S-cones and the circadian system

It is relatively well known that exposure to light, especially blue-green light, can influence the master clock of the circadian system and block melatonin production by the pineal gland. The discovery of the photo-pigment melanopsin in rodents was exactly related to this topic since it was first identified in rodents that lacked sensitivity to light yet, were capable of circadian entrainment. We completed a recent blog post about Melanopsin and Retinal ganglion cellsthat provides a basic understanding of the topic but there are other cells in the retina that are also sensitive to short wavelength light exposure, the S-Cones. In this post, we would like to review some of the most recent scientific papers about the potential role of S-cones (blue-cones) in the regulation of the circadian system.

Retinal cones, cone cells, or simply “cones”, are light receptor cells (photoreceptors) that are present in the retina. Cones react differently to light of different wavelengths, and are responsible for color vision. There are three types of cones:

• L-Cones: also known as red-cones, are the most common ones and respond to light with longer wavelength; the letter “L” stands for “long”. Sensitivity of L-cones peaks at 560 nm.
• M- Cones: also known as green-cones, are the second most common type of cones and have a peak sensitivity with light at 530 nm of wavelength.
• S-Cones: or blue-cones, account for only 2% of the total population of cone cells and have a peak sensitivity for light with a wavelength between 420 and 440 nm.

Some of the initial papers that described the role of melanopsin, looked at the action spectrum of melatonin suppression and the evidence pointed clearly towards the existence of a mechanism that was independent of cones and rods. We all agree that circadian function and melatonin suppression are “mainly” driven by melanopsin but: can we say that other cones are not involved in melatonin suppression at all? Here is some of the evidence:

No role for S-Cones:

Spitschan et al designed a very elegant experiment that consisted in exposing subjects to two light sources with different levels of S-cone stimulation. One stimulus involved low activation of the S-cones while the other one activated provided maximal stimulation of the S-cones. Both stimuli provided the same degree of stimulation to other cones (L and M), rods, and melanopsin. In order to study the circadian impact of S-Cone activation, the authors look at the melatonin secretion profile of 15 subjects. The authors did NOT find a difference in the melatonin profile of the subjects based on the level of S-cone stimulation profile. There was also no difference in the level of alertness or sleepiness that was observed with either maximal stimulation of the S-Cones or Low- Stimulation.

Some role for S-Cones

Mouland et al studied the role that naturalistic color changes could play in circadian regulation using mice with altered cone spectral sensitivity (Opn1mwR).  During the experiment, the authors varied the spectral composition of light in order to change the degree of activation of L-cones without changing the activation of rods or melanopsin. The authors were able to alter the circadian system by changing the degree of activation of the S-Cones without changing the activation of melanopsin. The authors hypothesize that changes in color composition (yellow vs blue) are used by mammals to entrain the mast clock.

Brown et al published results of a recent experiment involving six healthy male participants. During the experiment, the authors exposed the subject to 30 minutes of blue light with a wavelength of 415 nm and changed the level or irradiance. The authors then compared data from this experiment with previous data about the action spectrum of melanopsin and proposed a model in which melanopsin and S-cones both contribute to melatonin suppression with a 2:1 ratio.

Conclusions:

It is important to mention that all the experiments that were discussed here are subject to some limitations. This discussion is not settled yet, the field of visual research related to color generation and retinal cones is significantly older and more robust than our knowledge about the circadian system, melanopsin, and retinal ganglion cells. The mere existence of melanopsin was not known just a few years ago. While the role of S-cones in circadian regulation can be the subject of some controversy, the reality is that the exact group of cells that control circadian input is not very relevant, at the end what matters is that exposure to blue light can affect the circadian system and suppress melatonin production by the pineal gland.

References:

• Brainard G.C., Hanifin J.P., Greeson J.M., Byrne B., Glickman G., Gerner E., Rollag M.D. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J. Neurosci. 2001;21:6405–6412. [PMC free article] 
• Thapan K., Arendt J., Skene D.J. An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J. Physiol. 2001;535:261–267. [PMC free article] 
• Hull J.T., Czeisler C.A., Lockley S.W. Suppression of melatonin secretion in totally visually blind people by ocular exposure to white light: clinical characteristics. Ophthalmology. 2018;125:1160–1171. 
• Spitschan M, Lazar R, Yetik E, Cajochen C. No evidence for an S cone contribution to acute neuroendocrine and alerting responses to light. Curr Biol. 2019;29(24):R1297-R1298. doi:10.1016/j.cub.2019.11.031
• Mouland JW, Martial F, Watson A, Lucas RJ, Brown TM. Cones Support Alignment to an Inconsistent World by Suppressing Mouse Circadian Responses to the Blue Colors Associated with Twilight. Curr Biol. 2019;29(24):4260-4267.e4. doi:10.1016/j.cub.2019.10.028
• Brown TM, Thapan K, Arendt J, Revell VL, Skene DJ. S-cone contribution to the acute melatonin suppression response in humans.J Pineal Res. 2021 Jan 29:e12719. doi: 10.1111/jpi.12719.