LIGHT timing for circadian entrainment

Basically, this much is pretty obvious now: LIGHT and food in the morning + darkness after sunset = proper circadian entrainment.  But the how is pretty cool; LIGHT affects different biochemical pathways at different times of the day, which is how it can either advance or delay your circadian phase.

LIGHT entering the eyes is perceived by ipRGCs which then dish out glutamate and PACAP.  These mediators go on to activate receptors in the SCN (the “Master Clock”).

Depending on the time of day, glutamate and PACAP affect different pathways.



It took me a seriously long time to work through the following graphic:



Fortunately, I found a few articles breaking down the individual components.

LIGHT at pre-sunrise (“late night”), during the dark-to-light transition AKA sunrise, and even in the early afternoon: the most important mediator is PACAP, which activates PAC1 receptors and cAMP -> PKA -> transcription of circadian genes and voila, phase advance.

Interestingly, activating this pathway downstream of PACAP at night doesn’t work, and it’s thought that PACAP is responsible for “sensitizing” the PKA pathway specifically for daytime activation (eg, Michel et al., 2006).



Glutamate hits SCN NMDA receptors which, via calcium signalling, makes nitric oxide -> guanylate cyclase -> PKG -> transcription of circadian genes and voila, phase advance.

Interestingly, in the early evening or at sunset, light-induced glutamate-nitric oxide targets ryanodine receptors (as opposed to guanylate cyclase) which release calcium and activates ERK signaling -> transcription of circadian genes and voila, phase DELAY!





Nitric oxide at night: PKG & phase advance.

Nitric oxide in the morning: ERK & phase delay.


NO day night


PACAP at night: PKA & phase delay.  And it seems you can’t do this by activating PKA downstream of PACAP — light-induced PACAP is essential for this.

How does melatonin come into play?  One way is via directly activating SCN melatonin receptors -> induce potassium influx -> inhibition of neuronal firing -> sleep induction.  Interestingly, potentially an overlapping role for vasopressin and other blood pressure modulatory hormones here.

The exact reasons aren’t known why light-induced nitric oxide does ryanodine, ERK, & phase delay in the early evening vs. guanylate cyclase, PKG, and phase advance in the early morning.  But it’s still pretty cool, imo.



A little non sequiter from review articles (or just more terms to keep in mind):


1. “Day domain” – PACAP, PKA, phase advance

2. “Night domain” –
2a) muscarinic acetylcholinergic receptor, PKG, phase advance
2b) nitric oxide: phase advance if early morning, phase delay if early evening

And all of this initiated by LIGHT!  Now at least we know some of the pathways:





Daytime: SCN reduced (eg, NADPH, reduced glutathione, melatonin “sensitizes” the system), increased neuronal activity, SCN fuel use doubled.

Night: SCN oxidized (eg, NADP+, oxidized glutathione), reduced SCN neuronal activity.

Keep an eye out for PACAP and REV-ERB alpha in the future of research into circadian biology; I think they’re important.

that’s all, for now

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  • Jack Kruse

    You said, ” Nitric oxide at night: PKG & phase advance.
    Nitric oxide in the morning: ERK & phase delay.”

    “The exact reasons aren’t known why light-induced nitric oxide does ryanodine, ERK, & phase delay in the early evening vs. guanylate cyclase, PKG, and phase advance in the early morning.”

    My response: UV light makes things in a cell more transparent to scattering. This is daytime adaptation for a deep reason. With red light or IR light, that should dominate night time due to its persistence night or day and its release from our mitochondria when we are ketotic, this make cell less transparent or opaque.

    I have deep sense that transparency and opaqueness is the basis of how cells tell night and day inside cells to form the basis of all circadian signaling. The memory of these cycles is buried in water’s hydrogen bonding network as a molecular mirror.

    • Jack Kruse

      Why do I believe this? The physics of organisms and how light works at surfaces and inside a cell where EZ water become like a quasi crystal. Crystals are anisotropic. The optical properties of a tissue affect both diagnostic and therapeutic applications of light.

      The ability of light to penetrate a tissue, interrogate the tissue components, then escape the tissue for detection is key to diagnostic applications. The ability of light to penetrate a tissue and deposit energy via the optical absorption properties of the tissue is key to therapeutic applications. Hence, specifying the optical properties of a tissue is the first step toward properly designing devices, like the Quantlet.

      The second step is to use the optical properties in a light transport model to predict the light distribution and energy deposition.

      Research has tabulated the optical properties of absorption, scattering, anisotropy, reduced scattering, refractive index of various tissues measured at some/many wavelengths and such tabulations have been useful for clinicians who understand how to use it. My position is that most clinicians have no idea how the optics of thick skin in diabetes and psoriasis differs or is similar.

      Research used math to tabulate optical properties but does nature use math to in vivo? No it does not. This raises the question: With time, light, diurnally, and seasonal alters the surfaces that interact with light. The system is way more dynamic than even we appreciate right now in medicine.

      Tabulated values may not be accurate due to measurement artifacts. Moreover, the living tissue of a particular person is subject to variations in blood content, water content, collagen content and fiber development. The tabulated values may not include the specific wavelength of interest during the day or the season.

      For example we know that diabetics are quite dehydrated and loss water via urination and improper sweating. Psoriasis patients are also dehydrated but at not as severe level. Since water is anisotropic, how does this make thickness of the skin and hydration unique variables few clinicians even think about? They do not understand the physics of surfaces of organisms. When you look at graphs that plot anisotropy versus wavelength we see something physically that is hard to believe. There is a lot of variation in the data on tissues, but in general the values of anisotropy are rather high. There appears to be a trend toward increasing anisotropy as the wavelength increases. This observation, if true, is surprising from a physics perspective. This means red light makes water more liquid crystalline. It begins to make sense why red light is the optimal chromophore for water.

      If the small sub-wavelength structures within a cell are scattering light (water), then as the wavelength increases toward UV ranges the ratio of structure size to wavelength should decrease, and the scattering should become more Rayleigh-like, (i.e. the lower anisotropy will be) . Why does anisotropy increase with increasing ?? This is one of the reasons why I am intrigued with why all stressed cells release ELF-UV. It is one of the greatest mysteries I have uncovered in the last decade. I believe it is the key to understand brain diseases like GBM, MS, and neuro-degeneration.

      This contradiction between experiment and expectation is, in my opinion, an opportunity to better understand the nature of light scattering in tissues. The optics of light is believed to be well understood but my belief is there is an aspect of light we still are clueless about because of this finding.

      Perhaps the Mie scattering from the nuclei dominates in certain experiments, which keeps anisotropy high. Perhaps the size and shape changes of the mitochondria also change the optics to lead to epigenetic programing? I personally believe this is the trap door to understanding epigenetic I think it is 100% a non linear optical function of cells. Perhaps there is some mesoscopic scale of structure in tissue, ?10 ?m, that generates constructive interference so that more light is forward-scattered and hence the anisotropy increases?

      The efficiency of the smallest scatterers inside our cells, decreases as ? of light increases, and perhaps their contribution to the apparent anisotropy simply diminishes, yielding a higher anisotropy at longer wavelengths. This means that the main difference between UV and IR light in the solar spectrum maybe how much anisotropy is developed within a cell for optical signaling.

      We already know anisotropy is a huge factor because of its importance in microscopy and interferometry, more studies on anisotropy should be a priority to understand quantum biologic processes.

      • Joe Gavin

        Jack, could Planck’s Radiation Law relate to what you wrote above regarding scattering and wavelength?

        • Jack Kruse

          I believe so. Our cells are a play ground for photons from the sun. This makes cells like a “medical spa” for wave forms using a vortex. Vortex are understood using mathematics, but they are essentially a torus or circular. The juno probe showed us a toroid vortex on Jupiter’s pole today. The wave function of all electromagnetic radiations are at a 90 degree angle to the electric field and the magnetic field, both of which function at a 90 degree angle to each other. This is why atoms combine in a crystalline shape. It is why water in cells is anisotropic and liquid crystalline in nature. Crystals seek out a primary shape, trying to approximate the spiraling circle. Fibonacci’s sequence is sacred geometry for this reason. Everything in the universe starts out as a circle. The circle keeps dividing to form crystalline shapes. When we figure out how the crystalline shapes in the cells of our bodies are formed through the action of light waves, we will have figured out life’s greatest mystery. Consciousness.

          • Jack Kruse

            Magnetism is orthogonal to electric current for one major reason: Local geometry can then be preserved and this preserves nature’s symmetry as a collateral event. When intersecting or lying at right angles, a matrix can preserves length or distance, and this is important with respect to time and geometric scale. It is critical to motion. At large scales, this orthogonal relationship remains tight. At the smallest scales, in mitochondria, this relationship dissipates. This is why gravity exists at cosmic levels and is feeble at the smallest scales. At the larger scales in the cosmos, where humans exist and observe nature, using their senses, they are all attuned to using specific wavelengths in electromagnetic fields on Earth that defines our sensory experience. These specific wavelengths are designed to propagate in electric and magnetic field of action found on Earth. That native environment allows for the preservation and precision in motion of things we observe. This implies that the physics of other worlds will offer our sense different field of actions, and what we observe may not be reality at all. They maybe asymmetric illusions created by the interaction of sunlight and the electric and magnetic fields of this alien environment. This notion of intersecting things, like waves and new fields, that our nature isn’t accustomed too, goes beyond the normal quantum bliss our brain expects. When you begin to intersect things that haven’t been mixed before, new possibilities arise in biology, and maybe in the world’s ecosystem too. Within those new possibilities are new solutions to longstanding problems and new opportunities that can reshape outdated protocols. This is how epigenetics is fundamentally organized and changed by light and electromagnetic fields. These new interactions create evolution. In fact, evolution may occur just by changing large scale geometry of waves by shrinking them in small scales, creating new matter using light as its only source. I believe that formation occurs on water as a molecular mirror for light. Water at interfaces inside and outside of cells are the key to life. Why do I say this? Water at interfaces, such as membranes, must be in the excited state, requiring considerably less energy to split than water in the ground state. A sign of the excited water (EZ) is that a voltage should appear at the boundary between interfacial water and bulk water, which has indeed been observed now in experiments hundreds of times. EZ water surrounds our respiratory proteins in mitochondria. Even mitochondria have been shown to have diurnal changes associate with them. they too exhibit transparent and opaque times and both are linked to the presence or absence of light.

    • Jack Kruse

      In cosmology it is believed that UV light from stars eventually ended the dark ages of the early universe and made nebula more transparent and lit up the cosmos. I have a sense the same thing is true in cells between night and day. This changes their optical density and this is how circadian changes are truly accounted for using optics.

    • ? I wear my sunglasses at night ?

  • Jason Coates

    Proof again that the human skin is not just the casing on a human meat sausage. 🙂

  • rs711

    good explanation Bill

  • Eric – Golden, CO

    I’m about 1/2 way through Lights out: sleep, sugar, and survival and there is much talk about cryptochromes. I’m not seeing the connection in your post. Is there one? Sorry I don’t have enough background yet to formulate the question any better.

    • cryptochromes are circadian rhythm-related proteins that respond to light. Some respond directly to light/photons, others are downstream, but they’re all involved in circadian entrainment.

      P.S. I love that book!

  • Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs