Editing Chronobiology (section)

==The role of Retinal Ganglion cells==
===Melanopsin as a circadian photopigment===
In 2002, [[Samer Hattar|Hattar]] and his colleagues showed that [[melanopsin]] plays a key role in a variety of photic responses, including [[pupillary light reflex]], and synchronization of the [[Circadian rhythm|biological clock]] to daily light-dark cycles. He also described the role of melanopsin in [[intrinsically photosensitive retinal ganglion cell|ipRGCs]]. Using a rat melanopsin gene, a melanopsin-specific antibody, and [[Immunocytochemistry|fluorescent immunocytochemistry]], the team concluded that melanopsin is expressed in some RGCs. Using a [[Beta-galactosidase]] assay, they found that these RGC [[axons]] exit the eyes together with the [[optic nerve]] and project to the [[suprachiasmatic nucleus]] (SCN), the primary circadian pacemaker in [[mammal]]s. They also demonstrated that the RGCs containing melanopsin were intrinsically photosensitive. Hattar concluded that melanopsin is the photopigment in a small subset of RGCs that contributes to the intrinsic photosensitivity of these cells and is involved in their non-image forming functions, such as photic entrainment and pupillary light reflex.<ref name="Fly in mammalian eye" />

===Melanopsin cells relay inputs from rods and cones===
[[File:Phototransduction and ipRGCs in mammals.jpg|thumb|alt=Phototransduction and ipRGCs in mammals|Light enters the eye and hits the retinal pigmented epithelium (maroon). This excites rods (grey) and cones (blue/red). These cells synapse onto bipolar cells (pink), which stimulate ipRGCs (green) and RGCs (orange). Both RGCs and ipRGCs transmit information to the brain through the optic nerve. Furthermore, light can directly stimulate the ipRGCs through its melanopsin photopigment. The ipRGCs uniquely project to the superchiasmatic nucleus, allowing the organism to entrain to light-dark cycles.]]
Hattar, armed with the knowledge that melanopsin was the photopigment responsible for the photosensitivity of ipRGCs, set out to study the exact role of the ipRGC in [[Photoentrainment (chronobiology)|photoentrainment]]. In 2008, Hattar and his research team transplanted [[diphtheria]] toxin [[genes]] into the [[mouse]] melanopsin gene locus to create [[mutation|mutant]] mice that lacked ipRGCs. The research team found that while the mutants had little difficulty identifying visual targets, they could not entrain to light-dark cycles.  These results led Hattar and his team to conclude that ipRGCs do not affect image-forming vision, but significantly affect non-image forming functions such as photoentrainment.<ref name="Fly in mammalian eye">{{cite web|last1=Graham|first1=Dustin|title=Melanopsin Ganglion Cells: A Bit of Fly in the Mammalian Eye|url=http://webvision.med.utah.edu/book/part-ii-anatomy-and-physiology-of-the-retina/elanopsin-ganglion-cells-a-bit-of-fly-in-the-mammalian-eye/|website=Webvision The Organization of the Retina and Visual System|publisher=University of Utah School of Medicine|accessdate=9 April 2015|url-status=dead|archiveurl=https://web.archive.org/web/20110427132440/http://webvision.med.utah.edu/book/part-ii-anatomy-and-physiology-of-the-retina/elanopsin-ganglion-cells-a-bit-of-fly-in-the-mammalian-eye/|archivedate=27 April 2011}}</ref>

===Distinct ipRGCs===
Further research has shown that ipRGCs project to different brain nuclei to control both non-image forming and image forming functions.<ref name=":0">{{Cite journal|title = Blurring the boundaries of vision: novel functions of intrinsically photosensitive retinal ganglion cells|last = Matynia|first = Anna|date = September 3, 2013|journal = Journal of Experimental Neuroscience|doi = 10.4137/JEN.S11267|pmc = 4089729|pmid=25157207|volume=7|pages=43–50}}</ref> These brain regions include the SCN, where input from ipRGCs is necessary to photoentrain circadian rhythms, and the [[pretectal area|olivary pretectal nucleus]] (OPN), where input from ipRGCs control the pupillary light reflex.<ref name=":1">{{Cite journal|title = Retinal Ganglion Cell Maps in the Brain: Implications for Visual Processing|last1 = Dhande|first1 = OS|date = November 19, 2013|journal = Current Opinion in Neurobiology|doi = 10.1016/j.conb.2013.08.006|pmc = 4086677|last2 = Huberman|first2 = AD|volume=24|issue = 1|pages=133–142|pmid=24492089}}</ref> Hattar and colleagues conducted research that demonstrated that ipRGCs project to hypothalamic, thalamic, stratal, brainstem and limbic structures.<ref>{{Cite journal|title = Neuroimaging, Cognition, Light and Circadian Rhythms|author1=Gaggioni G |author2=Maquet P |author3=Schmidt C |author4=Dijk Dj |author5=Vandealle G |date = July 8, 2014|journal = Frontiers in Systems Neuroscience|doi = 10.3389/fnsys.2014.00126|pmc = 4086398|pmid=25071478|volume=8|pages=126|doi-access=free }}</ref> Although ipRGCs were initially viewed as a uniform population, further research revealed that there are several subtypes with distinct morphology and physiology.<ref name=":0" /> Since 2011, Hattar's laboratory<ref>{{cite web|title=The Hattar Lab|url=http://hattarlab.johnshopkins.edu/pages/research.php|publisher=Johns Hopkins University|accessdate=27 December 2016|date=2014}}</ref> has contributed to these findings and has successfully distinguished subtypes of ipRGCs.<ref name=":1"/>

===Diversity of ipRGCs===
Hattar and colleges utilized [[Cre-Lox recombination|Cre-based]] strategies for labeling ipRGCs to reveal that there are at least five ipRGC subtypes that project to a number of central targets.<ref name=":1"/> Five classes of ipRGCs, M1 through M5, have been characterized to date in rodents. These classes differ in morphology, dendritic localization, melanopsin content, electrophysiological profiles, and projections.<ref name=":0"/>

===Diversity in M1 cells===
Hattar and his co-workers discovered that, even among the subtypes of ipRGC, there can be designated sets that differentially control circadian versus pupillary behavior. In experiments with M1 ipRGCs, they discovered that the transcription factor [[POU4F2|Brn3b]] is expressed by M1 ipRGCs that target the OPN, but not by ones that target the SCN. Using this knowledge, they designed an experiment to cross Melanopsin-[[Cre-Lox recombination|Cre]] mice with mice that conditionally expressed a toxin from the Brn3b locus. This allowed them to selectively ablate only the OPN projecting M1 ipRGCS, resulting in a loss of pupil reflexes. However, this did not impair circadian photo entrainment. This demonstrated that the M1 ipRGC consist of molecularly distinct subpopulations that innervate different brain regions and execute specific light-induced functions.<ref name=":1"/> This isolation of a 'labeled line' consisting of differing molecular and functional properties in a highly specific ipRGC subtype was an important first for the field. It also underscored the extent to which molecular signatures can be used to distinguish between RGC populations that would otherwise appear the same, which in turn facilitates further investigation into their specific contributions to visual processing.<ref name=":1"/>