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Horacio de la Iglesia Department of Biology horaciod@u.washington

Horacio de la Iglesia Department of Biology horaciod@u.washington.edu. Organization of living matter. Spatial organization has been an key concept from the earliest studies of biology, and particularly physiology.

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Horacio de la Iglesia Department of Biology horaciod@u.washington

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  1. Horacio de la Iglesia Department of Biology horaciod@u.washington.edu

  2. Organization of living matter Spatial organization has been an key concept from the earliest studies of biology, and particularly physiology. Temporal organization is more subtle and usually overlooked, but equally important. The fitness of an organism depends on its physical structure and its relationship with the environment. The time domain of this physical structure, and of the relationship with the environment, is as important as the structural domain. Time as niche variable.

  3. Wake Sleep Wake Sleep Days Sleep wake cycle in a human being Days The persistence of rhythms in the absence of environmental cycles is taken as evidence of an innate self-sustained timekeeping biological mechanism, that is a Biological Clock

  4. Output pathways Input pathways I IX III VI Components of a Generic Biological Timing System Clock (suprachiasmatic nucleus) Overt circadian rhythms (e.g. sleep-wake cycle) Environmental Cycle (e.g.. light-dark cycle) Photoreceptors (retina)

  5. Virtually all known hormones show a daily pattern of secretion

  6. LD cycle Period = 24 h Days Free running in constant conditions (DD or LL) Period circa-24 h 0 24 24 0 Clock time 48 Analysis of circadian rhythms locomotor activity in nocturnal rodents

  7. Output pathways Input pathways I IX III VI Components of a Generic Biological Timing System Clock (suprachiasmatic nucleus) Overt circadian rhythms (e.g. sleep-wake cycle) Environmental Cycle (e.g.. light-dark cycle) Photoreceptors (retina)

  8. The same circadian oscillator appears to control locomotor activity and estrous Fitzgerald and Zucker (1976) PNAS 73: 2923-2927

  9. Looking for the Circadian Clock • Lesions of suspected site should abolish rhythmicity • Transplants of suspected site should restore circadian rhythmicity in lesioned animals. • Intrinsic properties of the suspected clock should be rhythmic: in vivo and in vitro • Identification of molecular and cellular mechanisms that generate rhythmicity • Mutations of specific genes should affect circadian rhythms • There should be a pathway communicating the synchronizer with the clock

  10. Lehman (1987) J. Neurosci. 7:1626-38

  11. The SCN is necessary and sufficient for expression of locomotor activity circadian rhythmicity Ralph & Lehman (1991) Trends Neurosci. 14:362

  12. 0 24 Lesions of the SCN abolish all endocrine circadian rhythms ?

  13. SCN lesions abolish the rhythm of corticosterone release Moore (1972) Brain Research 42: 201

  14. The release of hormones is initiated in the brain: Daily gating of the LH surge as an example Everett and Sawer (1950) Endocrinol. 47:198

  15. The release of hormones is initiated in the brain: Daily gating of the LH surge as an example

  16. % of women showing an LH surge, as determined by urinary LH Edwards (1981) Nature 293:253-256

  17. SCN transplants that restore locomotor activity rhythms do not restore endocrine rhythms Meyer-Bernstein et al. (1999) Endocrinol 140: 207-218

  18. Identification of molecular components of the clock The first mammalian clock mutant is found • It is a semi-dominant mutation • Heterozygous mice in constant darkness have a longer period than wildtypes • Homozygous mice in constant darkness have initially a very long period and then become arrhythmic • Vitaterna et al. (1994) Science 264:719-725

  19. Transcription Translation mRNA - Clock gene 1 Inhibition Protein (positive element) Delay (~24 h) Translation Protein (negative element) mRNA + Transcription Clock gene 2 mRNA or Protein level Time Transcription and translation feedback loops constitute the core clock mechanism

  20. Light Per1 expression Dark This unparalleled localization of function within the SCN makes the circadian system unique for the study of the neural and molecular bases of behavior and physiology

  21. Splitting in the hamster De la Iglesia et al. (2000) Science 290:799-801

  22. UNSPLIT HAMSTER in situ (SCN) L R Left SCN haPer1 RNA level Right SCN Time Locomotor activity ~24 hours

  23. SPLIT HAMSTER in situ (SCN) Left SCN haPer1 RNA level Right SCN Time Locomotor activity ~24 hours

  24. Dual Circadian Oscillators in the SCN The ensemble of oscillators is reflected in overt behavior Mechanism and “sticking” force? Clock outputs?

  25. The HPG Axis Split female hamsters present a circa-12-h LH surge. Swann and Turek (1985)

  26. The SCN could have input the neuroendocrine hypothalamus

  27. SCN efferents project to LHRH cells and these projections are believed to mediate the release of LHRH that triggers the LH surge. • The projections are predominantly ipsilateral.

  28. de la Iglesia et al. (2003) J. Neurosci., 23:7412-7412

  29. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neural and diffusible outputs of the clock. de la Iglesia and Schwartz Endocrinology (2006) 147:1148-1153

  30. SCN lesions abolish the LH surge Intracerebroventricular vasopressin induces a surge in the SCN-lesioned animals van der Beek et al. (1999) Neuroscience 93: 659-666

  31. Endocrinology (2012) 153: 2839–2850

  32. Smarr et al.

  33. I IX III VI Input pathways SCN Overt physiological and behavioral rhythms (activity, feeding, core body temperature, sleep-wake) Synchronization of peripheral clocks Other entraining inputs Kidney Liver Skeletal muscle

  34. GnRH cells and the pituitary show autonomous oscillations ov clock gene expression Chappell et al. (2003) J. Neurosci. 23: 11202-11213 Yoo et al. (2003) PNAS 101-5339-5346

  35. Sellix et al. (2003) Current Biol. 20:R266-R267

  36. ERa ERa ERa ? AVP AVP The HPG Axis ? GnRH neurons (slave oscillators?) SCN neurons VIP GnRH Median eminence Portal system Anterior pituitary (Peripheral clock?) LH E2 de la Iglesia and Schwartz Endocrinology (2006) 147:1148-1153 Ovary (Peripheral clock?)

  37. Miller et al.

  38. The HPA Axis

  39. Light induces expression of clock genes in the adrenal Ishida et al. (2005) Cell Metabolism 2:297-307

  40. Light induction of corticosterone release is ACTH-independent

  41. Light induction of Per2 expression and of corticosterone release depends on a n intact SCN

  42. SCN control of glucocorticoid release

  43. Pineal Melatonin Melatonin tracks night length in humans

  44. Light acutely inhibits melatonin production When humans are given light during the dark phase or in complete darkness when melatonin is high, melatonin levels in the blood quickly drop. Czeisler (1995) N.E.J.Medicine

  45. Light acutely inhibits melatonin production When humans are given light during the dark phase or in complete darkness when melatonin is high, melatonin levels in the blood quickly drop. This is even observed in some blind patients. Czeisler (1995) N.E.J.Medicine

  46. Melatonin and artificial light in humans

  47. Melatonin is a night time signal

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