Trends in Neurosciences
Strange vision: ganglion cells as circadian photoreceptors
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)
Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract
Brain Res.
(1988)The circadian visual system
Brain Res. Brain Res. Rev.
(1994)Morphological characteristics of retinal ganglion cells projecting to the suprachiasmatic nucleus: a horseradish peroxidase study
Brain Res.
(1980)- et al.
Comparison of visual sensitivity for suppression of pineal melatonin and circadian phase-shifting in the golden hamster
Brain Res.
(1991) Luminance coding in a circadian pacemaker: the suprachiasmatic nucleus of the rat and the hamster
Brain Res.
(1986)- 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) Shedding light on the biological clock
Neuron
(1998)Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice
Behav. Brain Res.
(2001)The circadian clock of fruit flies is blind after elimination of all known photoreceptors
Neuron
(2001)- et al.
Absence of extra-ocular photoreception in diurnal and nocturnal rodents exposed to direct sunlight
Comp. Biochem. Physiol. A
(1981)
Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics
Brain Res.
Characterization of a novel human opsin gene with wide tissue expression and identification of embedded and flanking genes on chromosome 1q43
Genomics
Cryptochromes: sensory reception, transduction, and clock functions subserving circadian systems
Curr. Opin. Neurobiol.
The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems
Neurosci. Biobehav. Rev.
The primary visual pathway in humans is regulated according to long- term light exposure through the action of a nonclassical photopigment
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
Science
Melanopsin: a novel photopigment involved in the photoentrainment of the brain's biological clock?
Ann. Med.
Tales from the crypt(ochromes)
J. Biol. Rhythms
Cryptochrome: the second photoactive pigment in the eye and its role in circadian photoreception
Annu. Rev. Biochem.
Photolyase/cryptochrome blue-light photoreceptors use photon energy to repair DNA and reset the circadian clock
Oncogene
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2022, Ageing Research ReviewsCitation 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).