What do we know about the sensitivity of our clocks to light and other stimuli?



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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…

  • 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…



What do we know about the sensitivity of our clocks to light and other stimuli?

  • What do we know about the sensitivity of our clocks to light and other stimuli?

  • What do we know about the health consequences of clock desynchrony?

  • How can we apply our knowledge of clock synchrony mechanisms to our benefit?



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.

  • 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.







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).

  • 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).





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, 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?



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).

  • 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).



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)

  • 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)



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.

  • 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)



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

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



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).

  • 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).



Humans exhibit a PRC to light similar to other organisms (Khalsa et al 2003).

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







Light signals to reset our circadian clocks are transduced by specialized cells and a pigment (melanopsin) in our retinas.

  • 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.



What do we know about the sensitivity of our clocks to light and other stimuli?

  • 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?



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

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



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

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



Jet lag also induces “transient internal desynchronization”

  • Jet lag also induces “transient internal desynchronization”

  • (Pittendrigh, 1981).



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

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



Repeated jet lag can shrink your brain!

  • Repeated jet lag can shrink your brain!

  • Cho (2001)



Repeated jet lag can dumb you down! Cho 2001.

  • Repeated jet lag can dumb you down! Cho 2001.



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

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



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

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



Health Effects of Shiftwork

  • 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.



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).

  • 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.



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.

  • 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.



What do we know about the sensitivity of our clocks to light and other stimuli?

  • 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?































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.

  • 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.





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