The sleep -wake cycle synchronising between the internal and external environment is circadian rhythm. The physiology and metabolism of our body oscillates as per light and dark cycle. The rhythm is generated endogenously every 24 hrs from suprachiasmatic nucleus (SCN) of hypothalamus. It occurs in all species regulating the vital aspects of physiology like, sleep-wake cycle, feeding, metabolism, etc. Any kind of alterations in circadian rhythm leads to metabolic syndromes.

The biological markers for measuring circadian rhythm in mammals are
• Melatonin secretion by the pineal gland
• Core body temperature
• Plasma level of cortisol

The biological rhythm must meet four key criteria to be called as circadian rhythm:

• The rhythm must repeat once a day
• The rhythm should persist even in the absence of external cues
• The rhythm could be adjusted to match the local time
• The rhythm maintains circadian periodicity over a range of physiological temperatures.

Effect of Circadian rhythm on metabolism and physiology

The levels of body temperature, blood pressure, adrenal corticosterone, neurotransmitter, pituitary hormone, energy metabolism, gluconeogenesis, gene transcription alter according to light and dark cycle. The initial stage of sleep is characterized by slow wave sleep, elevated growth hormone level and increased blood glucose concentration. The cortisol rises in the night hours and contributes to enhanced cardiovascular system and glucose utilization.

Human sleep duration declines with age. An infant sleeps for 16 to 20 hours. The younger children sleep for 10 to 12 hours. The sleeping hours depreciates further in adolescents and elderly population.

The master clock of our body, suprachiasmatic nucleus is located in the anterior hypothalamus. It coordinates central and peripheral rhythms. Many hormones and neurotransmitters like, GABA, vasopressin, acetylcholine, etc are synthesized and released in circadian manner. Any damage to the SCN results in disturbed cycle that is not synchronized to the external environmental patterns of light and dark.

SCN sends information to pineal gland using several sympathetic neurons of superior cervical ganglion, thus regulating the rhythmic secretion of melatonin. Production of melatonin by the pineal gland is inhibited by light to the retina and permitted by darkness. So more melatonin is produced during night which makes us feel sleepy.

SCN receives light via retino-hypothalamic tract which originates in ganglion cells. These cells are distinct from rods and cones, and contain photopigment melanopsin. This tract regulates the synthesis of melatonin pineal gland. The external light enters through retina, reaches suprachiasmatic nucleus (SCN) and moves to pineal gland via superior cervical ganglion.

Melatonin is a potential antioxidant that can easily cross blood brain barrier. It exhibits a circadian rhythm. The enzyme serotonin N acetyltransferase in pineal gland is essential for the periodic release of melatonin as it serves as a rate limiting step in melatonin syntheses. The precursor of melatonin is serotonin, a neurotransmitter that itself is derived from the amino acid tryptophan. Within the pineal gland, serotonin is acetylated and then methylated to yield melatonin. Melatonin plays a key role in many pathological states like, neurodegenerative disorders, circadian rhythm sleep disorders, depression, cardiovascular diseases, tumor growth, immune pathologies. Thus it also has an important therapeutic approach.

Circadian rhythms can be found in many organs and cells in the body apart from suprachiasmatic nuclei. These are peripheral oscillators, seen in oesophagus, lungs, liver, pancreas, spleen, thymus, and the skin.

In addition to light, food also entrains circadian processes in neural and peripheral cells.

The food functions as a potential time giver for peripheral tissues showing relationship between circadian rhythm and metabolic processes. Thus, feeding and circadian rhythm is closely associated.

Circadian rhythm at gene level:

Per gene was the first circadian gene discovered in drosophila. It forms a dimer with tim and cry gene. Circadian clock is conserved from drosophila to mammals. Per and Cry genes in the nucleus are activated by the binding of the proteins BMAL1 and CLOCK to their promoters. Transcriptional activation results in the production of mRNA, which exits the nucleus through nuclear pores and is translated into protein by the ribosomes.

PER protein is susceptible to degradation unless it forms a dimer with per or cry gene. This dimer translocates into the nucleus. The dimers interact with BMAL1/CLOCK to block activation.

Disruption in Circadian Rhythm

The desynchronization between internal and external behavior results in disorder of circadian rhythm. Majorly there are two types of circadian rhythm disorders i.e. intrinsic and extrinsic.

Intrinsic circadian rhythm disorder is mainly due to internal factors. It includes, delayed sleep phase disorder, advanced sleep phase disorder and irregular sleep wake pattern.

Extrinsic circadian rhythm disorder is caused by external cues. It comprises of jet lag and shift work disorder. Alteration in the time zone or work schedule has an adverse effect on our sleep and wake cycle. These disorders leads to obesity, diabetes, depression, psychiatric disorders.

Therapeutic approach

Circadian rhythm regulates sleep-wake cycle, feeding behavior, heart rate, immune function, retinal functions, detoxification of free radicals, digestion, etc. The adequate treatments must be administered to avoid sleep disorders. Some of the appropriate treatemnts are:

• Phototherapy, where an individual is exposed to brighter light (full-spectrum light, heat lamps, or tanning lamps). This aids in depression, jet lag and sleep disorders by correcting the circadian rhythm.
• Blue blocking glass therapy is used as goggles that filter out this particular wavelength of light.
• Behavior therapy counseling about sleep hygiene, avoiding naps, caffeine, and other stimulants.
• Medications like melatonin and modafinil.
• Meditation and Yoga also helps in correcting sleep disorders.

References

1. Eckel-Mahan K, Sassone-Corsi P. Metabolism and the circadian clock converge. Physiol Rev, 2013;93(1):107-35.

2. Maury E, Ramsey K.M, Bass J. Circadian Rhythms and Metabolic Syndrome: From Experimental Genetics to Human Disease. Circ Res, 2010 Feb 19;106(3):447-62.


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