BioSci 24237 BIOLOGICAL RHYTHMS AND SLEEP

1. BioSci 24237BIOLOGICAL RHYTHMS AND SLEEP CLASS #9 History of Sleep and Circadian Rhythm Research February 4, 2003

2. EARLIEST CHRONOBIOLOGICAL OBSERVATIONS In plants Linnaeus “flower clock” (1707 - 1778) Jacques de Mairan (1729)

3. Jacques de Mairan (1729)

4. CIRCADIAN RHYTHMS IN THE 19th CENTURY First demonstration of a 24-hour rhythm in the human by the German Autenrieth for pulse rate 1842 First record of the 24-h rhythm of body temperature by Gierse, based on self measurements 1866 A British physician, William Ogle, publishes a paper entitled "On the diurnal variations in the temperature of the human body in health", and concludes "they are probably produced by periodic variations in the activity of the organic functions"

5. CIRCADIAN RHYTHMS IN THE FIRST HALF OF THE 29th CENTURY • 1906 Simpson and Galbraith in the UK measure the temperature of five • monkeys every 2 hours for 60 days and demonstrate the persistence of • the rhythm in constant dark and constant light, and the inversion of • the rhythm when the light-dark cycle is inverted. • 1907 Demonstration of diurnal variation in cognitive function • 1910 Circadian rhythms serve to measure time. Demonstrated in • bees by Swiss physician Forel and subsequent authors. • 1922 Curt Richter publishes his thesis "A behavioristic study of the activity of the rat", demonstrating the endogenous nature of circadian locomotor activity in the rat

6. CIRCADIAN RHYTHMS IN MODERN TIMES 1954-60 Pittendrigh (US) enunciates the formal properties of circadian rhythms, based on extensive studies in the fruit fly Drosophila 19sixties Circadian rhythmicity is demonstrated for a large number of physiological and behavioral variables by a number of investigators, including Halberg in Minnesota and Mills in the UK. The implications for drug treatment (chronopharmacology - chronotherapy) are beginning to be recognized. 1962-64 First experiments in temporal isolation; in a cellar below a Munich hospital by Aschoff; by the French speleologist Siffre in an underground cavern. Demonstration of endogenous nature of human circadian rhythmicity.

7. Catecholamines EARLY STUDIES OF HUMAN CIRCADIAN RHYTHMS 17-OHCS Deviation from 4-day mean (%) Circadian rhythms of three urine constituents and of rectal temperature in six subjects following the same routine for 4 days. Shaded area, sleep in darkness. Potassium Rectal Temperature 0.93 Deviation from 4-day mean (°C) Aschoff, J., Fatranska, M., Giedke, H., Doerr, P., Stamm, D., and Wisser, H. (1971): Human circadian rhythms in continuous darkness: Entrainment by social cues. Science, 171:213-215.

8. Circadian rhythms in wakefulness and sleep, of rectal temperature, and of urinary cortisol excretion in a blind subject living alone in the isolation chamber. Door of the chamber closed after day 7. Lund, R. (1974): Circadiane Periodik physiologischer und psychologischer Variablen bei 7 blinden Versuchspersonen mit und ohne Zeitgeber. Med. Thesis Müchen.

9. Where is the “clock” ? - First Step • 1965: After decades of work, Curt Richter identifies the hypothalamus as the location of the circadian clock • Method: using the free-running rhythm of blinded rats, he subjected the animals to “almost every conceivable kind of metabolic, endocrinologic and neurologic interference” • Methods included: surgical removal of adrenals, gonads, pituitary, thyroid, pineal, pancreas; electroshock administration; inducing convulsions; prolonged anesthesia; alcoholic stupor

10. hypothysectomy adrenalectomy pinealectomy Electric shock

11. Where is the “clock” ? - 2nd step • Having eliminated “peripheral” sites as possible location of the circadian clock, Richter placed hundreds of lesions in various parts of the rat’s brain • The only location where lesions were found to influence the free-running rhythm was the hypothalamus • Richter then performed more than 200 lesions of the hypothalamus and reported that the location of the circadian clock was in the anterior hypothalamus

13. Lesions of the anterior hypothalamus abolish the rhythms of wheel-running activity, feeding and drinking

14. Where is the “clock” ? - 3rd step • Since circadian rhythms are entrained by the light-dark cycle, there must be neural pathways from the retina to the clock • Injecting a radiolabeled substance in the eye and tracking its pathway in the brain led to the identification of the retino-hypothalamic tract (RHT) • The RHT terminates in the circadian clock, specifically in the paired suprachiasmatic nuclei (SCN) • Lesions of the SCN were shown to result in loss of circadian rhythmicity by two independent investigators

15. THE MAMMALIAN CIRCADIAN PACEMAKER (1972) retino-hypothalamic tract suprachiasmatic nuclei hypothalamus Moore (1973).

17. Day synchronized free-running FREE-RUNNING RHYTHM OF BODY TEMPERATURE IN TEMPORAL ISOLATION Czeisler, C. A. (1986). Clock Time

18. average duration of sleep episodes (min ± SD) CIRCADIAN REGULATION OF SLEEP percent REM during sleep (mean ± SEM) percent of time asleep (mean ± SEM) core body temperature (°C) (mean ± SEM) Czeisler, Zimmerman, Ronda, Moore-Ede & Weitzman (1980). circadian phase(degrees) Approximate clock time 6 am 6 pm

19. Distribution of wakefulness in intact and SCN-lesioned squirrel monkeys Edgar DM, Dement WC, Fuller CA, J Neurosci 1993.

20. The “opponent process” model Edgar DM, 1996.

21. HISTORY OF RESEARCH ON SLEEP EGYPT: dream interpretation covered in Chester Beatty papyrus (1350 BC) - “contrary predictions” CHINA: “Yin-Yang” concept - sleep important for health because it is a state of unity with the universe (300 BC) GREECE: “dream incubation” : awakenings to obtain dream reports and help medical diagnosis - Hypnos: god of sleep- But “Sleep and death are twin brothers” (Homer; Iliad, ca 850 BC). BIBLE: dreams are a way of communicating with God

24. 1834 Robert McNish (Glasgow) “The Philosophy of Sleep” Sleep is the intermediate state between wakefulness and death Sleep is thought to be due to cardiovascular congestion of the brain

25. 1836 Charles Dickens (London) “The Posthumous Papers of the Pickwick Club” First description of the sleep apnea syndrome

26. 1861 Alfred Maury (France) “Le Sommeil et les Reves” Self-experimentation - sleep-onset dreaming actvity - Pre-sleep stimuli

28. Father of modern neurobiology 1906 Nobel prize for physiology and medicine Describes the neuron

29. Early 19th Century First demonstration of an anatomical basis for sleep and wakefulness Rolando and Flourens both show independently that a state of sleepiness occurs when certain lesions are made in the brain of pigeons.

30. 1900 Freud (Vienna, Austria) “The Interpretation of Dreams” The interpretation of dreams is the royal road to a knowledge of the part the unconscious plays in the mental life

32. 19th century sleep theories “anemia theory”: sleep is due to insufficient blood in the brain “hypnotoxin theory”: sleep is due to the accumulation of substances during waking; confirmed in 1907 by the French physiologist and psychologist Henri Pieron (transfers spinal fluid from sleep-deprived dogs)

33. von Economo, Austria 1915 Patients with brain influenza (encephalitis lethargica) are unable to stay awake: damage to brainstem neurons

34. Milestones of the early 20th century In 1928, Hans Berger, a German psychiatrist, records brain electrical activity in humans and demonstrates wake vs sleep differences In 1937-39, investigators at Harvard and the University of Chicago describe the wake and sleep EEG

36. Bremer, Belgium, 1930 Midbrain transections

37. Walter Hess Switzerland, 1950 Stimulation of the thalamus of waking cats produces sleep Magoun and Moruzzi Northwestern Univ. 1949 Stimulation of the midbarin of sleeping cats produces wake

40. States of Being Wake NREM Sleep REM Sleep

42. Michel Jouvet Lyon, France, 1962 The “pontine” cat

45. Obesity Trends* Among U.S. AdultsBRFSS, 1985 (*BMI 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Source: Mokdad AH.

46. Obesity Trends* Among U.S. AdultsBRFSS, 1990 (*BMI 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Source: Mokdad AH.

47. Obesity Trends* Among U.S. AdultsBRFSS, 1995 (*BMI 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16

48. Obesity Trends* Among U.S. AdultsBRFSS, 2000 (*BMI 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Source: Mokdad A H, et al. J Am Med Assoc 2001;286:10

49. Self-reported Sleep and the Prevalence of Obesity in the US 9 25% 20% 8 15% Sleep (hours) Obesity prevalence 7 10% 6 5% Sleep (adult) Obesity 0% 5 1950 1960 1970 1980 1990 2000 2010