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Melanopsin-Expressing Intrinsically Photosensitive Retinal Ganglion Cells in Retinal Disease

Feigl, Beatrix*; Zele, Andrew J.

doi: 10.1097/OPX.0000000000000284
Pathogenesis: Reviews

Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are a class of photoreceptors with established roles in non–image-forming processes. Their contributions to image-forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. Intrinsically photosensitive retinal ganglion cells can be divided into five ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioral marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma, and hereditary optic neuropathy. We briefly review the anatomical distributions, projections, and basic physiological mechanisms of ipRGCs and their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the PLR can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction.

*MD, PhD

PhD

Medical Retina and Visual Science Laboratories, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia (both authors).

Beatrix Feigl Institute of Health and Biomedical Innovation Queensland University of Technology 60 Musk Ave Brisbane, QLD 4059 Australia e-mail: b.feigl@qut.edu.au

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the third photoreceptor class in the eye.1–3 Intrinsically photosensitive retinal ganglion cells are an atypical photoreceptor type separate from the rod and cone photoreceptor classes that have an intrinsic photoresponse and extrinsically transmit outer retinal photoreception. They signal locally within the retina and distribute light information across more than a dozen distinct brain regions.1,2,4–8 The primary function of ipRGCs is for non–image-forming photoreception, but emerging evidence indicates that they have roles in image-forming vision.8,9 The non–image-forming functions include the signaling of environmental irradiance level to entrain the central body clock located in the suprachiasmatic nucleus (SCN) to the solar day to maintain the circadian rhythm to near a 24-hour day-and-night cycle and for mediating the pupil light reflex (PLR) via signaling to the olivary pretectal nucleus (OPN).1,2,10–12 The most prominent ipRGC contribution to the PLR is the postillumination pupil response (PIPR), the sustained constriction after offset of high-irradiance, short-wavelength light; this characteristic affords the direct measurement of ipRGC function in humans.11,13,14 Although there is a long history of research of conventional retinal ganglion cell morphology, physiology, connectivity, function, and central projections,3,15 ipRGC research into their subtypes, central projections, and function is still in its infancy. Moreover, our knowledge is predominantly derived from transgenic animal models (for comprehensive reviews, see Refs.3,14,16) and new areas of investigations are beginning to define the functional roles of ipRGCs in humans,11,17–19 with important reference to applications in the detection and monitoring of inner and outer retinal disease.14,20–25 This review will consider the effect of retinal disease on ipRGC function and will introduce new paradigms for measuring inner and outer retinal function in age-related macular degeneration (AMD).

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ipRGCs: THE “NOVEL-OLD” CELL

The initial evidence of a third photoreceptor class was available as early as 1927 when Keeler26 demonstrated that mice with severe outer retinal photoreceptor loss retained a pupil light response. More recently, normal photoentrainment and pupil responses were observed in humans who were blind owing to extensive outer retinal damage.27 The photopigment melanopsin (opn4) was first discovered in the frog (Xenopus laevis) skin melanophores, deep brain nuclei, the iris and retina,4 and then in a distinct ganglion cell population in humans, the ipRGCs.8,28 The melanopsin photopigment is diffusely expressed along the dendrites and soma of ipRGCs (∼3 molecules μm−2)7 and is lower in density compared with rod and cone photopigments (∼25,000 molecules μm−2), but the melanopsin signal amplification is higher. Whereas rods and cones signal with graded membrane voltages, melanopsin phototransduction shows different electrophysiological responses to light; ipRGCs signal to the brain using action potentials (spikes), the single photon absorption response is larger than in rods,7 and their response is sluggish in onset and slow in termination,1 lasting some 10 seconds, which is about 100-fold longer than that in cones and 20-fold longer than that in rods.7 Recent measurements show that 10 hours of constant light activation of ipRGCs continuously evoke action potentials, such that irradiance changes can feasibly be tracked during the day.29 The long operational timescales and slow kinetics of ipRGCs increase sensitivity through long temporal summation.

Evidence from studies of the human PLR indicates that melanopsin is a bistable photopigment, and unlike conventional photopigments that are dependent on exogenous supply of a chromophore, melanopsin is thought to regenerate from photoconversion.17 The intrinsic ipRGC response gives maximum depolarization in response to short-wavelength (blue appearing light), high–retinal irradiance (>∼11.5 log quanta s−1 cm−2) lights with a λ max of about 482 nm.1,8,11 The data in Fig. 1 show that the peak opn4 ipRGC spectral sensitivity derived from a criterion PIPR in humans is positioned in the short-wavelength region of the spectrum between the S-cone and rod nomograms. The half-maximal PIPR occurs at a retinal irradiance of about 13.7 log quanta s−1 cm−2 in humans. The ipRGCs also receive extrinsic input from rods and cones as shown in mice and primates,8,30,31 presumably via bipolar (excitatory) and amacrine (inhibitory) cells16,31 that subserve a faster temporal response than the melanopsin-elicited intrinsic response.32 Intrinsically photosensitive retinal ganglion cells are thought to have unmyelinated axons consistent with the slow conduction velocities of fibers within the retinohypothalamic tract as shown in studies of primates.33

FIGURE 1

FIGURE 1

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MORPHOLOGICAL DIVERSITY OF ipRGCs

Since their initial discovery, five ipRGC subtypes (M1 to M5) have been identified using transgenic mouse models. They are defined based on the stratification of their dendrites within the extreme outer and inner laminae of the inner plexiform layer (IPL). Three subtypes have been identified in rats, with dendrites stratifying in either the outer margin (M1) or inner side (M2) of the IPL, or stratifying in both the outer and inner plexuses (M3).34 Similar dendritic stratifications have been described for M1 and M2 cells in primate retinae.31 Intrinsically photosensitive retinal ganglion cells have the largest identified retinal ganglion cell dendritic fields (∼400 to 1200 μm) but have small somata and represent only a small subset (∼3000 cells or ∼0.2 to 4%) of the total ganglion cell population.8 The dendritic fields form a photoreceptive network that is concentrated parafoveally as evidenced in macaque retinas.8 The ipRGC subclasses show morphological and functional diversity and the different cortical projections are thought to evoke different behaviors (for a review, see Ref. 16). Given that there appears to be some conservation of ipRGC subtypes and pathways between species,35 the quantification of ipRGC structure and function in animal models will promote development of new methods for observing ipRGC activity in humans. In brief, M1 cell’s dendrites stratify in the OFF sublamina (outer IPL), whereas M2 subclasses stratify in the inner IPL (ON sublamina). M3 cells are bistratified and extend their dendrites into both sublaminae. There are discrepancies in the estimates of the relative proportions of these three subclasses, with the proportion of M1 cells varying between 22 and 68%, the proportion of M2 cells varying between 40 and 53%, and the proportion of M3 cells varying between 7 and 26%,36,37 the variation possibly arising because of methodological differences in their labeling. Moreover, dendritic arbors of M1 and M2 subtypes show a large amount of overlap38 with M2 subtypes having larger and complex dendritic fields and larger somata compared with M1 subtypes16,39; M1 cells display larger membrane depolarization compared with M2 and are about 10-fold more sensitive to light.40 Primate M1 cells also show intraretinal branching to provide synaptic feedback, an atypical morphological feature of ganglion cells exiting the retina.35 The M3 subtype is morphologically comparable to M2,40 but its dendrites are absent in some areas of the retina38; hence, M3 subtypes might only play a role in non–image-forming visual processes because complete coverage of the visual field by ganglion cells is important for image-forming vision.40

In mammals, M1 cells have the highest expression of the opn4 melanopsin photopigment followed by M2 and M3. In mice, M1 and M2 cells primarily receive excitatory inputs from ON pathways and M1 exhibiting much larger synaptic responses than M2 cells.40 There is evidence in mice that M1 and M2 convey light information differently with M2 being more reliant on outer retinal synaptic inputs than M1 cells that seem to respond to light using the intrinsic melanopsin pathway only.40 Primate ipRGCs also have a spatially overlapping, color-opponent (L+M-cone)-ON and (S-cone)-OFF receptive field structure, with projections to the LGN.8 Two additional subtypes of ipRGC cells have been discovered in mice. These are classified as M4 and M5 and stratify in the inner sublamina, with M4 being the largest of all ipRGC subtypes.40 M4 and M5, however, do not show melanopsin immunostaining but are still capable of a weak intrinsic response.39 Although both M1 and M2 cell subtypes are found in primate retinae,8,35 it remains subject to further in-depth investigations if the subtypes have similar characteristics to those as shown in rodents.

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ipRGC PROJECTIONS AND THEIR FUNCTIONAL CHARACTERISTICS

The axons of an ipRGC can branch out to multiple brain regions.41 In rodents, about 80% of M1 cells project to the SCN, the master circadian clock.37 Similarly, 80% of M1 and M2 cells project to the OPN, the control center of the pupillary light reflex, with M1 cells predominantly projecting to the OPN shell and a larger amount of non-M2 cells predominantly projecting to the OPN core.37 The reason for differential inputs from M1 and M2 to the SCN and OPN is unknown, but it is thought that it may play a role in the overall dynamic range of the response to retinal irradiance.37 M1 ipRGCs are considered to predominantly drive the PLR in rodents and humans.11,42 There is evidence that Brn3b transcription factor–negative M1 cells in mice innervate the SCN, whereas Brn3b-positive M1 cells project to all other brain regions receiving ipRGC inputs, including those for the pupil control pathway, yet these cells have the same morphological and electrophysiological characteristics.43

ipRGC subtypes further project to the intergeniculate leaflet, the center for circadian entrainment; the ventrolateral preoptic nucleus, the control center of sleep; the dorsal and ventral lateral geniculate nucleus (LGN); the lateral habenula; the medial amygdala; the supraoptic nucleus; the posterior pretectal nucleus; the superior colliculus; and many more brain regions.5,9,39 Although the projections of M3 cells are not known, most of the M2, M4, and M5 cells project to dorsal LGN, suggestive of a role for these subclasses in image-forming vision, in addition to projections to the core of the OPN, but for which there is presently no assigned function.39

Melanopsin-derived activity in the normal mouse dorsal LGN is evident as a prolonged firing of neurons when stimulated with long-duration, high-irradiance, short-wavelength stimuli, and the discrimination of high-irradiance lights from a dark background in rodless/coneless mice may reflect melanopsin signaling.9 Given that bipolar cells and conventional ganglion cells signal contrast, determining the role of melanopsin for signaling the perceptual correlate of brightness will be important for explaining human behavioral magnitude estimation of brightness44 and luxotonic units in the visual cortex as identified in cat45 and macaque.46 Melanopic metamers can produce perceptible changes in human brightness perception, but not in chromaticity,47 although the cone-opponent receptive fields in primate ipRGCs8 indicate that brightness changes should be accompanied by a chromaticity change. As the understanding of ipRGC contributions to image-forming vision advances, there will likely be a redefining of the standard model of human trichromacy48 and of photometry and melanopsin photoreception.49

There is emerging evidence that light information mediated via ipRGCs can directly influence higher cognitive function and brain processing for emotions.50,51 Studies demonstrate that ipRGCs can influence mood and learning through projections to the limbic areas of the brain including the lateral habenula and the medial amygdala.2,5,51 Aberrant light cycles can cause depression-like behaviors in animals with intact ipRGCs, whereas ipRGC knock out animals do not have these symptoms.51 A link between ipRGCs and exacerbation of migraine headache by light has been proposed based on observations that axons from ipRGCs project to dura-sensitive neurons in the posterior thalamus.52 Photosensitive blind individuals with migraine still show a PLR and photoentrainment indicative of functional ipRGCs. Light has also been shown to enhance learned fear in transgenic mice, and that this requires signaling via ipRGC pathways.50 The development of new assessment paradigms in humans, especially through use of the PLR, will provide novel techniques for assessing behaviors beyond its traditional application as an objective measure of visual and pupillary pathways linking midbrain and autonomic function.

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THE LIGHT REFLEX OF THE PUPIL: AN OBJECTIVE, BEHAVIORAL MEASURE OF INNER AND OUTER RETINAL FUNCTION

Since Loewenfeld’s53 seminal contribution on the pupil, the ipRGCs have been identified as a primary neural substrate of the pupillary control pathway. The PLR is the only measureable, noninvasive physiological response to directly reflect the behavior of the three retinal photoreceptor classes in the human eye: rods, cones, and ipRGCs. As such, noninvasive pupillometry techniques afford objective measurement of inner retinal (ipRGC) function and outer retinal (rod and cone) function13,14,19,21,25,54,55 in response to high–retinal irradiance, long- and short-wavelength lights that favor outer and inner retinal responses, through analysis of the components of the light response of the pupil including the latency to constriction, the transient pupil response, the constriction amplitude,54,55 the PIPR amplitude, and redilation time constant (Fig. 2).13,14,18,20–22,24,54–56

FIGURE 2

FIGURE 2

The current understanding is that the initial pupil constriction amplitude is mediated by outer retinal (rod and cone) contributions.13,42 The outer retinal contribution to steady-state pupillary response is dominated by rods with a smaller contribution by cones for light presentations of shorter than 10 seconds; the ipRGC contribution increases with longer presentation durations, but the rod photoreceptor still makes large contributions.13 The L- and M-cone contribution to the steady-state pupil diameter is more than a factor of three less than the ipRGC contribution.57 At light levels above which rods are incapable of supporting image-forming vision, rods signal via the rod-cone pathway and extrinsically via the ipRGC pathway for circadian photoentrainment.58

The inner retinal contribution from intrinsic ipRGC activity is observed as a sustained constriction of the PIPR after offset of the high-irradiance, short-wavelength light (Fig. 2)11; the PIPR can be measured as a percentage (or millimeter difference) to the resting baseline pupil diameter during the plateau, which is typically 30 seconds after light offset11,14,19; as the net PIPR, which is the difference in the plateau amplitude of the long and short wavelength18; as the amplitude at 6 seconds postillumination21; and as the early and late area under the curve (AUC).56 That the sustained PIPR derived from the plateau metric is controlled by the ipRGC photoresponse when assayed with high-irradiance, 10-second light pulses has been confirmed by spectral sensitivity of the plateau PIPR by our group (Fig. 1) and Gamlin and colleagues.11,14 Additional PIPR metrics such as the 6-second metric and early and late AUC have not been confirmed by spectral sensitivity but are most likely controlled by the intrinsic ipRGC response as the PIPR amplitude is wavelength and irradiance dependent.

Despite recent advances in understanding ipRGC function in nocturnal animal models (e.g., mice), there are significant knowledge gaps about how the fundamental properties and functional signatures of the ipRGC light response translate to diurnal humans. There are few investigations of these unique cells and their various roles in human eye diseases. Our group established the role of ipRGCs in the functional differentiation of early and advanced glaucoma25 and in the measurement of the progression of diabetes using the PLR.54 The study of ipRGC function in advanced glaucoma has shown that the PIPR amplitude correlates with the visual field defect.20 A study by La Morgia et al.59 observed that ipRGCs are resistant in mitochondrial optic neuropathies such as Leber hereditary optic neuropathy and dominant optic atrophy. Retinitis pigmentosa (RP) has been studied in humans14,21,23,60 using the PLR to differentiate between extrinsic (rod and cone) and intrinsic ipRGC contributions, showing that extrinsic and intrinsic losses increase with disease progression.23 Morphological studies in a rat model of RP show that ipRGC density and dendritic arborization decrease in advanced stages of the disease.34 Persons with seasonal affective disorder (SAD) have a reduced PIPR, indicative of altered light signaling via ipRGCs and may have a genetic variation within the opn4 gene, suggestive of a possible role of ipRGCs in its pathogenesis.61,62

Under experimental conditions controlling exogenous cues of circadian activity, our laboratory provided the initial evidence that ipRGCs have a circadian response synchronized to melatonin onset in humans whereas outer retinal inputs to the pupil did not,19 thereby indicating the PIPR as a noninvasive marker of the circadian rhythm. Munch et al.63 have independently confirmed this influence of the circadian clock on ipRGC inputs to the PIPR function. As the current test protocols are refined and new, rapid test methodologies emerge, the PLR assessment of inner and outer retinal dysfunction in retinal disease will find new roles in the detection and monitoring of progression of retinal and optic nerve disease and for the assessment of circadian function and dysfunction.

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THE PLR IN AMD

The primary anatomical and functional changes observed in AMD occur in the paracentral retina64; ipRGCs spiral around the foveal pit and have their highest distribution paracentrally,8 thus making these cells a likely target in this condition. In particular, AMD affects the outer and inner retinal layers, including retinal ganglion cells in advanced stages.65,66 There is histological evidence of an age-related loss of ganglion cells and almost 50% loss of ganglion cells in neovascular AMD.65 The effect of age on the ipRGC-controlled PIPR, however, has been considered in only two studies: one showed that the PIPR was independent of age18 and the other showed enhanced pupil responses in healthy older persons24; hence, further investigations are required to understand these relationships.

Although established psychophysical methods such as dark adaptation,67 mesopic vision,68 flicker perimetry,69 and electrophysiological techniques70,71 can be effective and valuable for determining functional deficits in different retinal layers and different stages of AMD, they are limited to the measurement of specific retinal layers, do not assess inner and outer retina simultaneously under the same test and adaptation conditions, and can be time consuming. Pupil measurements have been recorded in AMD, although they only assessed outer retinal (rod and/or cone) contributions to the pupillary control pathway,72,73 and the studies generally observed that pupil responses on the measured variables were dysfunctional. The measurement of ipRGC function in AMD using pupil paradigms remains to be determined.

The PLR response to high-irradiance rectangular light pulses (e.g., 10-second pulse as shown in Fig. 2) is now routinely measured in clinical studies,18–20,23,54 and here we introduce a sinusoidal test paradigm that allows the study of inner and outer retinal contributions to the phasic pupil response. Informed consent was obtained from all participants, and the experiments were approved by the Queensland University of Technology Human Ethics Committee and conducted in accordance with the principles expressed in the Declaration of Helsinki. Fig. 3 shows the PLR of a 59-year-old healthy female control participant (visual acuity [VA], 6/6) without any ocular disease. The pupil trace is the response to a large 34-degree-diameter, 0.5-Hz sinewave stimulus (6 cycles, 11.9-second duration; 464 nm or 635 nm) centered on the pupil in Maxwellian view and with a corneal irradiance of 15.1 log photon cm−2 s−1. As per the response to a 10-second pulse (Fig. 2), the sustained PIPR for the 0.5-Hz stimulus is observed after offset of the short-wavelength (464 nm) stimulus light, and the response to the control long-wavelength stimulus (638 nm) returns to baseline within about 20 seconds after light offset. As for the pulsed stimuli, metrics are available to quantify outer retinal function (e.g., maximum and transient constriction amplitudes) and inner retinal function (e.g., PIPR metrics). In addition, the phasic pupillary response to the sinewave stimulus allows analysis of the phase and peak-to-trough amplitude during the sinusoidal stimulus presentation. A “phase amplitude percentage” (PAP) parameter can then be determined from the average long-wavelength (638 nm) and short-wavelength (464 nm) peak-to-trough phase amplitudes according to equation 1:

FIGURE 3

FIGURE 3

Figure

Figure

The PAP metric (equation 1) reflects inner and outer retinal interactions. For retinal irradiances below melanopsin threshold that are driven by rods and cones only,74,75 the peak-to-trough amplitudes of the phasic response for long and short wavelengths are similar (i.e., the PAP approaches zero). However, for retinal irradiances above melanopsin threshold where the phasic response is predominantly driven by cones but with ipRGC contributions75 (Fig. 3), the short-wavelength peak-to-trough phase amplitude is lower relative to the long-wavelength amplitudes (i.e., the PAP is nonzero), possibly due to ipRGC contributions that are inhibitory in nature.31

In the following, we present a framework and application of the PLR as an objective behavioral measure of inner and outer retinal function in AMD. We propose that for light levels that activate melanopsin, the PAP and the PIPR metrics will be reduced if disease causes an alteration in ipRGC function. Given that PLR further provides a measure of rod and cone function as derived from the transient pupil constriction or the amplitude of constriction, these components may be reduced owing to disease causing outer retinal deficits. The relative level of defect observed for a recording condition will depend on test parameters including the stimulus size76 and retinal irradiance14,21,75; larger stimulus sizes will be more sensitive to inner retinal function owing to the larger receptive fields of ipRGCs (conversely, smaller stimulus sizes are more sensitive to outer retinal dysfunction,77 and retinal irradiances below melanopsin threshold provide isolation of outer retinal function).14,21 When this framework is applied to AMD, distinct patterns of inner and outer retinal functional deficits should be apparent depending on the AMD stage, as predicted from histological,66 psychophysical, and electrophysiological data.78 Here, we focus on stimulus conditions designed to optimize ipRGC activation.

In the following exemplars in Fig. 4, we report the PLR in two AMD stages (early and neovascular) using large stimuli and high retinal irradiances (cf. Fig. 3) to illustrate the effect of manifest AMD on ipRGC function. Fig. 4A shows the PLR for a male patient (76 years old; VA, 6/6 both eyes) with early AMD (intermediated drusen >125 μm; AREDS [Age-Related Eye Disease Study] classification), and Fig. 4B shows the PLR for a female patient (74 years old; VA, 6/12 both eyes) with advanced neovascular AMD (AREDS 4b) who is currently undergoing anti-VEGF treatment in both eyes. Table 1 shows the outer and inner retinal metrics and includes the confidence limits of a healthy control group for comparison (n = 5; mean, 60 years; range, 56 to 69 years; three women, two men; VA, 6/6). Of note, the PIPR metrics are reduced, indicating that both the early and neovascular AMD patients have altered inner retinal ipRGC inputs to the pupillary control pathway, with the late AMD patient having predominantly a larger level of ipRGC dysfunction. There is also evidence of outer retinal dysfunction with these large, high-irradiance stimuli, in accordance with photoreceptor alterations that can occur with drusen as shown with psychophysical methods in early AMD. Future investigations are now required to comprehensively study ipRGC function in AMD and its relationship to outer retinal function with a view to developing these novel test protocols for quantifying retinal inputs to the pupillary control pathway to determine different stages of disease and possibly for monitoring progression.

TABLE 1

TABLE 1

FIGURE 4

FIGURE 4

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CONCLUSIONS AND FUTURE DIRECTIONS

Light is required every day, with very specific irradiance, duration, and timing, to reset the circadian “body clock” and to regulate many neuronal processes. This light is received, transduced, and transmitted to the brain by ipRGCs. Research is now beginning to discover the roles of ipRGCs in human eye disease, with advances identifying the roles of ipRGCs in different stages of glaucoma,20,25 RP,14,21,23,34,60 Leber hereditary optic neuropathy and dominant optic atrophy,59 diabetic retinopathy,54 and circadian health.19,61,63 It is now becoming clear that the PLR will have a role as a rapid clinical assessment tool to simultaneously determine inner and outer retinal function in patients with eye diseases including AMD. Novel pupil paradigms and metrics such as the sinusoidal stimuli protocol proposed here may be particularly helpful in discriminating functional impairment in AMD, in addition to other retinal/optic nerve disease, and research is ongoing to understand the sensitivity and specificity of these tests for detection and the monitoring of progression.

ipRGCs signal to brain areas linked with depression51 and sleep,1,11 but whether reduced ipRGC function is associated with depression and sleep disorders that are commonly found in AMD (and other ocular disease) is still to be determined. At present, ipRGC dysfunction has been associated with SAD, with patients showing gene variants in the opn4 photopigment having a higher risk for developing SAD.62 Importantly, a potent treatment of SAD is short-wavelength (blue light) light therapy at irradiance levels that activate ipRGCs. Melatonin is released by the SCN to initiate the sleep phase, and melatonin secretion is suppressed by light.79 There is evidence that AMD patients can show higher-than-normal melatonin levels.80 Our working hypothesis is that patients with advanced AMD may have uninhibited melatonin release owing to abnormal ipRGC inputs to the SCN; therefore, these patients may be more likely to develop depression and sleep disorders. Research is currently ongoing in our laboratory to define and understand these relationships between ipRGC function and nonretinal symptoms in AMD.

Beatrix Feigl

Institute of Health and Biomedical Innovation

Queensland University of Technology

60 Musk Ave

Brisbane, QLD 4059

Australia

e-mail: b.feigl@qut.edu.au

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ACKNOWLEDGMENTS

This work was supported by Australian Research Council Discovery Projects (ARC-DP140100333 to BF and AJZ). We thank Daniel S. Joyce, Michelle L. Maynard, and Prakash Adhikari for contributions to data collection.

Received December 11, 2013; accepted February 18, 2014.

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REFERENCES

1. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002; 295: 1070–3.
2. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002; 295: 1065–70.
3. Pickard GE, Sollars PJ. Intrinsically photosensitive retinal ganglion cells. Rev Physiol Biochem Pharmacol 2012; 162: 59–90.
4. Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD. Melanopsin: an opsin in melanophores, brain, and eye. Proc Natl Acad Sci U S A 1998; 95: 340–5.
5. Hattar S, Kumar M, Park A, Tong P, Tung J, Yau KW, Berson DM. Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J Comp Neurol 2006; 497: 326–49.
6. Gooley JJ, Lu J, Chou TC, Scammell TE, Saper CB. Melanopsin in cells of origin of the retinohypothalamic tract. Nat Neurosci 2001; 4: 1165.
7. Do MT, Kang SH, Xue T, Zhong H, Liao HW, Bergles DE, Yau KW. Photon capture and signalling by melanopsin retinal ganglion cells. Nature 2009; 457: 281–7.
8. Dacey DM, Liao HW, Peterson BB, Robinson FR, Smith VC, Pokorny J, Yau KW, Gamlin PD. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 2005; 433: 749–54.
9. Brown TM, Gias C, Hatori M, Keding SR, Semo M, Coffey PJ, Gigg J, Piggins HD, Panda S, Lucas RJ. Melanopsin contributions to irradiance coding in the thalamo-cortical visual system. PLoS Biol 2010; 8: e1000558.
10. Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 2001; 4: 621–6.
11. Gamlin PD, McDougal DH, Pokorny J, Smith VC, Yau KW, Dacey DM. Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells. Vision Res 2007; 47: 946–54.
12. Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 2002; 298: 2213–6.
13. McDougal DH, Gamlin PD. The influence of intrinsically-photosensitive retinal ganglion cells on the spectral sensitivity and response dynamics of the human pupillary light reflex. Vision Res 2010; 50: 72–87.
14. Markwell EL, Feigl B, Zele AJ. Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm. Clin Exp Optom 2010; 93: 137–49.
15. Lee BB, Martin PR, Grunert U. Retinal connectivity and primate vision. Prog Retin Eye Res 2010; 29: 622–39.
16. Sand A, Schmidt TM, Kofuji P. Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res 2012; 31: 287–302.
17. Mure LS, Cornut PL, Rieux C, Drouyer E, Denis P, Gronfier C, Cooper HM. Melanopsin bistability: a fly’s eye technology in the human retina. PLoS One 2009; 4: e5991.
18. Kankipati L, Girkin CA, Gamlin PD. Post-illumination pupil response in subjects without ocular disease. Invest Ophthalmol Vis Sci 2010; 51: 2764–9.
19. Zele AJ, Feigl B, Smith S, Markwell EL. The circadian response of intrinsically photosensitive retinal ganglion cells. PLoS One 2011; 6: e17860.
20. Kankipati L, Girkin CA, Gamlin PD. The post-illumination pupil response is reduced in glaucoma patients. Invest Ophthalmol Vis Sci 2011; 52: 2287–92.
21. Park JC, Moura AL, Raza AS, Rhee DW, Kardon RH, Hood DC. Toward a clinical protocol for assessing rod, cone, and melanopsin contributions to the human pupil response. Invest Ophthalmol Vis Sci 2011; 52: 6624–35.
22. Kawasaki A, Herbst K, Sander B, Milea D. Selective wavelength pupillometry in Leber hereditary optic neuropathy. Clin Experiment Ophthalmol 2010; 38: 322–4.
23. Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A. Chromatic pupillometry in patients with retinitis pigmentosa. Ophthalmology 2011; 118: 376–81.
24. Herbst K, Sander B, Lund-Andersen H, Broendsted AE, Kessel L, Hansen MS, Kawasaki A. Intrinsically photosensitive retinal ganglion cell function in relation to age: a pupillometric study in humans with special reference to the age-related optic properties of the lens. BMC Ophthalmol 2012; 12: 4.
25. Feigl B, Mattes D, Thomas R, Zele AJ. Intrinsically photosensitive (melanopsin) retinal ganglion cell function in glaucoma. Invest Ophthalmol Vis Sci 2011; 52: 4362–7.
26. Keeler CE. Iris movements in blind mice. Am J Physiol 1927; 81: 107–12.
27. Zaidi FH, Hull JT, Peirson SN, Wulff K, Aeschbach D, Gooley JJ, Brainard GC, Gregory-Evans K, Rizzo JF 3rd, Czeisler CA, Foster RG, Moseley MJ, Lockley SW. Short-wavelength light sensitivity of circadian, pupillary, and visual awareness in humans lacking an outer retina. Curr Biol 2007; 17: 2122–8.
28. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci 2000; 20: 600–5.
29. Wong KY. A retinal ganglion cell that can signal irradiance continuously for 10 hours. J Neurosci 2012; 32: 11478–85.
30. Altimus CM, Guler AD, Villa KL, McNeill DS, Legates TA, Hattar S. Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation. Proc Natl Acad Sci U S A 2008; 105: 19998–20003.
31. Jusuf PR, Lee SC, Hannibal J, Grunert U. Characterization and synaptic connectivity of melanopsin-containing ganglion cells in the primate retina. Eur J Neurosci 2007; 26: 2906–21.
32. Wong KY, Dunn FA, Graham DM, Berson DM. Synaptic influences on rat ganglion-cell photoreceptors. J Physiol 2007; 582: 279–96.
33. Ogden TE, Miller RF. Studies of the optic nerve of the rhesus monkey: nerve fiber spectrum and physiological properties. Vision Res 1966; 6: 485–506.
34. Esquiva G, Lax P, Cuenca N. Impairment of intrinsically photosensitive retinal ganglion cells associated with late stages of retinal degeneration. Invest Ophthalmol Vis Sci 2013; 54: 4605–18.
35. Joo HR, Peterson BB, Dacey DM, Hattar S, Chen SK. Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells. Vis Neurosci 2013; 30: 175–82.
36. Muller LP, Do MT, Yau KW, He S, Baldridge WH. Tracer coupling of intrinsically photosensitive retinal ganglion cells to amacrine cells in the mouse retina. J Comp Neurol 2010; 518: 4813–24.
37. Baver SB, Pickard GE, Sollars PJ, Pickard GE. Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus. Eur J Neurosci 2008; 27: 1763–70.
38. Berson DM, Castrucci AM, Provencio I. Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. J Comp Neurol 2010; 518: 2405–22.
39. Ecker JL, Dumitrescu ON, Wong KY, Alam NM, Chen SK, LeGates T, Renna JM, Prusky GT, Berson DM, Hattar S. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision. Neuron 2010; 67: 49–60.
40. Schmidt TM, Kofuji P. Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J Neurosci 2009; 29: 476–82.
41. Morin LP, Blanchard JH, Provencio I. Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: bifurcation and melanopsin immunoreactivity. J Comp Neurol 2003; 465: 401–16.
42. Guler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao HW, Barnard AR, Cahill H, Badea TC, Zhao H, Hankins MW, Berson DM, Lucas RJ, Yau KW, Hattar S. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature 2008; 453: 102–5.
43. Chen SK, Badea TC, Hattar S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature 2011; 476: 92–5.
44. Barlow RB Jr, Verrillo RT. Brightness sensation in a ganzfeld. Vision Res 1976; 16: 1291–7.
45. Barlow HB, Levick WR. Changes in the maintained discharge with adaptation level in the cat retina. J Physiol 1969; 202: 699–718.
46. Kayama Y, Riso RR, Bartlett JR, Doty RW. Luxotonic responses of units in macaque striate cortex. J Neurophysiol 1979; 42: 1495–517.
47. Brown TM, Tsujimura S, Allen AE, Wynne J, Bedford R, Vickery G, Vugler A, Lucas RJ. Melanopsin-based brightness discrimination in mice and humans. Curr Biol 2012; 22: 1134–41.
48. Horiguchi H, Winawer J, Dougherty RF, Wandell BA. Human trichromacy revisited. Proc Natl Acad Sci U S A 2013; 110: E260–9.
49. Enezi J, Revell V, Brown T, Wynne J, Schlangen L, Lucas R. A “melanopic” spectral efficiency function predicts the sensitivity of melanopsin photoreceptors to polychromatic lights. J Biol Rhythms 2011; 26: 314–23.
50. Warthen DM, Wiltgen BJ, Provencio I. Light enhances learned fear. Proc Natl Acad Sci U S A 2011; 108: 13788–93.
51. LeGates TA, Altimus CM, Wang H, Lee HK, Yang S, Zhao H, Kirkwood A, Weber ET, Hattar S. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature 2012; 491: 594–8.
52. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci 2010; 13: 239–45.
53. Loewenfeld IE. The Pupil: Anatomy, Physiology and Clinical Applications. Boston, MA: Butterworth-Heinemann; 1999.
54. Feigl B, Zele AJ, Fader SM, Howes AN, Hughes CE, Jones KA, Jones R. The post-illumination pupil response of melanopsin-expressing intrinsically photosensitive retinal ganglion cells in diabetes. Acta Ophthalmol 2012; 90: e230–4.
55. Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A. Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex. Ophthalmology 2009; 116: 1564–73.
56. Herbst K, Sander B, Milea D, Lund-Andersen H, Kawasaki A. Test-retest repeatability of the pupil light response to blue and red light stimuli in normal human eyes using a novel pupillometer. Front Neurol 2011; 2: 10.
57. Tsujimura S, Ukai K, Ohama D, Nuruki A, Yunokuchi K. Contribution of human melanopsin retinal ganglion cells to steady-state pupil responses. Proc Biol Sci 2010; 277: 2485–92.
58. Altimus CM, Guler AD, Alam NM, Arman AC, Prusky GT, Sampath AP, Hattar S. Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities. Nat Neurosci 2010; 13: 1107–12.
59. La Morgia C, Ross-Cisneros FN, Sadun AA, Hannibal J, Munarini A, Mantovani V, Barboni P, Cantalupo G, Tozer KR, Sancisi E, Salomao SR, Moraes MN, Moraes-Filho MN, Heegaard S, Milea D, Kjer P, Montagna P, Carelli V. Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain 2010; 133: 2426–38.
60. Kawasaki A, Crippa SV, Kardon R, Leon L, Hamel C. Characterization of pupil responses to blue and red light stimuli in autosomal dominant retinitis pigmentosa due to NR2E3 mutation. Invest Ophthalmol Vis Sci 2012; 53: 5562–9.
61. Roecklein K, Wong P, Ernecoff N, Miller M, Donofry S, Kamarck M, Wood-Vasey WM, Franzen P. The post illumination pupil response is reduced in seasonal affective disorder. Psychiatry Res 2013; 210: 150–8.
62. Roecklein KA, Rohan KJ, Duncan WC, Rollag MD, Rosenthal NE, Lipsky RH, Provencio I. A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder. J Affect Disord 2009; 114: 279–85.
63. Munch M, Leon L, Crippa SV, Kawasaki A. Circadian and wake-dependent effects on the pupil light reflex in response to narrow-bandwidth light pulses. Invest Ophthalmol Vis Sci 2012; 53: 4546–55.
64. Swann PG, Lovie-Kitchin JE. Age-related maculopathy. II: the nature of the central visual field loss. Ophthalmic Physiol Opt 1991; 11: 59–70.
65. Medeiros NE, Curcio CA. Preservation of ganglion cell layer neurons in age-related macular degeneration. Invest Ophthalmol Vis Sci 2001; 42: 795–803.
66. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996; 37: 1236–49.
67. Dimitrov PN, Guymer RH, Zele AJ, Anderson AJ, Vingrys AJ. Measuring rod and cone dynamics in age-related maculopathy. Invest Ophthalmol Vis Sci 2008; 49: 55–65.
68. Feigl B, Cao D, Morris CP, Zele AJ. Persons with age-related maculopathy risk genotypes and clinically normal eyes have reduced mesopic vision. Invest Ophthalmol Vis Sci 2011; 52: 1145–50.
69. Phipps JA, Dang TM, Vingrys AJ, Guymer RH. Flicker perimetry losses in age-related macular degeneration. Invest Ophthalmol Vis Sci 2004; 45: 3355–60.
70. Feigl B, Brown B, Lovie-Kitchin J, Swann P. Adaptation responses in early age-related maculopathy. Invest Ophthalmol Vis Sci 2005; 46: 4722–7.
71. Feigl B, Morris CP, Brown B, Zele AJ. Relationship among CFH and ARMS2 genotypes, macular pigment optical density, and neuroretinal function in persons without age-related macular degeneration. Arch Ophthalmol 2012; 130: 1402–9.
72. Brozou C, Fotiou D, Androudi S, Theodoridou E, Giantselidis C, Alexandridis A, Brazitikos P. Pupillometric characteristics in patients with choroidal neovascularization due to age-related macular degeneration. Eur J Ophthalmol 2009; 19: 254–62.
73. Sabeti F, James AC, Essex RW, Maddess T. Multifocal pupillography identifies retinal dysfunction in early age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2013; 251: 1707–16.
74. Gooley JJ, Ho Mien I, St Hilaire MA, Yeo SC, Chua EC, van Reen E, Hanley CJ, Hull JT, Czeisler CA, Lockley SW. Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans. J Neurosci 2012; 32: 14242–53.
75. Barrionuevo PA, Nicandro N, McAnany JJ, Zele AJ, Gamlin P, Cao D. Assessing rod, cone, and melanopsin contributions to human pupil flicker responses. Invest Ophthalmol Vis Sci 2014; 55: 719–27.
76. Atchison DA, Girgenti CC, Campbell GM, Dodds JP, Byrnes TM, Zele AJ. Influence of field size on pupil diameter under photopic and mesopic light levels. Clin Exp Optom 2011; 94: 545–8.
77. Feigl B. Age-related maculopathy—linking aetiology and pathophysiological changes to the ischaemia hypothesis. Prog Retin Eye Res 2009; 28: 63–86.
78. Feigl B, Greaves A, Brown B. Functional outcomes after multiple treatments with ranibizumab in neovascular age-related macular degeneration beyond visual acuity. Clin Ophthalmol 2007; 1: 167–75.
79. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in humans. Science 1980; 210: 1267–9.
80. Schmid-Kubista KE, Glittenberg CG, Cezanne M, Holzmann K, Neumaier-Ammerer B, Binder S. Daytime levels of melatonin in patients with age-related macular degeneration. Acta Ophthalmol 2009; 87: 89–93.
Keywords:

melanopsin-containing intrinsically photosensitive retinal ganglion cells; pupil light reflex; age-related macular degeneration; ipRGC; PIPR

© 2014 American Academy of Optometry