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'''Photosensitive ganglion cells''', also called '''photosensitive Retinal Ganglion Cells''' (pRGC), '''intrinsically photosensitive Retinal Ganglion Cells''' (ipRGC) or '''melanopsin-containing ganglion cells''', are a type of nerve [[cell (biology)|cell]] in the [[retina]] of the mammalian [[eye]]. 
They were discovered in the early 1990’s<ref name="Oxford">{{cite web |url= http://www.neuroscience.ox.ac.uk/directory/russell-foster | title= Seven new Royal Society Fellows |accessdate= 2010-01-24 |author= |last= |first= |coauthors= |date= |year= 2008 |month= |format= |work= |publisher= The Medical Sciences Division, University of Oxford |doi= | quote= }}</ref> 
and are, unlike other retinal [[ganglion cell]]s, intrinsically [[photosensitive]]. This means that they are a third class of retinal [[Photoreceptor cell|photoreceptor]]s, excited by light even when all influences from classical photoreceptors ([[rod cell|rods]] and [[cone cell|cones]]) are blocked (either by applying [[pharmaceuticals|pharmacological agent]]s or by dissociating the ganglion cell from the retina). Photosensitive ganglion cells contain the [[photopigment]] [[melanopsin]]. The [[giant retinal ganglion cells]] 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.<ref>{{cite journal | last = Wong | first = Kwoon Y. | coauthors = Dunn, Felice A.; Berson, David M. | date = 22 December 2005 | year = | title = Photoreceptor Adaptation in Intrinsically Photosensitive Retinal Ganglion Cells | journal = Neuron | volume = 48 | issue = 6| pages = 1001–1010 | publisher = | location = | issn = | pmid = 16364903| doi = 10.1016/j.neuron.2005.11.016| url = http://www.neuron.org/content/article/fulltext?uid=PIIS0896627305009645 | format = HTML: Full text | accessdate = 2008-05-11 | quote = }}</ref> 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]]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 tract]] directly to the [[circadian]] pacemaker of the [[brain]], the [[suprachiasmatic nucleus]] of the [[hypothalamus]]. The physiological properties of these ganglion cells match known properties of the daily light [[Entrainment (chronobiology)|entrainment]] ([[synchronization]]) mechanism  regulating circadian rhythms. 

* Photosensitive ganglion cells also innervate other brain targets, such as the center of [[pupillary reflex|pupillary control]], the [[olivary pretectal nucleus]] of the [[midbrain]]. They contribute to the regulation of [[pupil]] 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]] from the [[pineal gland]].

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]].

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.<ref>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 Dec 18;17(24):2122-8 [http://www.current-biology.com/content/article/abstract?uid=PIIS0960982207022737 Abstract] </ref> 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<ref name=Berson>{{cite_doi | 10.1007/s00424-007-0242-2}}</ref>).  The [[phototransduction]] mechanism in these cells is not fully understood, but seems likely to resemble that in invertebrate [[rhabdom]]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. Foster]] 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.<ref>Foster RG, Provencio I, Hudson D, Fiske S, De Grip W, Menaker M. Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol [A]. 1991 Jul;169(1):39-50 [http://www.ncbi.nlm.nih.gov/pubmed/1941717 Abstract] </ref>
Foster was elected a fellow of the [[Royal Society]] in 2008.<ref>{{cite web |url=http://www.ox.ac.uk/media/news_stories/2008/080516c.html | title= Russell Foster BSc PhD FRS |accessdate= 2009-07-05 |author= |last= |first= |coauthors= |date= |year= 2007 |month= |format= |work= |publisher= The University of Oxford |doi= | quote= }}</ref> 
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 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.<ref>Foster RG.Bright blue times. Nature. 2005 Feb 17;433(7027):698-9</ref> 
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.<ref>Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci. 2000 Jan 15;20(2):600-5  [http://www.jneurosci.org/cgi/content/full/20/2/600 Full text] </ref> 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.<ref>Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci. 2001 Jun;4(6):621-6</ref> 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 <ref>Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci. 2001 Jun;4(6):621-6</ref>. 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 [[opsin]]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.<ref>Hattar S, Liao HW, Takao M, Berson DM, Yau KW.Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. 2002 Feb 8;295(5557):1065-70</ref> This work is regarded by [[Current Biology]], [[New Scientist]] 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).<ref>Van Gelder RN. Non-visual photoreception: sensing light without sight. Curr Biol. 2007 Dec 18;17(24):2122-8.</ref> 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.<ref>Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW. Addition of human melanopsin renders mammalian cells photoresponsive; Nature. 2005 Feb 17;433(7027):741-5</ref><ref>Qiu X, Kumbalasiri T, Carlson SM, Wong KY, Krishna V, Provencio I, Berson DM. Induction of photosensitivity by heterologous expression of melanopsin. Nature 2005 Feb 17;433(7027):745-9</ref> 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.<ref> 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 Feb 17;433(7027):749-54.</ref><ref>Berson DM (2003). Strange vision: ganglion cells as circadian photoreceptors. ''Trends in Neuroscience'' 26:314-320.</ref> Previously only projections to the midbrain (pre-tectal nucleus) and hypothalamus ([[Suprachiasmatic nucleus|supra-chiasmatic nuclei]], 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.<ref>Van Gelder RN. Non-visual photoreception: sensing light without sight. Curr Biol. 2007 Dec 18;17(24):2122-8.</ref>  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.<ref>Cell Press. Blind humans lacking rods and cones retain normal responses to nonvisual effects of light. Genova, Cathleen, for Cell Press, December 13, 2007.www.eurekalert.org/pub_releases/2007-12/cp-bhl121307.php - 11k - </ref><ref> Coghlan A. Blind people 'see' sunrise and sunset. New Scientist, 26 December 2007.Magazine issue 2635.</ref><ref>Medical News Today. Normal Responses To Non-visual Effects Of Light Retained By Blind Humans Lacking Rods And Cones. 14 December 2007. http://www.medicalnewstoday.com/articles/91836.php </ref>  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.<ref> Cell Press. Blind humans lacking rods and cones retain normal responses to nonvisual effects of light. Genova, Cathleen, for Cell Press, December 13, 2007.www.eurekalert.org/pub_releases/2007-12/cp-bhl121307.php - 11k - </ref><ref> Coghlan A. Blind people 'see' sunrise and sunset. New Scientist, 26 December 2007. Magazine Issue 2635.</ref><ref>Medical News Today. Normal Responses To Non-visual Effects Of Light Retained By Blind Humans Lacking Rods And Cones. 14 December, 2007.http://www.medicalnewstoday.com/articles/91836.php </ref> 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.<ref>{{cite web |url= http://www.denvernaturopathic.com/bluelightandmelatonin.htm |title= Blue Light and Melatonin  |accessdate= 2008-05-30 |last= Schor |first= Jacob |date= 2008-04-19 |format= web page |work= Morning Light |publisher= |pages= |quote= }}</ref>

==== 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.<ref>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 Dec 18;17(24):2122-8. http://www.current-biology.com/content/article/abstract?uid=PIIS0960982207022737</ref> 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 vision]] and the old theory of a purely [[duplex retina]] 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.<ref>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 Dec 18;17(24):2122-8. http://www.current-biology.com/content/article/abstract?uid=PIIS0960982207022737</ref> 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 [[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&nbsp;nm, though a minority of groups reported it being lower, as far as 420&nbsp;nm. Steven Lockley et al. in 2003 showed that 460&nbsp;nm (violet) wavelengths of light suppress melatonin twice as much as longer 535&nbsp;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&nbsp;nm stimulus - this means that the receptor in visual terms enables some rudimentary vision maximally for blue light.<ref>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 Dec 18;17(24):2122-8</ref> 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.

==See also==
*[[Bistratified cell]]
*[[Midget cell]]
*[[Parasol cell]]

==References==
{{reflist|2}}

{{Human cell types derived primarily from ectoderm}}
{{Nervous tissue}}

==External links==
*[http://neuroscience.brown.edu/faculty/berson.html David Berson's lab at Brown University]

[[Category:Eye]]
[[Category:Histology]]
[[Category:Photoreceptor cells]]
[[Category:Circadian rhythms]]
[[Category:Visual system]]

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