Photosensitive ganglion cell
Encyclopedia
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
(nerve cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, 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 retina
Retina
The 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 eye
Eye
Eyes are organs that detect light and convert it into electro-chemical impulses in neurons. The simplest photoreceptors in conscious vision connect light to movement...
.
They were discovered in the early 1990s
and are, unlike other retinal ganglion cell
Ganglion cell
A 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, intrinsically photosensitive. This means that they are a third class of retinal photoreceptors, excited by light even when all influences from classical photoreceptors (rods
Rod cell
Rod 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 visual photoreceptor, cone cells. Named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision. On...
and cones
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
) are blocked (either by applying pharmacological agents or by dissociating the ganglion cell from the retina). Photosensitive ganglion cells contain the photopigment
Photopigment
Photopigments 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...
melanopsin
Melanopsin
Melanopsin 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 cells
Giant retinal ganglion cells
Giant 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. They represent a small subset (~1-3%) of the retinal ganglion cells. 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 rhythmCircadian rhythmA circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in 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 tractRetinohypothalamic 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 brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, the suprachiasmatic nucleusSuprachiasmatic nucleusThe suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
of the hypothalamusHypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. The physiological properties of these ganglion cells match known properties of the daily light entrainmentEntrainment (chronobiology)Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
(synchronizationSynchronizationSynchronization 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 innervate other brain targets, such as the center of pupillary controlPupillary reflexThe 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, thereby assisting in adaptation to various levels of darkness and light, in addition to retinal sensitivity...
, the olivary pretectal nucleus of the midbrain. They contribute to the regulation of pupilPupilThe pupil is a hole 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. In...
size and other behavioral responses to ambient lighting conditions.
- They contribute to photic regulation of, and acute photic suppression of, release of the hormone melatoninMelatoninMelatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
from the pineal glandPineal glandThe pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal 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 pigmentosa
Retinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. 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...
.
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. Work by Farhan H. Zaidi and colleagues showed that photoreceptive ganglion cells may have a visual function and can be isolated in humans.
The photopigment of 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 rhabdomeric 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
In 1991 Russell G. FosterRussell G. Foster
Russell Grant Foster, FRS is a British professor of circadian neuroscience, currently based at Brasenose College at the University of Oxford. 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...
and colleagues including Ignacio Provencio
Ignacio Provencio
Ignacio Provencio is an American neuroscientist and the discoverer of melanopsin, a photopigment found in specialized photosensitive ganglion cells of the mammalian retina...
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.
Foster was elected a fellow of the Royal Society
Royal Society
The Royal Society of London for Improving Natural Knowledge, known simply as the Royal Society, is a learned society for science, and is possibly the oldest such society in existence. Founded in November 1660, it was granted a Royal Charter by King Charles II as the "Royal Society of London"...
in 2008.
The fact that such a landmark discovery was published in a relatively obscure science journal indicates the initial skepticism within the scientific community about the existence of non-rod, non-cone photoreceptors. That community continued for several years to believe that the only photoreceptors were rods and cones. 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 researchers 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. These novel cells express the photopigment melanopsin
Melanopsin
Melanopsin 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...
which was first identified by Provencio and colleagues who published in the Journal of Neuroscience in 2000. 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 FosterRussell G. Foster
Russell Grant Foster, FRS is a British professor of circadian neuroscience, currently based at Brasenose College at the University of Oxford. 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...
were the first to show conclusively that cells containing the photopigment melanopsin absorb light maximally at a 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
David Berson
David M. Berson is Professor of Medical Science at Brown University. He helped lead the way in the discovery of a third class of mammalian photoreceptors by providing the first electrophysiological recordings from intrinsically photosensitive retinal ganglion cells.-External links:*Critical Review ...
in 2002 showed that in the rat, intrinsically photosensitive retinal ganglion cells invariably expressed melanopsin, and so melanopsin (and not rod or cone opsin
Opsin
Opsins 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 Biology
Current Biology
Current 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 Scientist
New Scientist
New Scientist is a weekly non-peer-reviewed English-language international science magazine, which since 1996 has also run a website, covering recent developments in science and technology for a general audience. Founded in 1956, it is published by Reed Business Information Ltd, a subsidiary of...
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. There are thus two parallel and anatomically distinct photoreceptor pathways.
In the same year, 2005, Melyan and Qiu together with colleagues including Lucas, Mark W. Hankins and 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 nucleus
Lateral geniculate nucleus
The lateral geniculate nucleus is the primary relay center for visual information received from the retina of the eye. The LGN is found inside the thalamus of the brain....
(LGN). Previously only projections to the midbrain (pre-tectal nucleus) and hypothalamus (supra-chiasmatic nuclei
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
, SCN) had been shown. However a visual role for the receptor was still unsuspected and unproven.
Research in humans
Attempts were 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 Zaidi and colleagues including Foster, George Brainard, Charles Czeisler
Charles Czeisler
Charles A. Czeisler is a researcher and author in the field of circadian rhythms and sleep medicine. He holds both an M.D. and a Ph.D. and is currently the Chief and Director of the Division of Sleep Medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, MA, USA...
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 identity of the non-rod, non-cone photoreceptor in humans was found to be a ganglion cell in the inner retina exactly as previously shown in rodless, coneless models in some other mammals. The work was done using patients with rare diseases that wiped out classic rod and cone photoreceptor function but preserved ganglion cell function. Despite having no rods or cones, the patients continued to exhibit circadian photoentrainment, circadian behavioural patterns, melatonin 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 in conscious sight
The use of rodless, coneless humans allowed another possible role for the receptor to be studied. In 2007, a new role was found for the photoreceptive ganglion cell. Zaidi and colleagues including Foster, Brainard, Czeisler and Lockley, showed that, at least in humans, the retinal ganglion cell photoreceptor contributes to consciousConsciousness
Consciousness is a term that refers to the relationship between the mind and the world with which it interacts. It has been defined as: subjectivity, awareness, the ability to experience or to feel, wakefulness, having a sense of selfhood, and the executive control system of the mind...
sight as well as to non-image-forming functions like circadian rhythms, behaviour and pupillary reactions. 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. Since these cells respond mostly to blue light, it has been suggested that they have a role in mesopic vision
Mesopic vision
Mesopic vision is a combination of photopic vision and scotopic vision in low but not quite dark lighting situations. Mesopic light levels range from luminances of approximately 0.001 to 3 cd m-2. Most night-time outdoor and traffic lighting scenarios are in the mesopic range.Humans see...
and that the old theory of a purely duplex retina
Duplex retina
A 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. Zaidi and colleagues' work with rodless, coneless human subjects hence also opened the door into image-forming (visual) roles for the ganglion cell photoreceptor.
The discovery that there are parallel pathways for vision was made - 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 functions 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 glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, 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.