Strange vision: ganglion cells as circadian photoreceptors

doi:10.1016/S0166-2236(03)00130-9

Trends in Neurosciences

Volume 26, Issue 6, June 2003, Pages 314-320

https://doi.org/10.1016/S0166-2236(03)00130-9 Get rights and content

Abstract

A novel photoreceptor of the mammalian retina has recently been discovered and characterized. The novel cells differ radically from the classical rod and cone photoreceptors. They use a unique photopigment, most probably melanopsin. They have lower sensitivity and spatiotemporal resolution than rods or cones and they seem specialized to encode ambient light intensity. Most surprisingly, they are ganglion cells and, thus, communicate directly with the brain. These intrinsically photosensitive retinal ganglion cells (ipRGCs) help to synchronize circadian rhythms with the solar day. They also contribute to the pupillary light reflex and other behavioral and physiological responses to environmental illumination.

Section snippets

Synchronization of circadian rhythms

The roots of this discovery lie in the field of circadian physiology. Circadian rhythms are biological cycles that have period of about a day. Body temperature, hormonal levels, sleep, cognitive performance and countless other physiological variables exhibit such daily oscillations. In mammals, a pacemaker in the hypothalamus called the suprachiasmatic nucleus (SCN) drives these rhythms [1]. Lesions of the SCN abolish circadian rhythms and SCN grafts can restore rhythms in arrhythmic hosts. The

Behavioral evidence for novel ocular photoreceptors

In mammals, light adjusts circadian phase by activating the retinohypothalamic tract, a direct pathway linking a small population of retinal ganglion cells (RGCs) to the SCN 5, 7, 8, 9, 10, 11, 12. In the conventional view of retinal organization, these RGCs, like all others, would derive their visual responsiveness solely from synaptic inputs and, ultimately, from the classical photoreceptors. According to this view, rods and/or cones would be the photoreceptors through which light influenced

Melanopsin – a candidate circadian photopigment

A key strategy in the hunt for these enigmatic photoreceptors was to seek candidate photopigments within the inner retina. Attention initially focused on the cryptochromes, blue-light-absorbing flavoproteins that function as circadian photopigments in invertebrates 38, 39, 40. Despite some evidence supporting an equivalent role in mammals (see following discussion), cryptochromes have been eclipsed, at least momentarily, by melanopsin. This novel vertebrate opsin, discovered by Provencio and

Intrinsic photosensitivity of ganglion cells innervating the circadian pacemaker

To determine whether ganglion cells innervating the SCN were directly photosensitive, Berson et al. [48] made whole-cell recordings from such cells in isolated rat retinas. Light strongly depolarized the cells, triggering sustained spiking. These responses persisted even when rods and cones were severely photobleached and their synaptic influences on ganglion cells were thoroughly blocked. Most tellingly, the cell bodies of these ganglion cells still responded to light when physically

Functional features of ipRGCs

The intrinsic light responses of ipRGCs differ radically from those of rods and cones [48] (Table 1). Light depolarizes ipRGCs but hyperpolarizes rods and cones (Fig. 1a). The ipRGCs are less sensitive than the classical photoreceptors and are far more sluggish, with response latencies as long as one minute (Fig. 1a). Bright continuous illumination evokes a remarkably sustained depolarization in ipRGCs that faithfully encodes stimulus energy. This sets these cells apart from essentially all

Congruence of ipRGC light responses with properties of the photoentrainment mechanism

Many of the distinctive features of the light responses of ipRGCs parallel the unusual properties of circadian photoentrainment. By comparison with pattern vision, the photoentrainment mechanism is insensitive and responds poorly to brief stimuli, but is able to integrate photic energy over much longer periods 14, 15, 18, 52. These characteristics seem likely to reflect in part the high thresholds and sluggish, tonic responses of ipRGCs, although the quantitative discrepancies between

Is melanopsin the photopigment of intrinsically photosensitive ganglion cells?

At present, melanopsin is by far the best candidate for the ipRGC photopigment. This opsin protein is found within, and perhaps only within, these novel photoreceptors 43, 45, 47. It is located not only in their cell bodies but also in their proximal axons and throughout their dendrites 43, 45, 46. This satisfies an important criterion for the photopigment in ipRGCs, because their dendrites are independently photosensitive [48]. Perhaps most tellingly, genetic deletion of melanopsin eliminates

Morphology of ipRGCs

In rodents, ∼1000–2000 ganglion cells (∼1–3% of all ganglion cells) contain melanopsin [45]. Most reside in the ganglion cell layer but a few are displaced to the inner nuclear layer 37, 42, 45. Melanopsin-positive RGCs are present throughout the retina, with somewhat higher density superiorly 43, 45. Their dendrites form an extensively overlapping plexus in the inner plexiform layer (IPL) 37, 45, 46. Dendritic profiles of individual melanopsin-positive RGCs (or ipRGCs) are large (Fig. 1c and e

Intraretinal synaptic modulation: influences of rods and cones

The dendrites of ipRGCs serve, like rod and cone outer segments, as sites of phototransduction. In addition, however, they also play a role more typical of ganglion-cell dendrites, as targets of synaptic input from amacrine and bipolar cells (Fig. 1d). Rods or cones drive brisk, synaptically mediated excitatory ON responses in some ipRGCs when recorded under appropriate conditions (F.A. Dunn and D.M. Berson, unpublished) and melanopsin-immunopositive dendrites receive synaptic contacts from

Beyond circadian entrainment: other functional roles of ipRGCs

Intrinsically photosensitive RGCs appear to contribute to photic regulation of pineal melatonin release. Light at night suppresses otherwise high nocturnal plasma melatonin levels through a circuitous pathway originating with the retinohypothalamic tract [77] (Fig. 2). Such photic melatonin suppression persists in rodless and coneless mice and in some blind people 29, 78, and its action spectrum bears some resemblance to that of ipRGCs 79, 80. Changes in day length act through this pathway to

Concluding remarks

Recent findings have identified a novel photoreceptor of the mammalian retina. The ipRGC is a rare type of ganglion cell with distinctive morphological and functional features. This photoreceptor appears to sacrifice spatial and temporal resolution so as to encode faithfully the intensity of bright environmental illumination. It plays a key role in diverse physiological responses to daylight, including setting the biological clock, regulating activity and melatonin levels, and adjusting pupil

Acknowledgments

I am grateful to many colleagues for helpful discussions, especially to Felice Dunn, Motoharu Takao, Ignacio Provencio, Mark Rollag, King-Wai Yau, Samer Hattar and Russell Van Gelder. I thank Russell Van Gelder and anonymous referees for their critiques of the manuscript. The intracellular fill illustrated in Fig. 1(e) was generated by Felice Dunn. Supported by NIH grant R01 EY12793.

References (90)

R.F. Johnson
Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract
Brain Res.
(1988)
L.P. Morin
The circadian visual system
Brain Res. Brain Res. Rev.
(1994)
G.E. Pickard
Morphological characteristics of retinal ganglion cells projecting to the suprachiasmatic nucleus: a horseradish peroxidase study
Brain Res.
(1980)
D.E. Nelson et al.
Comparison of visual sensitivity for suppression of pineal melatonin and circadian phase-shifting in the golden hamster
Brain Res.
(1991)
J.H. Meijer
Luminance coding in a circadian pacemaker: the suprachiasmatic nucleus of the rat and the hamster
Brain Res.
(1986)
S. Ebihara et al.
Entrainment of the circadian activity rhythm to the light cycle: effective light intensity for a Zeitgeber in the retinal degenerate C3H mouse and the normal C57BL mouse
Physiol. Behav.
(1980)
R.G. Foster
Shedding light on the biological clock
Neuron
(1998)
R.J. Lucas
Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice
Behav. Brain Res.
(2001)
C. Helfrich-Forster
The circadian clock of fruit flies is blind after elimination of all known photoreceptors
Neuron
(2001)
R.J. Nelson et al.
Absence of extra-ocular photoreception in diurnal and nocturnal rodents exposed to direct sunlight
Comp. Biochem. Physiol. A
(1981)

I. Provencio et al.

Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics

Brain Res.

(1995)

S. Halford

Characterization of a novel human opsin gene with wide tissue expression and identification of embedded and flanking genes on chromosome 1q43

Genomics

(2001)

J.C. Hall

Cryptochromes: sensory reception, transduction, and clock functions subserving circadian systems

Curr. Opin. Neurobiol.

(2000)

M.E. Harrington

The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems

Neurosci. Biobehav. Rev.

(1997)

M.W. Hankins et al.

The primary visual pathway in humans is regulated according to long- term light exposure through the action of a nonclassical photopigment

Curr. Biol.

(2002)

D.C. Klein

Suprachiasmatic Nucleus: The Mind's Clock

(1991)

P.F. Devlin et al.

Circadian photoperception

Annu. Rev. Physiol.

(2001)

D.P. King et al.

Molecular genetics of circadian rhythms in mammals

Annu. Rev. Neurosci.

(2000)

S.M. Reppert et al.

Coordination of circadian timing in mammals

Nature

(2002)

M.A. Rea

Photic entrainment of circadian rhythms in rodents

Chronobiol. Int.

(1998)

T. Roenneberg et al.

Twilight times: light and the circadian system

Photochem. Photobiol.

(1997)

R.Y. Moore et al.

A retinohypothalamic projection in the rat

J. Comp. Neurol.

(1972)

R.Y. Moore

The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells

J. Comp. Neurol.

(1995)

A. Sousa-Pinto et al.

Light microscopic observations on the possible retinohypothalamic projection in the rat

Exp. Brain Res.

(1970)

R.G. Foster

Keeping an eye on the time: the Cogan Lecture

Invest. Ophthalmol. Vis. Sci.

(2002)

D.E. Nelson et al.

Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus)

J. Physiol. (Lond.)

(1991)

J.S. Takahashi

Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms

Nature

(1984)

O. Dkhissi-Benyahya

Effects of irradiance and stimulus duration on early gene expression (Fos) in the suprachiasmatic nucleus: temporal summation and reciprocity

J. Neurosci.

(2000)

R.G. Foster

Circadian photoreception in the retinally degenerate mouse (rd/rd)

J. Comp. Physiol. [A]

(1991)

E.B. Klerman

Photic resetting of the human circadian pacemaker in the absence of conscious vision

J. Biol. Rhythms

(2002)

M.S. Freedman

Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors

Science

(1999)

J. Shand et al.

The extraretinal photoreceptors of non-mammalian vertebrates

B. Vigh

Nonvisual photoreceptors of the deep brain, pineal organs and retina

Histol. Histopathol.

(2002)

B.D. Zivkovic

Circadian ovulatory rhythms in Japanese quail: role of ocular and extraocular pacemakers

J. Biol. Rhythms

(2000)

C.A. Czeisler

Suppression of melatonin secretion in some blind patients by exposure to bright light

N. Engl. J. Med.

(1995)

S.W. Lockley

Relationship between melatonin rhythms and visual loss in the blind

J. Clin. Endocrinol. Metab.

(1997)

S. Yamazaki

No evidence for extraocular photoreceptors in the circadian system of the Syrian hamster

J. Biol. Rhythms

(1999)

S.S. Campbell et al.

Extraocular circadian phototransduction in humans

Science

(1998)

C.I. Eastman

Failure of extraocular light to facilitate circadian rhythm reentrainment in humans

Chronobiol. Int.

(2000)

N. Lindblom

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms

NeuroReport

(2000)

K.P. Wright et al.

Absence of circadian phase resetting in response to bright light behind the knees

Science

(2002)

J. Hannibal et al.

Melanopsin: a novel photopigment involved in the photoentrainment of the brain's biological clock?

Ann. Med.

(2002)

R.N. Van Gelder

Tales from the crypt(ochromes)

J. Biol. Rhythms

(2002)

A. Sancar

Cryptochrome: the second photoactive pigment in the eye and its role in circadian photoreception

Annu. Rev. Biochem.

(2000)

C.L. Thompson et al.

Photolyase/cryptochrome blue-light photoreceptors use photon energy to repair DNA and reset the circadian clock

Oncogene

(2002)

Cited by (429)

Blue light and intraocular lenses (IOLs): Beliefs and realities
2024, Journal Francais d'Ophtalmologie
Les premiers implants intraoculaires utilisés pour la chirurgie de la cataracte transmettaient à la fois les rayonnements ultraviolets (UV) et la lumière visible à la rétine. Des implants incolores bloquant les UV ont été introduits et rapidement adoptées dans les années 1980. Des implants bloquant le bleu (ou filtrant le bleu), teintées en jaune, ont été commercialisées au début des années 1990. Ces implants visaient à simuler le jaunissement du cristallin âgé et réduire la cyanopsie signalée par certains patients après chirurgie de la cataracte. Par la suite, lorsque ces implants filtrant le bleu ont été introduits en Amérique du Nord, ils ont été présentés par les fabricants comme un moyen de protéger les patients de la dégénérescence maculaire liée à l’âge (DMLA). Le terme « toxicité de la lumière bleue » provient de constatations expérimentales selon lesquelles les expositions aiguës à une lumière anormalement intense sont potentiellement plus phototoxiques pour la rétine lorsque des longueurs d’onde courtes sont utilisées. Ainsi, lors d’expositions brèves à des sources lumineuses intenses comme pour la soudure à l’arc, les UV sont plus dangereux que la lumière bleue, qui est elle-même plus dangereuse que la lumière verte ou rouge, de plus grande longueur d’onde. Les commissions internationales ont précisé à plusieurs reprises que les risques associés à la lumière bleue ne s’appliquent pas aux expositions normales à la lumière à l’intérieur ou à l’extérieur. Pourtant, cette notion de risque reste encore utilisée dans un but commercial pour suggérer que la lumière ambiante pourrait provoquer une phototoxicité rétinienne aiguë et augmenter le risque de DMLA. Les implants filtrant le bleu n’ont pourtant pas montré de réduction de l’incidence ni de la progression de la DMLA dans les études épidémiologiques réalisées sur de très grands échantillons. La lumière bleue est essentielle pour la photoréception scotopique des personnes âgées, nécessaire pour réduire le risque de chute nocturne et les blessures qui y sont liées. Elle est également essentielle pour la photoréception circadienne, indispensable à la santé, au sommeil et aux performances cognitives. Le myosis pupillaire lié à l’âge, la perte de bâtonnets et de cellules ganglionnaires ainsi que la diminution de l’activité en plein air réduisent la quantité de lumière bleue dont disposent les personnes âgées. Les implants filtrant le bleu restreignent encore davantage la lumière bleue disponible au moment où les personnes âgées en ont le plus besoin. Les patients et les ophtalmologues sont exposés à des publicités qui vantent divers dispositifs optiques filtrants qui suppriment la lumière bleue pourtant essentielle tant pour la vision avec un faible éclairage, que pour le maintien d’une bonne santé physique et mentale. Le choix des lunettes et des implants intraoculaires devrait reposer sur des faits scientifiques et non sur des conjectures. Nous devons aux patients une information claire, loyale et appropriée, basée sur les connaissances actuelles. Ce devoir d’information impose une contrainte de temps mais le choix de l’implant associé à la chirurgie de la cataracte est définitif. Il est donc nécessaire de prévenir les patients que le choix d’un implant jaune filtrant les bleus limiterait leur vision de façon permanente en échange d’une protection contre un risque non prouvé. Dans notre pratique, le volume de patients, l’organisation des consultations, les relations médecin-fabricant pourraient parfois réduire la possibilité d’information et de ce choix éclairé entre un implant incolore transmettant les bleus ou un implant jaune filtrant les bleus. Chaque ophtalmologiste doit décider lui-même s’il souhaite donner ce choix à ses patients.
The first intraocular lenses (IOLs) used for cataract surgery transmitted both ultraviolet (UV) radiation and visible light to the retina. Colorless UV-blocking IOLs were introduced and rapidly adopted in the 1980s. Yellow-tinted blue-blocking (also known as blue-filtering) IOLs were marketed in the early 1990s. Blue-blocking IOLs were intended to simulate age-related crystalline lens yellowing to reduce the cyanopsia that some patients experienced after cataract surgery. When blue-filtering IOLs were introduced in North America, however, blue-blocking chromophores were advocated as a way to protect patients from age-related macular degeneration (AMD) despite the lack of evidence that normal environmental light exposure causes AMD. The “blue light hazard” is a term that describes the experimental finding that acute, abnormally intense light exposures are potentially more phototoxic to the retina when short rather than long wavelengths are used. Thus, in brief exposures to intense light sources such as welding arcs, ultraviolet radiation is more hazardous than blue light, which is more hazardous than longer wavelength green or red light. International commissions have cautioned that the blue light hazard does not apply to normal indoor or outdoor light exposures. Nonetheless, the hazard is used for commercial purposes to suggest misleadingly that ambient environmental light can cause acute retinal phototoxicity and increase the risk of AMD. Very large epidemiological studies show that blue-blocking IOLs do not reduce the risk or progression of AMD. Additionally, blue-filtering IOLs or spectacles cannot decrease glare disability, because they decrease image and glare illuminance in the same proportion. Blue light is essential for older adults’ scotopic photoreception needed to reduce the risk of nighttime falling and related injuries. It is also critical for circadian photoreception that is essential for good health, sleep and cognitive performance. Unfortunately, age-related pupillary miosis, retinal rod and ganglion cell photoreceptor degeneration and decreased outdoor activity all reduce the amount of healthful blue light available to older adults. Blue-restricting IOLs further reduce the available blue light at a time when older adults need it most. Patients and ophthalmologists are exposed to hypothesis-based advertisements for blue-filtering optical devices that suppress short wavelength light critical for vision in dim lighting and for good physical and mental health. Spectacle and intraocular lens selections should be based on scientific fact, not conjecture. Ideal IOLs should improve photoreception rather than limit it permanently. Practice efficiency, surgical convenience and physician-manufacturer relationships may eliminate a patient's opportunity to choose between colorless blue-transmitting IOLs and yellow-tinted, blue-restricting IOLs. Cataract surgeons ultimately determine whether their patients have the opportunity to make an informed choice about their future photoreception.
A systematic literature review: Building window's influence on indoor circadian health
2023, Renewable and Sustainable Energy Reviews
Light has been shown to have a non-visual impact on the biological aspects of human health, particularly on circadian rhythms. Building windows are a potential means of regulating daylight conditions for circadian health and well-being. As a result of advancements in window and glazing technologies and variations in outdoor solar/sky conditions, understanding daylight's spectral characteristics, which pass through building window systems, is complex. Therefore, a systematic review and summary of the knowledge and evidence available regarding windows' impact on human circadian health is necessary. This study provides an overview of research in this domain, compares approaches and evaluation metrics, and underscores the importance of window parameters' influence on circadian health. Published studies available on various online databases since 2012 were evaluated. The findings of this study define a holistic approach to the melanopic performance of windows and provide an overview of current knowledge regarding the effect of windows on circadian health. Additionally, this work identifies future research directions based on the studies reviewed. This research contributes to the growing body of knowledge on the impact of windows on circadian health, which has implications for the design and construction of buildings in ways that support indoor human health and well-being from the circadian light adequacy perspective.
The stress of losing sleep: Sex-specific neurobiological outcomes
2023, Neurobiology of Stress
Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies. Advancing our understanding of the role of biological sex in the responses to sleep loss stands to greatly improve our ability to understand and treat health consequences of insufficient sleep. As such, this review discusses sex differences in response to sleep deprivation, with a focus on the sympathetic nervous system stress response and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We review sex differences in several stress-related consequences of sleep loss, including inflammation, learning and memory deficits, and mood related changes. Focusing on women's health, we discuss the effects of sleep deprivation during the peripartum period. In closing, we present neurobiological mechanisms, including the contribution of sex hormones, orexins, circadian timing systems, and astrocytic neuromodulation, that may underlie potential sex differences in sleep deprivation responses.
Circadian clock organization in the retina: From clock components to rod and cone pathways and visual function
2023, Progress in Retinal and Eye Research
Circadian (24-h) clocks are cell-autonomous biological oscillators that orchestrate many aspects of our physiology on a daily basis. Numerous circadian rhythms in mammalian and non-mammalian retinas have been observed and the presence of an endogenous circadian clock has been demonstrated. However, how the clock and associated rhythms assemble into pathways that support and control retina function remains largely unknown. Our goal here is to review the current status of our knowledge and evaluate recent advances. We describe many previously-observed retinal rhythms, including circadian rhythms of morphology, biochemistry, physiology, and gene expression. We evaluate evidence concerning the location and molecular machinery of the retinal circadian clock, as well as consider findings that suggest the presence of multiple clocks. Our primary focus though is to describe in depth circadian rhythms in the light responses of retinal neurons with an emphasis on clock control of rod and cone pathways. We examine evidence that specific biochemical mechanisms produce these daily light response changes. We also discuss evidence for the presence of multiple circadian retinal pathways involving rhythms in neurotransmitter activity, transmitter receptors, metabolism, and pH. We focus on distinct actions of two dopamine receptor systems in the outer retina, a dopamine D₄ receptor system that mediates circadian control of rod/cone gap junction coupling and a dopamine D₁ receptor system that mediates non-circadian, light/dark adaptive regulation of gap junction coupling between horizontal cells. Finally, we evaluate the role of circadian rhythmicity in retinal degeneration and suggest future directions for the field of retinal circadian biology.
Müller glial cell photosensitivity: A novel function bringing higher complexity to vertebrate retinal physiology
2023, Journal of Photochemistry and Photobiology
The retina of vertebrates is responsible for detecting and capturing ambient light for image and non-image forming (NIF) functions through diverse projections to the brain which regulate visual processing, pupillary light responses, photic synchronization of circadian rhythms and suppression of pineal melatonin, among others. For this, vertebrates have retained through evolution at least two sets of photoreceptors specialized primarily in such visual and NIF tasks: visual photoreceptors cones and rods responsible for day/night vision, and intrinsically photosensitive retinal ganglion cells (ipRGC) together with horizontal cells in some vertebrates, expressing melanopsin (Opn4). Interestingly, Opn4 as well as encephalopsin (Opn3) and neuropsin (Opn5), responding to blue and UV light, respectively, are expressed in the inner retina and command light detection in the blue range of the visible spectra; they are responsible for a number of NIF functions still lacking characterization. Though most retinal photoreceptors are derived from ciliary or neuronal progenitor cells, in recent years Müller glial cells (MCs), the most abundant retinal glial cell type, have been shown to express different blue opsins (Opn3 and Opn5) and the photoisomerase retinal G protein-coupled receptor (RGR), and to respond directly to light. MCs display different essential functions to maintain the homeostasis and cell survival of the whole retina, contributing to glutamate metabolism and chromophore recycling. The novel photoreceptive capacity of MCs, mainly in the blue region, offers several highly intriguing possibilities that increase the complexity levels for light detection in the retina and its light-activated circuits, calling for further investigation. The goal of the present review is to discuss the state of the art of research on the principal macroglial cells in the retina, focusing mainly on the novel photic responses driven by MCs, the biochemical mechanisms triggered after light stimulation and their putative functions and implications.
Interplay between aging and other factors of the pathogenesis of age-related macular degeneration
2022, Ageing Research Reviews
Citation Excerpt :
In mammals, light absorption occurs only in the retina by photoreceptors: cones, rods and intrinsically photosensitive retinal ganglion cells (ipRGCs) (Paul and Elabi, 2022). In contrary to “classical” photoreceptors, ipRGCs may directly communicate with the master circadian pacemaker located in the SCN and other structures of the brain, so they may also affect some physiological functions independently of the retinal circadian system (Berson, 2003). Impairment of retinal clocks may be involved in pathogenesis of retinal diseases (Bery et al., 2022).
Age-related macular degeneration (AMD) is a complex eye disease with the retina as the target tissue and aging as per definition the most serious risk factor. However, the retina contains over 60 kinds of cells that form different structures, including the neuroretina and retinal pigment epithelium (RPE) which can age at different rates. Other established or putative AMD risk factors can differentially affect the neuroretina and RPE and can differently interplay with aging of these structures. The occurrence of β-amyloid plaques and increased levels of cholesterol in AMD retinas suggest that AMD may be a syndrome of accelerated brain aging. Therefore, the question about the real meaning of age in AMD is justified. In this review we present and update information on how aging may interplay with some aspects of AMD pathogenesis, such as oxidative stress, amyloid beta formation, circadian rhythm, metabolic aging and cellular senescence. Also, we show how this interplay can be specific for photoreceptors, microglia cells and RPE cells as well as in Bruch’s membrane and the choroid. Therefore, the process of aging may differentially affect different retinal structures. As an accurate quantiﬁcation of biological aging is important for risk stratiﬁcation and early intervention for age-related diseases, the determination how photoreceptors, microglial and RPE cells age in AMD may be helpful for a precise diagnosis and treatment of this largely untreatable disease.

View all citing articles on Scopus

View full text

Trends in Neurosciences

Strange vision: ganglion cells as circadian photoreceptors

Abstract

Section snippets

Synchronization of circadian rhythms

Behavioral evidence for novel ocular photoreceptors

Melanopsin – a candidate circadian photopigment

Intrinsic photosensitivity of ganglion cells innervating the circadian pacemaker

Functional features of ipRGCs

Congruence of ipRGC light responses with properties of the photoentrainment mechanism

Is melanopsin the photopigment of intrinsically photosensitive ganglion cells?

Morphology of ipRGCs

Intraretinal synaptic modulation: influences of rods and cones

Beyond circadian entrainment: other functional roles of ipRGCs

Concluding remarks

Acknowledgments

Brain Res.

Brain Res. Brain Res. Rev.

Brain Res.

Brain Res.

Brain Res.

Physiol. Behav.

Neuron

Behav. Brain Res.

Neuron

Comp. Biochem. Physiol. A

Brain Res.

Genomics

Curr. Opin. Neurobiol.

Neurosci. Biobehav. Rev.

Curr. Biol.

Suprachiasmatic Nucleus: The Mind's Clock

Circadian photoperception

Annu. Rev. Physiol.

Molecular genetics of circadian rhythms in mammals

Annu. Rev. Neurosci.

Coordination of circadian timing in mammals

Nature

Photic entrainment of circadian rhythms in rodents

Chronobiol. Int.

Twilight times: light and the circadian system

Photochem. Photobiol.

A retinohypothalamic projection in the rat

J. Comp. Neurol.

The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells

J. Comp. Neurol.

Light microscopic observations on the possible retinohypothalamic projection in the rat

Exp. Brain Res.

Keeping an eye on the time: the Cogan Lecture

Invest. Ophthalmol. Vis. Sci.

Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus)

J. Physiol. (Lond.)

Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms

Nature

Effects of irradiance and stimulus duration on early gene expression (Fos) in the suprachiasmatic nucleus: temporal summation and reciprocity

J. Neurosci.

Circadian photoreception in the retinally degenerate mouse (rd/rd)

J. Comp. Physiol. [A]

Photic resetting of the human circadian pacemaker in the absence of conscious vision

J. Biol. Rhythms

Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors

Science

The extraretinal photoreceptors of non-mammalian vertebrates

Nonvisual photoreceptors of the deep brain, pineal organs and retina

Histol. Histopathol.

Circadian ovulatory rhythms in Japanese quail: role of ocular and extraocular pacemakers

J. Biol. Rhythms

Suppression of melatonin secretion in some blind patients by exposure to bright light

N. Engl. J. Med.

Relationship between melatonin rhythms and visual loss in the blind

J. Clin. Endocrinol. Metab.

No evidence for extraocular photoreceptors in the circadian system of the Syrian hamster

J. Biol. Rhythms

Extraocular circadian phototransduction in humans

Science

Failure of extraocular light to facilitate circadian rhythm reentrainment in humans

Chronobiol. Int.

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms

NeuroReport

Absence of circadian phase resetting in response to bright light behind the knees