The environment shows a plethora of patterns - day and night, the changing seasons, the lunar cycle and so on – that influence ecological factors critical to an organism’s success such as food availability, the chances of offspring’s survival and predator behaviour. The evolution of the biological clock allows the organism to adapt its behaviour and physiology to maximise the opportunities and minimise the threats associated with environmental changes. Cells, tissues and organs throughout the body express autonomous endogenous rhythms controlled by mutually reinforcing transcriptional and feedback loops. For example, diurnal variations in the expression of transcription factors encoded by the CLOCK and BMAL1 genes establish the biological rhythm for several key physiological processes. The specific pattern and timing of activation differs depending on the tissue. Mutations in these genes could predispose to some sleep disturbances. |
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The system is sensitive to environmental cues, such as synchronising with the current cycle of day and night . The retinohypothalamic tract connects retinal cells to the suprachiasmatic nucleus (SCN) in the hypothalamus, which acts as the body’s central pacemaker. The SCN modulates production of the hormone melatonin, which transmits information about the light/dark cycle to organs and tissues. This allows the body to adapt appropriately to changes in daylight hours. |
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The SCN synchronises the various cellular
rhyhms. As such, the SCN acts as an overall control for many physiological variables, including melatonin synthesis, the sleep/wake cycle, and core body temperature. Several nerve routes connect the SCN to the pineal gland. This allows the SCN to control the circadian activity of arylalkylamine N-acetyl-transferase (AANAT) in pinealocytes, based on the information on ambient light transmitted along the retinohypothalamic tract. AANAT is the rate-limiting enzyme controlling melatonin synthesis. As a result, light inhibits melatonin production by the pineal gland. On the other hand, melatonin secretion increases rapidly after the onset of darkness, peaks at 2-4 am and then declines during the second half of the night.
Melatonin binds to specific receptors (MT1, MT2), which promote sleep and resets the phase of the endogenous biological clock. Administering melatonin during the day increases fatigue, enhances sleepiness and modifies CNS activity in preparation for sleep. The sleep promoting effects of endogenous and exogenous melatonin peak around two hours after release from the pineal gland or administration. Numerous peripheral tissues express MT receptors – including blood vessels, the gastrointestinal tract, liver, kidney and bladder, ovary, testis, prostate, skin and the immune system. This expression profile allows melatonin to modulate circadian rhythms in peripheral tissues and organs.
References Barnard AR and Nolan PM When clocks go bad: neurobehavioural consequences of disrupted circadian timing PLoS Genet 2008;4:e1000040 Ko CH and Takahashi JS Molecular components of the mammalian circadian clock Hum Mol Genet 2006;15 Spec No 2:R271-7 Zeitzer JM, Duffy JF, Lockley SW, Dijk DJ, Czeisler CA Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake Sleep 2007;30:1437-43 Lemoine et al, 2007 Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007-16:372/380 Pandi-Perumal SR, Trakht I, Srinivasan V et al Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways Prog Neurobiol 2008;85:335-53 |
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