Hector Warnes: Historical Overview of Sleep Medicine
2. Chronobiology and periodicity
Chronobiology and periodicity
Jürgen Walther Ludwig Aschoff (a German physician, biologist and behavioral physiologist; 1913-1998) was persuaded in the ‘50s by Konrad Lorenz and Erich von Holst to work at the Max Planck Institute of Behavioral Physiology in Bavaria where he built his own department to pursue his research on biological timing. He investigated in birds and mammals the sensitivity of endogenous circadian systems to environmental stimuli (Zeitgebers or environmental synchronizers).
The circadian rhythms were the product of endogenous oscillators related to the light-dark cycles. Along with Erwin Bünning, Colin Pittendrigh and Franz Halberg (who directed the Chronobiology Laboratory at the University of Minnesota), who were considered to be the founders of the field of Chronobiology, Aschoff studied the ability of the circadian clock to adapt to environmental changes critical for maintaining homeostasis and preventing disease.
Aschoff proceeded to build an underground bunker to study in human subjects the impact of prolonged isolation from time cues (how it felt to be totally timeless). He was himself able to endure “this grueling experience” and recruited 300 other subjects, some who stayed at the facility for up to two years. For about 20 years his pioneering research led to our understanding of socio-medical problems caused by shift-work, affective disorder, sleep deprivation, sensory isolation, aging and jet-lag.
Oepen, Baldessarini and Salvatore, commenting on a paper published by Eliot Slater in 1938, agreed that there was an increasingly disproportionate representation of faster cycling in manic depressive patients and in sub-samples involving higher cycle-counts in pooled samples of subjects. We are well aware of early awakening and the worsening of mood of the endogenous depressed patient. Even the prevalence of suicide has been reported to be higher in early morning hours.
All biological functions have circadian (24 hs), ultradian (less than 22 hs) and infradian rhythms (greater than 26 hs). On awakening, our heart rate and blood pressure increase, as do platelet aggregability and other clotting factors. This coincides with the rise of cortisol and the acrophase of heart attacks, migraine, rheumatoid arthritis and strokes. It has been shown that there are periodic and or seasonal illnesses such as bipolar disorder, allergic rhinitis, asthma, hypertension, angina pectoris and several infectious diseases, that are influenced by circadian rhythms.
The circadian clock is bound to be sensitive to aging (besides the changes due to ion channels and neurotransmitters) which results in a reduction in the amplitude of the circadian timing signals produced by the suprachiasmatic nucleus and a weakening in the control of peripheral oscillators.
From the suprachiasmatic nucleus and the pineal gland two branches are projected: one goes to the hypophysis gland which secretes several hormones in a close circuit feedback and the other branch controls the functions of the sympathetic and parasympathetic systems. The Pineal gland secretes melatonin which acts as a neurotransmitter and rises with darkness reaching a peak at night between 2 and 6 a.m.
Two proteins, Clock and Bmall, bind together and move into the nucleus of the cell where they bind to specific sites in the DNA that activate specific genes: Period and Cryptochrome. This results in a rising and falling pattern of expression of the Period and Crytochrome gene products with a periodicity that is very close to 24 hours.
This year the Nobel Prize winners in physiology or medicine was a team of researchers from two US Universities (Brandeis University and the University of Texas, Austin) who, while working with fruit flies (Drosophila melanogaster), were able to decode the gene “period” which controls the circadian rhythm. The gene makes a protein which they called PER that accumulated at night and was degraded during the day. This latest discovery has underscored the fact that our biological clock regulates critical functions such as behavior, hormone levels, sleep, blood pressure, heart rate, alertness, body temperature and metabolism.
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Cornelissen G, Halberg F. Chronomedicine in: Armitage P, Colton T. (Eds) Encyclopedia of Biostatistics 2nd edition. Chichester, UK: John Wiley and Sons, pp. 796-812, 2005.
Oepen, G. Baldessarini R. J. Salvatore, P. On the periodicity of Manic-Depressive insanity, by Eliot Slater (1938). Journal of Affective Disorders. Vol. 78
1:1-9, Jan. 2004.
Cornelissen G. Otsuka K. Chronobiology of Aging: a mini-review. Gerontology 63 (2): 118-128, 2017.
Zehring, WA, Wheeler, DA, Reddy, P, Konopka, RJ, Kyriacou CP, Rosbash, M and Hall, JC.
P-element transformation with Period locus DNA restores rhythmicity to mutant arrhythmic Drosophila Melanogaster. Cell 39, 369-376, 1984.
Bargiello, TA, Jackson FR and Young MW. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752-754, 1984.
May 10, 2018