Pupillary Light Reflexes in Severe Photoreceptor Blindness Isolate the Melanopic Component of Intrinsically Photosensitive Retinal Ganglion Cells

Charng, Jason; Jacobson, Samuel G.; Hèon, Elise; Román, Alejandro J.; McGuigan, David B.; Sheplock, Rebecca; Kosyk, Mychajlo S; Świder, Małgorzata; Cideciyan, Artur V.

doi:10.1167/iovs.17-21909

Cited by 16 publications

(16 citation statements)

References 60 publications

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“…Direct evidence for a functional preservation of melanopsin-mediated ipRGC function has also been found in other retinal conditions (e.g. Leber congenital amaurosis, (16)). Importantly, however, these individuals do not necessarily experience the severe discomfort reaction to light typical for ACHM and therefore may indeed be exposed to much more daytime light levels than achromats.…”

Section: Introductionmentioning

confidence: 66%

Sleep and circadian phenotype in people without cone-mediated vision

Spitschan

Garbazza

Kohl

et al. 2020

Preprint

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17Light is strong zeitgeber to the human circadian system, entraining internal rhythms in 18 physiology and behaviour to the external world. This is mediated by the melanopsin-19 expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which sense 20 light in addition to the classical photoreceptors, the cones and rods. Circadian 21 responses depend on light intensity, with exposure to brighter light leading to bigger 22 circadian phase shifts and melatonin suppression. In congenital achromatopsia 23 (prevalence 1 in 30,000 to 50,000 people), the cone system is non-functional, resulting 24 in light avoidance and photophobia at light levels which are tolerable and habitual to 25 individuals with a normal, trichromatic retina. Here, we examined chronotype and self-26 reported sleep, actigraphy-derived rest-activity cycles and increases melatonin in the 27 evening in a group of genetically confirmed congenital achromats. We found normal 28 rest-activity patterns in all participants, and normal melatonin phase angles of 29 entrainment in 2/3 of our participants. Our results suggest that a functional cone 30 system and exposure to daytime light intensities are not necessary for regular 31 behavioural and hormonal entrainment. This may point to a compensation mechanism 32 in circadian photoreception, which in conjunction with non-photic zeitgebers, ensures 33 synchronisation of activity to the external world. 34Significance statement 35 Rhythms in physiology and behaviour are synchronised to the external cycle of light 36 exposure. This is mediated by the retinohypothalamic tract, which connects the 37 photoreceptors in the eye with the "circadian pacemaker" in our brain, the 38 suprachiasmatic nucleus. What happens to our circadian rhythm when we lack the 39 cone photoreceptors in the eye that enable us to see in daylight? We examined this 40 question in a group of rare congenital achromats. Our work reveals that normal 41 rhythms in rest and activity, and production of hormones, does not require a functional 42 cone system. 43 Light exposure at even moderate intensities at night attenuates the production of the 46 hormone melatonin and shifts circadian rhythms in physiology and behaviour (1, 2). 47Light acts as a zeitgeber, enabling synchronisation, or entrainment, of the circadian 48 clock to the periodic changes in ambient light levels (3). Generally, brighter light has a 49 stronger zeitgeber strength, thus providing a more powerful input drive to the circadian 50 timing system (3, 4). Circadian phase shifting follows a sigmoidal dose-response curve 51 (5, 6), with half-maximum responses occurring between 80 and 160 lux for fluorescent 52 white light (5). 53These non-visual effects of light on the circadian clock are mediated by the 54 retinohypothalamic pathway, which is largely driven by the intrinsically photosensitive 55 retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (1, 7, 8). The 56 ipRGCs are 'non-classical' photoreceptors signalling environmental light ...

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Section: Introductionmentioning

confidence: 66%

Sleep and circadian phenotype in people without cone-mediated vision

Spitschan

Garbazza

Kohl

et al. 2020

Preprint

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“… 38 Third, our results indicate that melanopsin-mediated pupillary constriction leads to a substantial reduction in the light sensitivity of optogenetically restored vision, which would pose a significant constraint for clinical applications because the melanopsin-mediated pupillary light reflex is present in patients with retinal degeneration. 39 Although pupillary constriction may be pharmacologically blocked by drugs such as atropine, a better solution would be to develop more light-sensitive optogenetic tools with a light sensitivity comparable to melanopsin.…”

Section: Discussionmentioning

confidence: 99%

A Robust Optomotor Assay for Assessing the Efficacy of Optogenetic Tools for Vision Restoration

Ganjawala

Hattar

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeTo develop an animal behavioral assay for the quantitative assessment of the functional efficacy of optogenetic therapies.MethodsA triple-knockout (TKO) mouse line, Gnat1−/−Cnga3−/−Opn4−/−, and a double-knockout mouse line, Gnat1−/−Cnga3−/−, were employed. The expression of channelrhodopsin-2 (ChR2) and its three more light-sensitive mutants, ChR2-L132C, ChR2-L132C/T159C, and ChR2-132C/T159S, in inner retinal neurons was achieved using rAAV2 vectors via intravitreal delivery. Pupillary constriction was assessed by measuring the pupil diameter. The optomotor response (OMR) was examined using a homemade optomotor system equipped with light-emitting diodes as light stimulation.ResultsA robust OMR was restored in the ChR2-mutant-expressing TKO mice; however, significant pupillary constriction was observed only for the ChR2-L132C/T159S mutant. The ability to evoke an OMR was dependent on both the light intensity and grating frequency. The most light-sensitive frequency for the three ChR2 mutants was approximately 0.042 cycles per degree. Among the three ChR2 mutants, ChR2-L132C/T159S was the most light sensitive, followed by ChR2-L132C/T159C and ChR2-L132C. Melanopsin-mediated pupillary constriction resulted in a substantial reduction in the light sensitivity of the ChR2-mediated OMR.ConclusionsThe OMR assay using TKO mice enabled the quantitative assessment of the efficacy of different optogenetic tools and the properties of optogenetically restored vision. Thus, the assay can serve as a valuable tool for developing effective optogenetic therapies.

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“…In humans, melanopsin photoreception occurs efficiently across the short wavelength range of the visible spectrum between 420 and 560 nm, with a peak sensitivity in vivo at ∼490 nm (13). Melanopsin-based signaling is more sluggish in onset and more sustained than rod or cone signaling (63)(64)(65). At least six subtypes of ipRGCs, M1-M6, have been identified in the mammalian retina (M1-M5 to date in humans) (66)(67)(68)(69).…”

Section: Retinal Photoreceptorsmentioning

confidence: 99%

The Lighting Environment, Its Metrology, and Non-visual Responses

Schlangen

Price

2021

Front. Neurol.

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International standard CIE S 026:2018 provides lighting professionals and field researchers in chronobiology with a method to characterize light exposures with respect to non-visual photoreception and responses. This standard defines five spectral sensitivity functions that describe optical radiation for its ability to stimulate each of the five α-opic retinal photoreceptor classes that contribute to the non-visual effects of light in humans via intrinsically-photosensitive retinal ganglion cells (ipRGCs). The CIE also recently published an open-access α-opic toolbox that calculates all the quantities and ratios of the α-opic metrology in the photometric, radiometric and photon systems, based on either a measured (user-defined) spectrum or selected illuminants (A, D65, E, FL11, LED-B3) built into the toolbox. For a wide variety of ecologically-valid conditions, the melanopsin-based photoreception of ipRGCs has been shown to account for the spectral sensitivity of non-visual responses, from shifting the timing of nocturnal sleep and melatonin secretion to regulating steady-state pupil diameter. Recent findings continue to confirm that the photopigment melanopsin also plays a role in visual responses, and that melanopsin-based photoreception may have a significant influence on brightness perception and aspects of spatial vision. Although knowledge concerning the extent to which rods and cones interact with ipRGCs in driving non-visual effects is still growing, a CIE position statement recently used melanopic equivalent daylight (D65) illuminance in preliminary guidance on applying “proper light at the proper time” to manipulate non-visual responses. Further guidance on this approach is awaited from the participants of the 2nd International Workshop on Circadian and Neurophysiological Photometry (in Manchester, August 2019). The new α-opic metrology of CIE S 026 enables traceable measurements and a formal, quantitative specification of personal light exposures, photic interventions and lighting designs. Here, we apply this metrology to everyday light sources including a natural daylight time series, a range of LED lighting products and, using the toobox, to a smartphone display screen. This collection of examples suggests ways in which variations in the melanopic content of light over the day can be adopted in strategies that use light to support human health and well-being.

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Pupillary Light Reflexes in Severe Photoreceptor Blindness Isolate the Melanopic Component of Intrinsically Photosensitive Retinal Ganglion Cells

Cited by 16 publications

References 60 publications

Sleep and circadian phenotype in people without cone-mediated vision

Sleep and circadian phenotype in people without cone-mediated vision

A Robust Optomotor Assay for Assessing the Efficacy of Optogenetic Tools for Vision Restoration

The Lighting Environment, Its Metrology, and Non-visual Responses

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