Introduction
The regulation of sleep is processed by the homeostatic physiology of the circadian rhythm, the sleep/wake cycle. Circadian rhythm is the 24-hour internal clock in our brain that regulates cycles of alertness and sleepiness by responding to light changes in our environment. Our physiology and behavior are shaped by the Earth’s rotation around its axis. This biological circadian system has evolved to help humans adapt to changes in our environment and anticipate changes in radiation, temperature, and food availability. Without this endogenous circadian clock, Homo sapiens would not be able to optimize energy expenditure and the internal physiology of the body.
Issues of Concern
Sleep is a vital activity that every organism needs to function properly. The lack of sleep or poor sleep patterns can have significant impacts on a variety of essential day to day functions. Memory consolidation, body healing, and metabolic regulation occur during the sleep cycle. This sleep-wake cycle can influence eating habits, digestion, body temperature, hormone release, and other bodily functions. Detrimental effects on sleep can negatively affect a person’s ability to properly function and can result in many disorders. The various chronic health conditions linked to irregular rhythms include diabetes, obesity, depression, bipolar disorder, seasonal affective disorder, and other sleep disorders.
Cellular Level
Examining the relationship between circadian rhythms in the human body and its cellular biology is essential to understand the underlying physiology and pathology in diseases. Disruptions in age, environment, or genetic mutation can have adverse effects on the cellular function and health of an organism. The circadian rhythm uses positive and negative molecular feedback loops as a mechanism to regulate their expression. There are several identified clock genes, BMAL1/BMAL2, CLOCK, CRY1/CRY2, and PER1/PER2/PER3, that regulate and control transcription and translation. Expression of these core clock genes inside the cell influence many signaling pathways which allows the cells to identify the time of day and perform appropriate function. Furthermore, phosphorylation of core clock proteins leads to degradation to keep the 24-hour cycle in sync. The presence of circadian rhythms in cells with and without nuclei indicate that the molecular clock is autonomous and external cues can be utilized for regulation.[1]
Development
The development of the circadian system occurs in mammals postnatally. The fetus is not subjected to external stimuli while in the womb, and thus neonates are born with an immature functioning system. The establishment of the 24-hour circadian rhythms occurs during the first 4 months of life as the newborn experiences rapid physiological changes and adapts to the environment. Since core body temperature is one of the most tightly regulated systems, deviations, among other things, reveal the establishment of circadian rhythm. Minimal deviations occur in the womb, but in the first few weeks of life, the perception of day and night differences begin. Spikes in core body temperature also begin to manifest just before the onset and first few hours of sleep. Melatonin, critical to the permanent establishment of circadian rhythms, emerges around 3 months of age. The production of cortisol, a key indicator of a properly functioning circadian rhythm, can occur as early as 8 weeks up to 9 months of age. As infants experience rapid physiological changes just after birth, deviations in core body temperature, as well as the production of melatonin and cortisol allow an infant to establish a stable circadian rhythm.[2]
Organ Systems Involved
The disruption of the circadian rhythm can have severe health implications for multiple organ systems including the immune, reproductive, gastrointestinal, skeletal, endocrine, renal, and cardiovascular systems. The central clock, or suprachiasmatic nucleus (SCN), is not the only internal mechanism of control, as recent discoveries have revealed the presence of secondary or peripheral oscillators throughout the body in a number of organs like the heart, liver, kidneys, lungs, intestines, skin, lymphocytes, esophagus, spleen, thymus, adrenal gland, prostate, and olfactory bulb. Although independent, these secondary clocks are still synchronized with the SCN and other factors like temperatures, the timing of meals, as well as external cues.
Function
The sleep/wake cycle is necessary to replenish and heal the body to ensure that it can function properly. Proper sleep allows the body to engage in circadian rhythms in the body, which initiates the build-up of energy stores for metabolic processes, neuronal remodeling for synaptic function, memory consolidation, and the assimilation of complex motor systems. The central nervous system (CNS) plays a critical role during the sleep cycle. As a result of the activation of the circadian system, the reticular activating system (RAS) in the brain stem is inhibited from inducing sleep. Sleep regulation is distinguished by the balance between the internal sleep homeostasis (process S) and the external circadian drive (process C).[3]
Mechanism
The circadian pacemaker is the suprachiasmatic nucleus (SCN) of the hypothalamus. As the body transitions from light to dark, the body sends inputs to the retinohypothalamic pineal pathway. During the light cycle, axons from the retinal ganglionic cells deliver signals that activate the suprachiasmatic nucleus via cranial nerve II, the optic nerve. The SCN then delivers a signal via the inhibitory neurotransmitter GABA (gamma-amino-butyric acid) that inhibits the paraventricular nucleus. Axons subsequently send impulses through the intermediate lateral column to inhibit the superior cervical ganglion thus inhibiting the sympathetic nervous system. As a result, melatonin does not get released from the pineal gland into circulation. As night approaches, the departure of light signals the retinal ganglion cells to inhibit the suprachiasmatic nucleus activating the paraventricular nucleus which then sends axons through the intermediolateral nucleus (IML) to the superior cervical ganglion stimulating the sympathetic nervous system which induces sleepiness. The pineal gland is mobilized to secrete melatonin into circulation.[4]
Related Testing
The best method of measuring the circadian rhythm includes monitoring the core body temperature and salivary/plasma melatonin levels. A rating scale, morningness-eveningness questionnaire (MEQ), can also be utilized to assess the circadian pattern. A noninvasive, but less common monitoring technique, actimetry, examines a person’s activity/rest cycle. Other long-term studies include the use of polysomnography and EEGs.
Pathophysiology
An individual’s environmental cues, also known as zeitgebers, drive the endogenous process of the circadian rhythm. The relationship between physiological and behavioral cues (timing of sleep, meals, work/social interactions) impact the timing of the sleep-wake cycle. Disturbances in an individual’s sleep cycle can have a significant detrimental effect on their overall health. Non-rhythmic regulations of core body temperature, cortisol levels, and melatonin secretion are all indicators of irregularities. Since fluctuations in body temperature occur systematically during the sleep/wake cycle, deviations from this cycle can indicate the onset of a disease or the nefarious presence of some external factor. Under the control of the SCN via the paraventricular nucleus of the hypothalamus, cortisol secretion is rhythmic, so the overproduction of cortisol can inhibit one’s ability to induce sleep. Likewise, the underproduction of melatonin can negatively impact one’s ability to fall asleep.[5]
Clinical Significance
Sleep disorders linked to the circadian rhythm are often overlooked and can have detrimental effects on the human body. Circadian rhythm sleep disorders typically manifest as a misalignment between a person’s sleep timeline and the physical/social 24-hour environmental cycle. The 2 more prevalent sleep disorders of circadian rhythms are advanced sleep phase (early onset, common in elders) and delayed sleep phase (later onset, common in adolescents). These 2 diagnoses often get misdiagnosed as insomnia or excessive sleepiness but are distinctly different disorders resulting from disruptions in the synchronization of the sleep/wake cycle. People prone to developing circadian rhythm sleep disorders include individuals who work evening shifts or have irregular shift schedules and the blind. Blind individuals are susceptible to develop these types of disorders because of their body’s inability to perceive light, and therefore, establish circadian rhythms. While blind individuals do have a pathway in the brain that functions as their body clock, roughly half of blind individuals experience non-24-hour sleep-wake rhythm disorder, during which their sleep cycles get later every night, jumps around, or results in waking up later in the day.[1] Irregular sleep-wake rhythm disorder, although rare, is found in people suffering from neurological disorders such as dementia, mental retardation, and brain damage. This disorder is characterized by excessively engaging in napping during both the day and night, having no distinct sleep pattern, difficulty in maintaining hard sleep, grogginess when awake, and an inability to maintain the amount of sleep needed for their age. Shift work disorder occurs when people have early-morning, night, or rotating shifts that disturb their normal 24-hour sleep/wake cycle. These individuals experience extreme fatigue and are at a greater risk for work place injuries and cognitive impairment due to an average of 4 hours or less sleep per night. When traveling across multiple time zones, a disassociation of the internal clock and environmental time can result in what is known as jet lag. Artificial illumination from computers, televisions, cell phones, and other electronic devices can also interfere with the body’s ability to maintain proper circadian rhythms.[6] Mounting evidence demonstrates the link between circadian rhythmicity and mood regulation disorders, such as seasonal affective disorder. Symptoms typical in patients suffering from depression can often be linked to that individual’s disruption of circadian rhythms. Treatment of these disorders includes a pharmacological approach in combination with light therapy and creating an effective, stable sleep/wake schedule.[7]
References
- 1.
Khan S, Nabi G, Yao L, Siddique R, Sajjad W, Kumar S, Duan P, Hou H. Health risks associated with genetic alterations in internal clock system by external factors.
Int J Biol Sci. 2018;14(7):791-798. [
PMC free article: PMC6001675] [
PubMed: 29910689]
- 2.
Rivkees SA. The Development of Circadian Rhythms: From Animals To Humans.
Sleep Med Clin. 2007 Sep 01;2(3):331-341. [
PMC free article: PMC2713064] [
PubMed: 19623268]
- 3.
Potter GD, Skene DJ, Arendt J, Cade JE, Grant PJ, Hardie LJ. Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures.
Endocr Rev. 2016 Dec;37(6):584-608. [
PMC free article: PMC5142605] [
PubMed: 27763782]
- 4.
Bass J, Takahashi JS. Circadian rhythms: Redox redux.
Nature. 2011 Jan 27;469(7331):476-8. [
PMC free article: PMC3760156] [
PubMed: 21270881]
- 5.
Monk TH. Enhancing circadian zeitgebers.
Sleep. 2010 Apr;33(4):421-2. [
PMC free article: PMC2849779] [
PubMed: 20394309]
- 6.
Duffy JF, Czeisler CA. Effect of Light on Human Circadian Physiology.
Sleep Med Clin. 2009 Jun;4(2):165-177. [
PMC free article: PMC2717723] [
PubMed: 20161220]
- 7.
McHill AW, Hull JT, Wang W, Czeisler CA, Klerman EB. Chronic sleep curtailment, even without extended (>16-h) wakefulness, degrades human vigilance performance.
Proc Natl Acad Sci U S A. 2018 Jun 05;115(23):6070-6075. [
PMC free article: PMC6003377] [
PubMed: 29784810]
Disclosure: Sujana Reddy declares no relevant financial relationships with ineligible companies.
Disclosure: Vamsi Reddy declares no relevant financial relationships with ineligible companies.
Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.
