Circadian Entrainment or Keeping Your Clock in Synch

1. Circadian EntrainmentorKeeping Your Clock in Synch Doug McMahon Department of Biological Sciences Vanderbilt University

2. Background The Daily Light/Dark cycle is the most powerful synchronizer of our circadian clocks. In the natural environment the regular alternation of light and dark (as surely as night follows day…) both reinforces the internal clock mechanism and sets it to local time. However, in our modern world we have invented “disruptive technologies” that expose our clocks to conflicting “unnatural” signals – the light bulb and light at night; the jet airplane and rapid trans-meridian travel. In this session we will consider…

3. Topics • What do we know about the sensitivity of our clocks to light and other stimuli? • Physiology – Specialized Retinal Cells • Timing - Phase Response Curves • What do we know about the health consequences of clock desynchrony? • Jet Lag, Shift Work, Light at Night • How can we apply our knowledge of clock synchrony mechanisms to our benefit?

4. Take Home Messages • Light is the strongest signal to our circadian clock. Our clocks are most sensitive to blue light. Light at night is an unnatural stimulus that can reset or desynchronize our clocks. • While acute jet lag is an inconvenience, there is growing evidence that long-term repeated exposure to clock desychronization through shift-work or light at night can have adverse health consequences. • By regulating the timing, brightness, and spectrum (color) of light exposure we can help our clocks stay in synchrony in our 24.7 modern world.

5. The Clock System

6. “Science as something already in existence, already completed, is the most objective, impersonal thing that we humans know. Science as something coming into being, as a goal, is just as subjectively, psychologically conditioned as are all human endeavors.” Albert Einstein Circadian Photoreceptors: A Tale of Scientific Dogma, Heresy, Excommunication and Redemption

7. Circadian Photoreception Occurs in the Eye • In mammals circadian phototransduction occurs in the eye and neural signals are conducted along the Retino-Hypothalamic Tract to the biological clock nucleus of the brain, the suprachiasmatic nucleus (SCN).

8. Circadian Photoreception Persists in Blind Mice! Freedman et al. 1999 Yoshimura and Ebihara, 1996 Russell Foster

9. Melanopsin: A Novel Vertebrate Photopigment With an Invertebrate-like Sequence • Melanopsin, a novel photopigment is cloned first from frogs (Provencio et al 1998), and its then in humans and mice (Provencio et al. 2000). • Melanopsin was related to, but clearly different from, rod and cone opsins. • Where was it expressed in mammals?

10. Melanopsin: A Novel Vertebrate Photopigment • Melanopsin antibody staining revealed a population of dispersed ganglion cells with large dendritic trees and prominent axons that comprised a small proportion (<2%) of GANGLION CELLS in mouse and rat (Provencio et al., 2002).

11. Melanopsin-Expressing Ganglion Cells are the Ganglion Cells that Project to the Biological Clock Nucleus • Expression of a tau lac-z transgene in melanopsin neurons showed they were indeed ganglion cells that projected their axons to the SCN. (Hattar et al., 2002)

12. Melanopsin Ganglion Cells are Intrinsically Photosensitive! • Electrophysiological recordings from melanopsin ganglion cells, identified with retrograde tracer from the SCN, revealed that melanopsin GC’s responded to light with depolarizing light responses even when all synaptic transmission from rods and cones was chemically blocked and when GC’s were physically isolated from all other retinal cells. • (Berson et al. 2002)

13. Human Circadian Photoreception • SCN-projecting ganglion cells contain melanopsin in humans (Hannibal et al 2004) and in primates (Dacey et al., 2005)

14. Human Circadian Photoreception • The human circadian system is most sensitive to blue light similar in wavelength to the melanopsin peak as measured by light suppression of plasma melatonin (Brainard et al., 2001; Lockley et al., 2003).

15. Entrainment - Light • Humans exhibit a PRC to light similar to other organisms (Khalsa et al 2003).

16. Entrainment - Melatonin

17. Phase-Response Curves Box = sleep time; Arrowhead = body temp minimum; Up Arrow = melatonin onset; Advance = setting your clock forward Delay = setting your clock back Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255.

18. Summary 1 • Light signals to reset our circadian clocks are transduced by specialized cells and a pigment (melanopsin) in our retinas. • Our clocks are sensitive to all wavelengths of light, but are most sensitive to blue light. • In terms of timing, our clocks are most sensitive to light exposure at night, which can reset or disrupt the timing of our biological clocks. • The hormone melatonin can be thought of as a biological signal for darkness as it is normally secreted at night. • Melatonin pills during the day can reset our clocks.

19. Topics • What do we know about the sensitivity of our clocks to light and other stimuli? • Physiology – Specialized Retinal Cells • Timing - Phase Response Curves • What do we know about the health consequences of clock desynchrony? • Jet Lag, Shift Work, Light at Night • How can we apply our knowledge of clock synchrony mechanisms to our benefit?

20. “Jet Lag” • Crossing 3 or more times zones in one day can induce physiological malaise called “jet lag”.

21. “Jet Lag” • A primary cause of jet lag is “external desynchrony” – having your internal rhythms out of synchrony with local environmental time.

22. “Jet Lag” • Jet lag also induces “transient internal desynchronization” (Pittendrigh, 1981).

23. “Jet Lag” • Jet lag can turn you into a “loser” (Recht et al., 1995).

24. Chronic “Jet Lag” • Repeated jet lag can shrink your brain! • Cho (2001)

25. Chronic “Jet Lag” • Repeated jet lag can dumb you down! Cho 2001.

26. Shift Work • Like repeated jet lag, night shift and rotating shift work pose extreme challenges to the human circadian system.

27. Shift Work • Efficiency is lowest and accident risk is highest near the normal phase of the body temp. minimum (Folkard and Akerstedt, 1991).

28. Shift Work • Health Effects of Shiftwork • 2x increase in peptic ulcers. • 40% increase in cardio. • Increase in risk of premature births. • No overall increase in cancer risk or mortality, but increased risk for specific forms of cancer (next slide). • Knuttson et al., 2003.

29. Shift Work • While there is no strong evidence of an overall increase in cancer risk with shiftwork, studies have indicated an increased for some specific forms of cancer, in particular breast cancer risk for female shiftworkers (flight attendants and nurses; Davis et al., 2001; Schernhammer et al., 2001). • Animal and cell culture studies have shown that melatonin suppresses growth of breast tumor cells in vitro and in vivo. • This has led to the World Health Organization declaring shift work and circadian disruption as a “probable carcinogen” in humans. • http://www.iarc.fr/en/media-centre/pr/2007/pr180.html • And to the “light at night” hypothesis of increased breast cancer risk.

30. Summary 2 • Our clocks can only reset by about 1 hour/day so rapid travel across multiple time zones produces “jet-lag” until our clocks can re-align. • “Jet lag” is a temporary external and internal disruption due to mis-alignment of our clocks with the environment. • Long-term misalignment through shift-work or light at night can contribute to long term adverse health consequences that include increased risks of ulcers, cardiovascular disease and breast cancer.

31. Topics • What do we know about the sensitivity of our clocks to light and other stimuli? • Physiology – Specialized Retinal Cells • Timing - Phase Response Curves • What do we know about the health consequences of clock desynchrony? • Jet Lag, Shift Work, Light at Night • How can we apply our knowledge of clock synchrony mechanisms to our benefit?

32. Tools for Synchrony Knowing the spectral and temporal sensitivity of our clock to light we can regulate our light exposure to promote and maintain synchrony of our internal clock with our environment. Our clocks are most sensitive to blue light. Our clocks are most affected by light at night from about 9PM to dawn.

33. Tools for Synchrony To Maintain and Reinforce our internal clock’s synchrony with our local environment: Daytime – maximize exposure to outdoor light, or indoor light with blue spectral component (“Daylight” bulb, color temperature 5000K or greater). Nighttime – minimize circadian clock light input past 9PM using “Soft white” bulb, color temperature 2500K which has reduced blue. Reduce blue in device screens using f.lux or other programs. Benefits – increased alertness in the day, increased sleep quality at night

34. Tools for Synchrony Fighting Jet Lag: 3 Strategies Plan ahead – pre-shift your clock to the new time (Dr. Malow). Rapidly re-establish synchrony with your local environment after travel. Don’t Shift – for short trips, just stay on your own time.

35. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

36. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 0 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

37. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 1 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

38. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 2 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

39. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 3 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

40. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 4 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

41. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 5 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

42. Tools for Synchrony Rapidly re-establish synchrony with your local environment after travel through regulation of light exposure and melatonin. Day 6 Paris Light Cycle Light Regulation Chicago Eastman CI, Burgess HJ. Sleep Med Clin. Sleep Med Clinics 2009 4(2):241-255. M = melatonin; D = Dark; S = sunlight; Arrowhead = body temp min; Pink = sleep

43. Formula One news Alonso won't adjust to local time zone in Singapore 22 September 2008Fernando Alonso has picked an interesting approach to the upcoming Singapore Grand Prix. The Renault F1 driver will not try to adjust to the local time zone but will try to remain on a European schedule to be as fit as possible for the race at night. Speaking about his preparations Alonso explained: "I have worked with my physiotherapist and other members of the team to decide the best way to manage the race weekend, especially in terms of sleep. In the end I've decided not to adjust to the local time zone and to remain on a European schedule, which will be best for my energy levels. Getting this right is an important element for the race, both for the drivers and members of the team. Post-script – Alonso went on to win the race!

44. Tools for Synchrony To invert your internal clock’s synchrony with our local environment (night shift): Nighttime – maximize exposure to indoor light with blue spectral component (“Daylight” bulb, color temperature 5000K or greater). Daytime – minimize circadian clock light input. Darkening shades, sunglasses that filter blue if you must go out in the day. Bulbs with minimal blue (soft white color temp 2500K).

45. Tools for Synchrony To fight the “winter blues”: Extend the “day” by early morning exposure to light with blue spectral component (“Daylight” bulb, color temperature 5000K or greater).

46. Take Home Messages • Light is the strongest signal to our circadian clock. Our clocks are most sensitive to blue light. Light at night is an unnatural stimulus that can reset or desynchronize our clocks. • While acute jet lag is an inconvenience, there is growing evidence that long-term repeated exposure to clock desychronization through shift-work or light at night can have adverse health consequences. • By regulating the timing, brightness, and spectrum (color) of light exposure we can help our clocks stay in synchrony in our 24.7 modern world.