms produced by the biological clock is the cardiovascular system. During ex vivo experiments, in human hearts clock genes were found to be expressed. A well-known circadian rhythm is the fluctuation between heart rate (HR) and blood pressure (BP) during the day and night. “In humans, there is a 24-h variation in BP with a sharp rise before awakening, the highest BP value is around midmorning” which in turn leads to most cardiovascular diseases occurring at this time of day as well (Lihong). Myocardial infractions (MI) are related to the circadian rhythm through the increase in systolic blood pressure and heart rate in the morning. These HR and BP increases result “in an increased energy and oxygen demand by the heart, while the vascular tone of the coronary artery rises in the morning, resulting in a decreased coronary blood flow and oxygen supply. This mismatch between supply and demand elicits the high frequency of the onset of MI” (Lihong). After MI’s occur, there is a “short-term disruption of diurnal rhythms after myocardial infarction adversely affected the early inflammatory phase of left ventricular remodeling” (Lihong). If the rhythms are not normal, they can interfere with a healthy recovery of the heart. If there are “clock gene deletion or mutation in mice dampened cardiovascular circadian rhythms accompanied by dilated cardiomyopathy, arterial stiffness, or endothelial dysfunction” (Lihong). On the other hand, the expression of clock genes can be affected by CVDs. Overall, disruptions in the circadian rhythm can lead to an increase in CVDs and adverse the effects of medications used to treat CVDs.
Specific diseases and disorders can be directly influenced by the biological clock. These diseases include sleep disorders, diabetes, and mood disorders such as depression, anxiety, and schizophrenia. Sleep disorders are the most common disorder due to an improperly functioning biological clock. A common form of a temporary sleep disorder is jet lag. It is developed when traveling and causes drowsiness. Eventually, the “biological clocks will reset, but this often takes a few days” (NIH). The body can naturally readjust and fix its biological clock in this case. Another example of a sleep disorder that is linked to the biological clock is delayed sleep disorder that’s more common in younger people who are “night owls”. Individuals with delayed sleep disorder “whose “night owl” tendencies delay sleep onset — often until 2 a.m. or later. If allowed to sleep in late (often as late as 3 p.m.), sleep deprivation does not occur. However, earlier wake up times can lead to daytime sleepiness and impaired work and school performance” (Cleveland Clinic). Shift work disorder is another sleep disorder that affects workers who constantly change shift times. Symptoms for this disorder include “constant or recurrent pattern of sleep interruption that results in insomnia or excessive sleepiness” (Cleveland Clinic). Type 1 and 2 diabetes have been found to be related to the circadian rhythms. The circadian rhythms that control the blood glucose levels affect diabetes as they are both diseases with mutations involving the glucose negative feedback loop in the body. The influence of circadian rhythm on obesity also plays a role in the effect on type 1 and type 2 diabetes.
Multiple psychological and psychiatric diseases have been found to have a link to improper circadian rhythms. Most disorders have multiple influential factors that can come from internal factors, such as genetic mutations and hormonal imbalance, or external factors, such as life events and negative environments. Depression is “a mood disorder that causes a persistent feeling of sadness and loss of interest” (Mayo Clinic). It was found that in depression there are discrepancies in the biological clock in the sleep wake cycle and at the molecular level. During “more severe depressive states are associated with the circadian pacemaker being more delayed relative to the timing of sleep onset” (Karatsoreos). Symptoms of depression can worsen due to issues with sleep. At the molecular level, it “is evident in the development and use of agomelatine, a melatonin agonist that also has serotonergic activity” (Karatsoreos). The use of agomelatine has been shown to improve depressive symptoms due to it initiating the release of serotonin from a neuron’s dendrites, which assists the biological clock with returning to its homeostatic state. Bipolar disorder, previously known as manic depression, is a mental condition “that causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression)” (Mayo Clinic). Research has shown a relation between manic states of bipolar disorder and disruptions in the circadian rhythms at the molecular level and in behavioral patterns. During manic states, an individual’s sleep patterns are extremely unstable and do not follow normal sleep wake cycle tendencies. Results from research on hamsters concluded that “detailed molecular work has shown that lithium treatment can alter several intracellular signaling cascades, including glycogen synthase kinase-3beta, a link to the circadian molecular clockworks” (Karatsoreos). Lithium is one of the most commonly known treatments for bipolar disorder and with the use of it on the hamsters, it showed improvement in the manic symptom. Schizophrenia is not as clearly defined in how it is related to circadian rhythms as the exact theory of how schizophrenia arises is still unknown. However, it is believed that schizophrenia is related to the circadian rhythm through the sleep wake cycle. “Epidemiological studies show that fragmented circadian rhythms, as measured by changes in rest–activity cycles or in sleep regulation, are observed in schizophrenic patients,” which supports this ideology (Karatsoreos).
Biological clocks play a large part of an organism’s success in life. Without the biological clock regulating most of the behavioral and physiological processes in the body, life would be difficult as the chemical reactions and homeostasis regulation would not have a control center. From controlling the bodies hormone balance to controlling the sleep wake cycle, the biological clock affects all areas of an organism’s well-being.
Works Cited
Chen, Lihong, and Guangrui Yang. “Recent Advances in Circadian Rhythm in Cardiovascular System.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, 1 Apr. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4381645/.

Cleveland Clinic. “Circadian Rhythm Disorders: Sleep Disorders.” Cleveland Clinic, 1 Oct. 2010, my.clevelandclinic.org/health/diseases/12115-circadian-rhythm-disorders.

Gillette, M U, and S A Tischkau. “Suprachiasmatic Nucleus: the Brain’s Circadian Clock.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/pubmed/10548871.

Gnocchi, Davide, and Giovannella Bruscalupi. “Circadian Rhythms and Hormonal Homeostasis: Pathophysiological Implications.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, Mar. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5372003/.

Kaeffer, Bertand, and Lissia Pardini. “Clock Genes of Mammalian Cells: Practical Implications in Tissue Culture.” BioOne Complete, Society for In Vitro Biology, 14 Sept. 2005, www.bioone.org/doi/full/10.1290/0506044.1.
Kalsbeek, Andries, et al. “Circadian Control of Glucose Metabolism.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, July 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4060304/.

Karatsoreos, Ilia N. “Links between Circadian Rhythms and Psychiatric Disease.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, 6 May 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4018537/.

Mayo Clinic. “Depression (Major Depressive Disorder).” Mayo Clinic, Mayo Foundation for Medical Education and Research, 3 Feb. 2018, www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007.

Mayo Clinic. “Bipolar Disorder.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 31 Jan. 2018, www.mayoclinic.org/diseases-conditions/bipolar-disorder/symptoms-causes/syc-20355955.
NIH. “What Are Circadian Rhythms?” Eunice Kennedy Shriver National Institute of Child Health and Human Development, U.S. Department of Health and Human Services, 1 Dec. 2016, www.nichd.nih.gov/health/topics/sleep/conditioninfo/circadian-rhythms.

NIH. “Circadian Rhythms.” National Institute of General Medical Sciences, U.S. Department of Health and Human Services, Aug. 2017, www.nigms.nih.gov/Education/Pages/Factsheet_CircadianRhythms.aspx.

NIH. “Tick Tock: Your Body Clocks.” National Institutes of Health, U.S. Department of Health and Human Services, 2 May 2018, newsinhealth.nih.gov/2018/04/tick-tock-your-body-clocks.