Photosensitive ganglion cells, also called
photosensitive Retinal Ganglion Cells (pRGC),
intrinsically photosensitive Retinal Ganglion Cells (ipRGC) or
melanopsin-containing ganglion cells, are a recently discovered type of nerve
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos...
in the
retinaThe vertebrate retina is a light sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
of the mammalian
eyeEyes are organs that detect light, and send electrical impulses along the optic nerve to the visual and other areas of the brain. Complex optical systems with resolving power have come in ten fundamentally different forms, and 96% of animal species possess a complex optical system...
which, unlike other retinal
ganglion cellA retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...
s, are intrinsically photosensitive. This means that they are a third class of retinal
photoreceptorA photoreceptor, or photoreceptor cell, is a specialized type of neuron found in the eye's retina that is capable of phototransduction. The great biological importance of photoreceptors is that as cells they convert light into the beginning of a chain of biological processes...
s, excited by light even when all influences from classical photoreceptors (
rodsRod cells, or rods, are photoreceptor cells in the retina of the eye that can function in less intense light than can the other type of photoreceptor, cone cells. Because they are more light sensitive, rods are responsible for night vision. Named for their cylindrical shape, rods are concentrated...
and
conesCone cells, or cones, are photoreceptor cells in the retina of the eye that function best in relatively bright light. The cone cells gradually become sparser towards the periphery of the retina....
) are blocked (either by applying pharmacological agents or by dissociating the ganglion cell from the retina). Photosensitive ganglion cells contain the
photopigmentPhotopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and photoreception...
melanopsinMelanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...
. The
giant retinal ganglion cellsGiant retinal ganglion cells are photosensitive ganglion cells with large dendritic trees discovered in the human and macaque retina by Dacey et al. ....
of the primate retina are examples of photosensitive ganglion cells.
Brief overview
Compared to the rods and cones, the ipRGC respond more sluggishly and signal the presence of light over the long term. Their functional roles are non-image-forming and fundamentally different from those of pattern vision; they provide a stable representation of ambient light intensity. They have at least three primary functions.
- They play a major role in synchronizing circadian rhythm
A circadian rhythm is a roughly-24-hour cycle in the biochemical, physiological or behavioral processes of living entities, including plants, animals, fungi and cyanobacteria...
s to the 24-hour light/dark cycle, providing primarily length-of-day and length-of night information. They send light information via the retinohypothalamic tractThe retinohypothalamic tract is a photic input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive Retinal Ganglion Cells , which contain the photopigment melanopsin...
directly to the circadian pacemaker of the brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
, the suprachiasmatic nucleusThe suprachiasmatic nucleus, or nuclei, , a tiny region on the brain's midline in a shallow impression of the optic chiasm, is responsible for controlling endogenous circadian rhythms...
of the hypothalamusThe hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
. The physiological properties of these ganglion cells match known properties of the daily light entrainmentIn chronobiology, entrainment of a circadian system is the alignment of its own period and phase to the period and phase of an external rhythm. A common example is the entrainment of endogenous circadian rhythms to the daily light-dark cycle...
(synchronizationSynchronization or synchronisation is timekeeping which requires the coordination of events to operate a system in unison. The familiar conductor of an orchestra serves to keep the orchestra in time....
) mechanism regulating circadian rhythms.
- Photosensitive ganglion cells also innervate other brain targets, such as the center of pupillary control
The pupillary light reflex is a reflex that controls the diameter of the pupil, in response to the intensity of light that falls on the retina of the eye. Greater intensity light causes the pupil to become smaller , whereas lower intensity light causes the pupil to become larger...
, the olivary pretectal nucleus of the midbrain. They contribute to the regulation of pupilThe pupil is an opening located in the center of the iris of the eye that allows light to enter the retina. It appears black because most of the light entering the pupil is absorbed by the tissues inside the eye. In humans the pupil is round, but other species, such as some cats, have slit pupils...
size and other behavioral responses to ambient lighting conditions.
- They contribute to photic regulation of, and acute photic suppression of, release of the hormone melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone found in animals and in some other living organisms, including algae. Circulating levels vary in a daily cycle, and melatonin is important in the regulation of the circadian rhythms of several...
from the pineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces melatonin, a hormone that affects the modulation of wake/sleep patterns and photoperiodic functions...
.
Photosensitive ganglion cells are also responsible for the persistence of circadian and pupillary light responses in mammals with degenerated rod and cone photoreceptors, such as humans suffering from
retinitis pigmentosaRetinitis pigmentosa is a group of genetic eye conditions. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some sight all their lives . Others go...
.
Recently photoreceptive ganglion cells have been isolated in humans where, in addition to the above functions shown in other mammals, they have been shown to mediate a degree of light recognition in rodless, coneless subjects suffering with disorders of rod and cone photoreceptors. This work by Zaidi and colleagues showed that photoreceptive ganglion cells may have a visual function and can be isolated in humans.
The photopigment of these photoreceptive ganglion cells, melanopsin, is excited by light mainly in the blue portion of the visible spectrum (absorption peaks at ~480 nanometers). The phototransduction mechanism in these cells is not fully understood, but seems likely to resemble that in invertebrate
rhabdomRhabdoms are transparent rods, found in the center of each ommatidium in the compound eye of arthropods. These rods are constructed from the eight photoreceptor cells in the ommatidium. Each photocell is long and thin. They pack their area of the ommatidium completely filling the space...
eric photoreceptors. Photosensitive ganglion cells respond to light by depolarizing and increasing the rate at which they fire nerve impulses. In addition to responding directly to light, these cells may receive excitatory and inhibitory influences from rods and cones by way of synaptic connections in the retina.
Discovery of photoreceptive ganglion cells
In 1991
Russell G. FosterRussell G. Foster is a British professor of circadian neuroscience. He and his group are credited with the discovery of the non-rod, non-cone, photosensitive ganglion cells in the mammalian retina which provide input to the circadian rhythm system....
and colleagues including Ignacio Provencio discovered a non-rod, non-cone photoreceptor in the eyes of mice where it was shown to mediate circadian rhythms i.e. the body's 24-hour biological clock. The fact that such a landmark discovery was published in a relatively obscure science journal indicates the initial skepticism about the existence of non-rod, non-cone photoreceptors within the scientific community, which continued to widely believe that the only photoreceptors were rods and cones as if this were written in stone - and why not, after all, as Foster himself notes, the eye had been the subject of detailed study for a continuous period of over 200 years, so at the time it seemed unlikely that great minds since Newton, Maxwell, through to Einstein and beyond, could have missed this receptor's existence, its functions, and its ramifications. But miss it they did and it fell to contemporary researchers to make the landmark discoveries in the field, ground-breaking discoveries that still continue to be made. These novel cells express the photopigment melanopsin which was first identified by Ignacio Provencio and colleagues who published in the Journal of Neuroscience in 2000. Note how after almost one whole decade, major advances in the field would henceforth only be published in major biology and science journals, reflecting the gradual acceptance of the novel receptor by the scientific community.
Melanopsin absorbs different maximal wavelength
Robert Lucas and colleagues including Russell Foster were the first to show conclusively that cells containing the photopigment melanopsin absorb light maximally at different wavelength than those of rods and cones. Lucas, Foster and colleagues also discovered that in mice the non-rod, non-cone photoreceptor had a role in initiating the pupil light reflex and not only circadian / behavioural functions as previously thought, though the latter were also demonstrated by them using genetically engineered rodless, coneless mice . Samer Hattar and colleagues including David Berson in 2002 showed that in the rat, intrinsically photosensitive retinal ganglion cells invariably expressed melanopsin, and so melanopsin (and not rod or cone
opsinOpsins are a group of light-sensitive 35-55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical...
s) was most likely the visual pigment of phototransducing retinal ganglion cells that set the circadian clock and initiated other non-image-forming visual functions. This work is regarded by
Current BiologyCurrent Biology is a scientific journal that covers all areas of biology, especially molecular biology, cell biology, genetics, neurobiology, ecology and evolutionary biology. The journal is published twice a month and includes peer-reviewed research articles, various types of review articles, as...
,
New ScientistNew Scientist is a weekly international science magazine and website covering recent developments in science and technology for a general English-speaking audience. Founded in 1956, it is published by Reed Business Information Ltd, a subsidiary of Reed Elsevier. New Scientist has maintained a...
and various other commentators as representing the discovery that the identity of the non-rod, non-cone photoreceptor in mice was a class of retinal ganglion cells (RGCs). This was highly significant anatomically - ganglion cells reside in the inner retina, while classic photoreceptors (rods and cones) inhabit the outer retina, suggesting two parallel and anatomically distinct photoreceptor pathways.
In the same year, 2005, Melyan and Qiu together with colleagues including Robert Lucas, Mark W. Hankins and David Berson, showed that the melanopsin photopigment was the phototransduction pigment in ganglion cells. Dennis Dacey with colleagues including Paul Gamlin showed in a species of Old World monkey that giant ganglion cells expressing melanopsin projected to the lateral geniculate nucleas. Previously only projections to the midbrain (pre-tectal nucleas) and hypothalamus (
supra-chiasmatic nucleasThe suprachiasmatic nucleus, or nuclei, , a tiny region on the brain's midline in a shallow impression of the optic chiasm, is responsible for controlling endogenous circadian rhythms...
, SCN) had been shown. However a visual role for the receptor was still unsuspected and unproven.
Research in humans
Attempts started to be made to hunt down the receptor in humans. But humans posed special challenges and demanded a new model - for unlike in animals, extensive ethical issues meant rod and cone loss could not be induced genetically or with chemicals so as to directly study the ganglion cells. For many years, only inferences could be drawn about the receptor in humans, though these were at times pertinent.
In 2007 the breakthrough came when Farhan H. Zaidi and colleagues including Russell Foster, George Brainard, Charles A. Czeisler and Steven Lockley, having teamed up with other researchers on both sides of the Atlantic, published their pioneering work using rodless, coneless humans. Current Biology subsequently announced in their 2008 editorial, commentary and despatches to scientists and ophthalmologists, that the non-rod, non-cone photoreceptor had been conclusively discovered in humans using landmark experiments on rodless, coneless humans by Zaidi and colleagues. The 2007 discovery of the novel receptor in humans, as well as the spectacular discovery, made alongside, that it mediated conscious sight, was trumpeted by Cell Press, New Scientist, and other science commentators in 2007. The workers found the identity of the non-rod, non-cone photoreceptor in humans to be a ganglion cell in the inner retina as had been shown previously in rodless, coneless models in some other mammals. The workers had tracked down patients with rare diseases wiping out classic rod and cone photoreceptor function but preserving ganglion cell function. Despite having no rods or cones the patients continued to exhibit circadian photoentrainment, circadian behavioural patterns, melanopsin suppression, and pupil reactions, with peak spectral sensitivities to environmental and experimental light matching that for the melanopsin photopigment. Their brains could also associate vision with light of this frequency. Jacob Schor comments that in addition to being an outstanding example of collaboration between different countries, as well as between clinicians and scientists, interest thenceforth started to be shown by clinicians including ophthalmologists with a view to understanding the new receptor's role in human diseases and as discussed below, blindness.
New role for conscious sight
The use of rodless, coneless humans allowed another possible role for the receptor to be studied. In 2007, arguably the most fascinating novel role was found for the photoreceptive ganglion cell. Farhan H. Zaidi and colleagues including Russell Foster, George Brainard, Charles A. Czeisler and Steven Lockley, showed that the retinal ganglion cell was a photoreceptor (at least in humans) for conscious sight and not only non-image-forming functions like circadian rhythms, behaviour and pupil reactions as previously thought. Humans were the perfect model in which to prove this function as they can describe sight readily to an observer, which animals cannot do. Hence the receptor by its location anatomically in the inner retina as shown by these researchers was the first cell to perceive light giving rise to vision. They also showed it responded most to blue light, suggesting it may have a role in
mesopic visionMesopic vision is a combination of photopic vision and scotopic vision in low but not quite dark lighting situations.The combination of the higher total sensitivity of the rods in the eye for the blue range with the color perception through the cones results in a very strong appearance of blue-ish...
and the old theory of a purely
duplex retinaA duplex retina is a retina consisting of both, rod cells and cone cells. In contrast to duplex retinas, pure rod and pure cone retinas have only rods or cones, respectively....
with rod (dark) and cone (light) light vision was simplistic. Hence, Zaidi and colleagues' work with rodless, coneless human subjects also opened the door into image-forming (visual) roles for the ganglion cell photoreceptor.
It also made the important discovery that there are parallel pathways for vision - one classic rod and cone-based arising from the outer retina, the other a rudimentary visual brightness detector arising from the inner retina and which seems to be activated by light before the other. Classic photoreceptors also feed into the novel photoreceptor system, and colour constancy may be an important role as suggested by Foster. Like many of the key discoveries about the new receptor, the work by Zaidi and colleagues shatters hundreds of years of what science thought it knew about the most basic function of the eye and vision.
The authors on the rodless, coneless human model summarised their landmark paper noting for the first time that the receptor could be instrumental in understanding many diseases including major causes of blindness worldwide such as
glaucomaGlaucoma is a group of diseases that affect the optic nerve and involves a loss of retinal ganglion cells in a characteristic pattern. It is a type of optic neuropathy. Raised intraocular pressure is a significant risk factor for developing glaucoma...
, a disease which affects ganglion cells. Study of the receptor offered potential as a new avenue to explore in trying to find treatments for blindness. It is in these discoveries of the novel photoreceptor in humans and in the receptor's role in vision, rather than its non-image-forming functions, where the receptor may have the greatest impact on society as a whole, though the impact of disturbed circadian rhythms is another area of relevance to clinical medicine.
Violet-to-blue light
Most work suggests that the peak spectral sensitivity of the receptor is between 460 and 484 nm, though a minority of groups reported it being lower, as far as 420 nm. Steven Lockley et al. in 2003 showed that 460 nm (violet) wavelengths of light suppress melatonin twice as much as longer 535 nm (green) light, the peak sensitivity of the photopic visual system. However, in more recent work by Farhan Zaidi, Steven Lockley and co-authors using a rodless, coneless human, it was found that what consciously led to light perception was a very intense 481 nm stimulus - this means that the receptor in visual terms enables some rudimentary vision maximally for blue light. A potential criticism that the responses could have been due to heat would be misplaced, as heat is dissipated at higher wavelengths and would cause the sensation of greatest response with long wavelength (yellow and red) light, and not with short wavelength blue light as the researchers found.
External links