No evidence for an S cone contribution to acute neuroendocrine and alerting responses to light

Abstract

SummaryExposure to even moderately bright short-wavelength light in the evening can strongly suppress the production of melatonin and delay our circadian rhythm. These effects are mediated by the retinohypothalamic pathway, connecting a subset of retinal ganglion cells to the circadian pacemaker in the suprachiasmatic nucleus (SCN) in the brain. These retinal ganglion cells express the photosensitive protein melanopsin, rendering them intrinsically photosensitive (ipRGCs). But ipRGCs also receive input from the classical photoreceptors — the cones and rods. Here, in human participants, we examined whether the short-wavelength-sensitive (S) cones contribute to the neuroendocrine response to light by using stimuli which differed exclusively in the amount of S cone excitation by almost two orders of magnitude (ratio 1:83), but not in the excitation of long-wavelength-sensitive (L) and medium-wavelength-sensitive (M) cones, rods, and melanopsin. We specifically examined the S cones since the previously published action spectra for melatonin suppression [1,2] pointed to a possible role of S cones in addition to melanopsin. We find no evidence for a role of S cones in the acute alerting and melatonin-supressing response to evening light exposure.

Circadian Photoentrainment in Mice and Humans

“…Intracellular recording from the macaque retina has shown that melanopsin pRGCs are inhibited by the short-wavelength cones (S cones), whilst the rods and medium-wavelength cones provide an excitatory input [ 60 ]. By contrast, recent studies in humans have failed to find evidence for an S cone contribution to acute neuroendocrine and alerting responses to light [ 138 ]. Finally, multiple lines of evidence from behavioral studies have implicated an input from the rods and cones [ 40 , 139 , 140 , 141 ], not least the finding that Opn 4 -/- (knockout) mice still show circadian entrainment, albeit in an attenuated form [ 67 , 68 , 69 ].…”

<strong>Recommendations for Healthy Daytime, Evening, and Night-Time Indoor Light Exposure</strong>

“…In total, the evidence from such studies [29][30][31][32][33][34][35][36][37] supports the view that, under most practically relevant situations (extended exposures to polychromatic light in the absence of pharmacological pupil dilation), light-sensitivity of human physiological responses can be reliably approximated by the α-opic irradiance for melanopsin or the corresponding EDI (melanopic EDI). Moreover, based on the consistency of melanopic irradiance-response relationships across studies 32 , it is now possible to define realistic, evidence-based recommendations for light exposures that target non-visual responses.…”

“…While data from two such studies are compatible with the possibilities that S-cones 38 or the photopic system 24 may contribute alongside melanopsin, a large body of data with and without use of pupil dilation indicates that for exposures of an hour or more, melatonin suppression can be reliably predicted by melanopic EDI 31,32,39,40 . This conclusion is further strengthened by findings from recent studies that have employed photoreceptor isolating stimuli to confirm that melanopsin-selective modulations in irradiance modulate melatonin production 34,35 but failed to find any effect of large variations in irradiance selectively targeting S-cones 36 . Further evidence consistent with a dominant role for melanopsin comes from earlier observations showing that totally visually blind humans (where remaining light responses match the spectral sensitivity expected for melanopsin) 18,20 can display near-full melatonin suppression 10,12,18 , as do individuals with colour-vision deficiencies 41 .…”

“…In particular, future work may reveal specific lighting conditions that maximise cone influence to produce practically relevant modulations in non-visual responses to light. At present, however, existing evidence indicates that the use of melanopic irradiance would not lead one to substantially over-or under-estimate biological and behavioural effects for the types of light exposure that are typically encountered across daily life [29][30][31][32][34][35][36][37] .…”

“…illuminance) of standard daylight (D65) that match the effective rates of photon capture for each opsin are reported as α-opic equivalent daylight illuminance (α-opic EDI, Figure 1B). Moreover, as originally envisaged 2 , the adoption of such approaches has facilitated a number of large scale retrospective evaluations of historical data [29][30][31][32][33] and informed new hypothesis-driven investigations [34][35][36][37] on the photoreceptive physiology for circadian, neuroendocrine and neurobehavioral responses in humans.…”