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Principal circadian oscillators in mammals.

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Almost all species exhibit daily changes in their biological activity with respect to a 24 hour light-dark cycle known as the circadian rhythm. The synchrony of an organism with both its external and internal environments is critical for the organism’s well-being and survival.
The presentation focuses on the fundamentals of circadian rhythm, components, development, molecular mechanism, functional and clinical implications of this astonishing system.

Published in: Science
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Principal circadian oscillators in mammals.

  1. 1. Principal circadian oscillator in mammals Subhadeep Dutta Gupta M.Phil Scholar Department of Neurophysiology, NIMHANS
  2. 2. tg
  3. 3. Introduction: • Physiological processes exhibit cyclic variation over time, ranging from hours to years. • This feature is ancient and ubiquitous. • Types of biological rhythms: -- Ultradian rhythm : shorter than a day -- Circadian rhythm : occurs once a day -- Infradian rhythm : occurs monthly -- Circannual rhythm : occurs yearly
  4. 4. Circadian Rhythm: • Physical, mental & behavioral changes that follow a roughly 24 hr cycle responding to light & darkness of the organism. • Latin word: ‘Circa’ means around and ‘diem’ means day. • Very essential for survival of organisms under natural conditions.
  5. 5. Historical background: • Greek poet Archilochus (675–635 BC) : author of the oldest written record of observations in circadian physiology. • Androsthenes of Thasus (4th century BC): recorded his observations of daily movements in plant leaves. • Jean-Jacques de Mairan (1678-1771) : daily rhythms may be endogenously generated ………. Mimosa pudica • Augustin Pyramus de Candolle (1778–1841) : period of the rhythm slightly shorter than 24 hours ………. existence of endogenous circadian rhythm.
  6. 6. h • John Davy (1844) : recorded his own body temperature in the morning and evening every day for 9 consecutive months. • Rogers & Greenbank (1930) : reported the existence of a daily rhythm of growth in colonies of bacteria (Escherichia coli).
  7. 7. g• Nathaniel Kleitman, (1938) : physiology of sleep and circadian rhythm Kleitman at work in Mammoth Cave, Kentucky (150 feet underground).
  8. 8. Properties of Circadian rhythm: • A rhythm with a periodicity ~ 24 hours, even in the absence of external time cues (Zeitgebers) [called a free-running rhythm]. • Reset by changes in environmental conditions, most notably the daily light-dark and temperature cycles. • Have an invariant period length over a wide range of physiologically relevant temperatures. -- Nat Rev Genet. 2005 Jul; 6(7): 544–556
  9. 9. Entrainment:
  10. 10. Concept of circadian oscillator: • Biological processes occurring within many cells and tissues that have the capacity to oscillate with a wide variety of periodicities. • They show peak-to-peak intervals, or periods of activity. • Circadian oscillators, express periods of ~ 24 hours and form the circadian biological clock.
  11. 11. Basic parts of circadian clock: • An input pathway -- receives environmental cues and transmits them to the circadian oscillator. • A circadian oscillator -- keeps circadian time and activates output pathways, & • Output pathways -- control various metabolic, physiological and behavioural processes. -- Fed. Proc.1979 (38), 2570-2572
  12. 12. Hierarchy of circadian system: -- Nature Reviews Neuroscience (13) 2012, 325
  13. 13. Suprachiasmatic Nucleus: • The central oscillator, or master clock, is located in the Suprachiasmatic Nucleus (SCN). • Small bilateral nuclei located in the rostral hypothalamic region, superior to the optic chiasma.
  14. 14. -- Paxinos & Watson,The Rat Brain; 5th Ed Location:
  15. 15. Location:
  16. 16. Time course of circadian development:
  17. 17. Evidences for SCN as principal circadian pacemaker: • Site of termination of a critical entrainment pathway. • Ablation of SCN abolishes circadian rhythm in many functions viz.. Sleep-wake cycle. • Isolated SCN neurons maintain circadian control of firing rate. • Transplantation of fetal SCN into the 3rd ventricle of an arrhythmic host with SCN lesion re-establishes rhythmicity. -- Brain Res Rev; 2005; 49(3):429-54.
  18. 18. Anatomy of SCN: • Two major subdivisions in mammals: A) Dorsomedial (Shell) B) Ventrolateral (Core) • Each SCN has a volume of less than 0.3 mm3. • Each SCN houses approx 10,000 (in rats)-50,000 (in human) neurons. DM (Shell) VL (Core) 3V OC
  19. 19. k Gap junction between SCN neurons. -- Neuroscience, 2004; 123: 87–99.
  20. 20. Connections of SCN :  Afferent pathways: -- Textbook of Circadian Physiology 2nd Edn
  21. 21. f• Other inputs from:  Limbic system  Pretectum  Paraventricular thalamic nucleus
  22. 22. u  Efferent pathways: -- TRENDS in Neuroscience 2005 (28) 3.
  23. 23. Hamster Mouse Rat Firingrate(Hz) Circadian time (hour) 8 0 12 24 Circadian variation in firing rate of SCN neurons: 8 0 12 24 8 0 24 Circadian rhythmicity in the SCN cells has been documented by electrophysiological recording. Functional properties of SCN neurons: -- Journal of Comparative Physiology ,2004; 190: 167–171
  24. 24. h• Greater proportion of rhythmic cells in the shell region than in the core region (Nakamura et al., 2001). • The RMP of SCN neurons is approximately –50 mV. • Firing rate: -- Subjective day : 8 Hz -- Subjective night : 2 Hz (Saeb-Parsy & Dyball, 2003)
  25. 25. Firing pattern of SCN neurons: • Most cells fire regularly, but some fire irregularly. • Contradictory role of GABA - both excitatory and inhibitory (Wagner et al., 1997). Single cell activity in brain slices of Rattus norvegicus exemplify the regular and irregular firing patterns of SCN neurons. -- Journal of Neurophysiology, 2004; 91: 267–273.
  26. 26. Activity of isolated SCN neurons: • Circadian variation in firing rate of four individual neurons in a dissociated culture system of SCN cells from the laboratory rat. • The overall period of the circadian oscillation generated by the SCN is the average of the period of the various cells. -- Neuron, 1995; 14: 697–706.
  27. 27. Neurochemistry of SCN: Major Neurotransmitters:  GABA  Arginine Vasopressin  Vasoactive Intestinal Polypeptide Other neurotransmitters:  Gastrin-releasing peptide  Somatostatin  Thyrotropin-releasing hormone  Angiotensin  Nitric oxide  Neuromedin U
  28. 28. Neurochemical subdivision -- Physiol Rev, 2010 (90): 1063-1102
  29. 29. Interaction with the Pineal Gland: -- Neurology 2008 (71), 594-598
  30. 30. What makes the clock tick? A simple molecular loop
  31. 31. Molecular circadian clock in mammals: --- TRENDS in Pharmacological Sciences 2013 (34), 11;605-619.
  32. 32. hh Clinical Implications
  33. 33. Circadian clock: Ageing and Cognitive functions. -- Nature Reviews Neuroscience (13) 2012, 325
  34. 34. Circadian clock-dependent regulation of neurodegeneration: -- Nature Reviews Neuroscience 2012 (13), 325
  35. 35. Circadian clocks as tumor suppressors: -- Nature, 2003 (3) 350- 361
  36. 36. Circadian disorders: • Common in elderly, blinds, and individuals with hypothalamic, pituitary, or optic tumours.  Circadian sleep disorders -- delayed or advanced sleep phase syndrome  Shift Work disorder -- insomnia during their off hours and hypersomnolence during their work hours. -- gastrointestinal discomfort
  37. 37. j Seasonal Affective Disorder/ Winter Depression • Depression • Lethargy • Hypersomnia • Weight gain • Carbohydrate cravings • Anxiety • Inability to concentrate and focus.
  38. 38. So……let there be ‘LIGHT’: • Bright light exposure (10,000 lux ; 30-120 minutes/ day) • Effective for patients suffering from: -- Sleep disorder -- Seasonal Affective disorder -- Bipolar disorder -- Neuropsychobiology 2011;64:152–162
  39. 39. Chronotherapy: • Use of circadian cycle in therapeutic application. • Medications prescribed a/c to the patient’s rhythm to maximize effectiveness. • Reduces side effects. • Effective in hypertension, asthma & depression.
  40. 40. f17th January, 1995 ----- Kobe earthquake, Japan In mice & catfish, drastic increase in locomotive activities during sleep and active periods before the earthquake began. Role of SCN in those animals’ perception?? -- Bioelectromagnetics 2003; 4(24):289-91
  41. 41. Bibliography: • Eskin, A. (1979). Identification and physiology of circadian pacemakers. Fed. Proc. 38, 2570-2572. • Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet. 2005 Jul; 6(7): 544–556. • Jobst, E. E., Robinson, D. W. & Allen, C. N. Potential pathways for intercellular communication within the calbindin subnucleus of the hamster suprachiasmatic nucleus. Neuroscience, 2004; 123: 87–99. • Burgoon, P. W., Lindberg, P. T. & Gillette, M. U. (2004). Different patterns of circadian oscillation in the suprachiasmatic nucleus of hamster, mouse, and rat. Journal of Comparative Physiology 190: 167–171.
  42. 42. g • Saeb-Parsy, K. & Dyball, R. E. J. (2003). Defined cell groups in the rat suprachiasmatic nucleus have different day/night rhythms of single-unit activity in vivo. Journal of Biological Rhythms 18: 26–42. • Kononenko, N. I. & Dudek, F. E. (2004). Mechanism of irregular firing of suprachiasmatic nucleus neurons in rat hypothalamic slices. Journal of Neurophysiology 91: 267–273. • Welsh, D. K., Logothetis, D. E., Meister, M. & Reppert, S. M. (1995). Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14: 697–706. • Bell-Pedersen, D., Cassone, V.M., Earnest, D.J., Golden, S.S., Hardin, P.E.,Thomas, T.L. and Zoran, M.J. (2005) Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet, 6, 544-556. • Young, M.W. and Kay, S.A. (2001) Time zones: a comparative genetics of circadian clocks. Nat Rev Genet, 2, 702-715. • Saper, Scammell & Lu. Hypothalamic regulation of sleep and circadian rhythms. (2005) Nature (437) 1257-1263.
  43. 43. h • Saper, Lu Chou and Gooley. TRENDS in Neurosciences Vol.28 No.3 March 2005. • Golombek DA, Bussi IL, Agostino PV. 2014 Minutes, days and years: molecular interactions among different scales of biological timing. Phil. Trans. R. Soc. B 369: 20120465. • Nakamura, W., Honma, S., Shirakawa, T. & Honma, K. (2001). Regional pacemakers composed of multiple oscillator neurons in the rat suprachiasmatic nucleus. European Journal of Neuroscience 14: 666–674. • Reciprocal interactions between the suprachiasmatic nucleus (SCN) and melatonin. Neurology 2008 (71), 594-598. • Mouse circadian rhythm before the Kobe earthquake in 1995. Yokoi S, Ikeya M, Yagi T, Nagai K. Bioelectromagnetics 2003 May; 4(24):289-91. • Gerald Pail Wolfgang Huf.Bright-Light Therapy in the Treatment of Mood Disorders Neuropsychobiology 2011;64:152–162. • Textbook of Circadian Physiology,2nd Edition, Roberto Refinetti.
  44. 44. d Feynman’s Conjecture: “The brain should have a master oscillator, like that found in a computer, that is responsible for coordinating the timing of all bodily activities”. -- Richard Feynman
  45. 45. h THANK YOU

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