Farmacología de La Miopía y El Papel Potencial de Los Ritmos Circadianos Intrínsecos de La Retina

8/10/2019 Farmacologa de La Miopa y El Papel Potencial de Los Ritmos Circadianos Intrnsecos de La Retina

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Pharmacology of myopia and potential role for intrinsic retinalcircadian rhythmsRichard A. Stone a , * , Machelle T. Pardue b, P. Michael Iuvone c, Tejvir S. Khurana da Department of Ophthalmology, University of Pennsylvania School of Medicine, Scheie Eye Institute, D-603 Richards Building,Philadelphia, PA 19104-6075, USAb Department of Ophthalmology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Atlanta, GA, USAc Departments of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA, USAd Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

a r t i c l e i n f o

Article history:Received 3 October 2012Accepted in revised form 2 January 2013Available online 8 January 2013

Keywords:ametropiaacetylcholinecircadian rhythmsclock genesdopamineemmetropiamyopiaretina

a b s t r a c t

Despite the high prevalence and public health impact of refractive errors, the mechanisms responsiblefor ametropias are poorly understood. Much evidence now supports the concept that the retina is centralto the mechanism(s) regulating emmetropization and underlying refractive errors. Using a variety of pharmacologic methods and well-de ned experimental eye growth models in laboratory animals, manyretinal neurotransmitters and neuromodulators have been implicated in this process. Nonetheless, anaccepted framework for understanding the molecular and/or cellular pathways that govern postnatal eyedevelopment is lacking. Here, we review two extensively studied signaling pathways whose general rolesin refractive development are supported by both experimental and clinical data: acetylcholine signalingthrough muscarinic and/or nicotinic acetylcholine receptors and retinal dopamine pharmacology. Themuscarinic acetylcholine receptor antagonist atropine was rst studied as an anti-myopia drug some twocenturies ago, and much subsequent work has continued to connect muscarinic receptors to eye growthregulation. Recent research implicates a potential role of nicotinic acetylcholine receptors; and the

refractive effects in population surveys of passive exposure to cigarette smoke, of which nicotine isa constituent, support clinical relevance. Reviewed here, many puzzling results inhibit formulatinga mechanistic framework that explains acetylcholine s role in refractive development. How cholinergicreceptor mechanisms might be used to develop acceptable approaches to normalize refractive devel-opment remains a challenge. Retinal dopamine signaling not only has a putative role in refractivedevelopment, its upregulation by light comprises an important component of the retinal clock networkand contributes to the regulation of retinal circadian physiology. During postnatal development, theocular dimensions undergo circadian and/or diurnal uctuations in magnitude; these rhythms shift ineyes developing experimental ametropia. Long-standing clinical ideas about myopia in particular havepostulated a role for ambient lighting, although molecular or cellular mechanisms for these speculationshave remained obscure. Experimental myopia induced by the wearing of a concave spectacle lens altersthe retinal expression of a signi cant proportion of intrinsic circadian clock genes, as well as genesencoding a melatonin receptor and the photopigment melanopsin. Together this evidence suggestsa hypothesis that the retinal clock and intrinsic retinal circadian rhythms may be fundamental to themechanism(s) regulating refractive development, and that disruptions in circadian signals may producerefractive errors. Here we review the potential role of biological rhythms in refractive development.While much future research is needed, this hypothesis could unify many of the disparate clinical andlaboratory observations addressing the pathogenesis of refractive errors.

2013 Elsevier Ltd. All rights reserved.

1. Introduction

The mechanisms responsible for ametropias and for recent in-creases in myopia prevalence are unknown. Because of its high

prevalence and public health impact, myopia is the form of ame-tropia that has received the most research attention. Long-heldclinical ideas propose that myopia represents a complex disor-der with both environmental and genetic causes ( Farbrother et al.,2004 ; Hornbeak and Young, 2009 ; Klein et al., 2005 ; Morgan andRose, 2005 ; Morgan et al., 2012 ; Zadnik, 1997 ). While genetic fac-tors have been associated with both myopia and hyperopia and

* Corresponding author. Tel.: 1 215 898 6950; fax: 1 215 898 0528.E-mail address: [email protected] (R.A. Stone).

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several chromosomal loci have been linked with human myopia(Hornbeak and Young, 2009 ; Wojciechowski, 2011 ; Wojciechowskiet al., 2005 ), the literature is inconsistent; and the relative impor-tance of genes vs. environment in myopia pathogenesis remainsuncertain and controversial ( Lyhne et al., 2001 ; Morgan and Rose,2005 ; Rose et al., 2002 ). Despite population differences in preva-lence levels ( Pan et al., 2012 ), the rapid and pronounced increasesin myopia prevalence ( Pan et al., 2012 ; Rahi et al., 2011 ; Vitale et al.,2009 ) strongly support the hypothesis that major environmentalin uences are superimposed on, or may even act independently of,anygenetic contribution to altered eye development ( Morgan et al.,2012 ; Wojciechowski, 2011 ).

In the search for underlying pathogenetic mechanisms, researchin laboratory animals has convincingly linked control of refractionto qualities of the visual image ( Stone, 1997 , 2008 ; Wallman, 1993 ;Wallman and Winawer, 2004 ). The laboratory ndings have beenextended to many species (e.g., chick, mouse, guinea pigs, treeshrew, various primates). The laboratory approaches most com-monly use one of two models: 1) form-deprivation myopia, whereblurring of the retinal image by an image diffusing goggle or eyelidsuture accelerates ipsilateral eye growth and produces myopia; and2) lens-inducedametropias, where shifting the imageplane in frontor behind the retina by spectacle lens wear produces compensatingchanges in eye growth that reposition the retina at the location of the shifted image position. Besides experimental animals, humanchildren also develop form-deprivation myopia from obstructionsin the visual axis that degrade the visual image, such as congenitalptosis or a scarred cornea ( Meyer et al., 1999 ). In addition, lens-induced defocus or an accommodative stimulus cause transientadjustments of axial dimensions in the eyes of younghuman adults(Mallen et al., 2006 ; Read et al., 2010 ; Woodman et al., 2011 ),although data are not yet available on whether or not these tran-sient adjustments in uence human refractive development. Nev-ertheless, the visual mechanisms in these experimental models, orat least components of them, seem active in humans as well asanimals ( Kee et al., 2007 ; Smith et al., 2002 ). Given the many par-

allels in the mechanisms of refractive development now identi edbetween chicks and mammals, including humans, the broad phy-logenetic conservation of the visual mechanisms governingrefraction is truly remarkable ( Stone, 2008 ; Wallman and Winawer,2004 ), despite species differences in scleral and uveal structure.

As reviewed elsewhere ( Norton, 1999 ; Stone, 1997 , 2008 ; Stoneand Khurana, 2010 ; Wallman and Nickla, 2010 ; Wallman andWinawer, 2004 ), much evidence now supports the notion thatthe visual mechanism(s) governing refractive development localizeprincipally, though not necessarily exclusively, to the retina; andnumerous retinal neurotransmitters or neuromodulators have nowbeen implicated in refractive development. Despite this progress,there is no comprehensive, even hypothetical, framework to ac-count for these diverse observations, and many questions remain.

Because no direct neural pathways connect the sensory retina toeither the choroid or sclera, even how retinal signals in uence theoverall growth of the eye remains speculative. One hypothesis isthat the retinal pigment epithelium lies anatomically within thegrowth pathway and that the retinal pigment epithelium respondsdirectly to retinal signals and/or transfers regulatory mediatorsbetween the retina and the choroid/sclera ( Rymer and Wildsoet,2005 ).

Detailed recent reviews of the application of contemporarypharmacology, emphasizing retinal mechanisms, are available(Ganesan and Wildsoet, 2010 ; Stone, 2008 ; Stone and Khurana,2010 ). Here, we shall address selected evidence demonstratingthat basic pharmacologic mechanisms uncovered in laboratorystudies are relevant to refractive development in children,

emphasizing cholinergic and dopaminergic pharmacology because

much applicable data are available in children. Further, we shalldiscuss a hypothesis emerging from our own recent ndings rela-ted to retinal dopamine mechanisms e namely, that endogenousretinal circadian rhythms may be fundamental to the mechanismsof emmetropization and that refractive errors might arise fromdisruptions of circadian control.

2. Cholinergic mechanisms and refractive development

2.1. Muscarinic acetylcholine receptor mechanisms

Muscarinic receptors are a group of G-protein coupled ace-tylcholine receptors, so-named because they historically werefound to be activated by the fungal product muscarine. Five re-ceptor subtypes are known in mammals that are designated m1 em5. Chicks, lacking a receptor homologous to the mammalian m1receptor, express four muscarinic receptor subtypes correspondingto the other mammalian subtypes; the chick muscarinic receptorsubtypes often are designated cm2 e cm5 ( Fischer et al., 1998a ).

Clinicians have long hypothesized a central role for reading andother close-up activities in causing myopia, although this long-heldbelief is questioned by many contemporary ndings ( Dirani et al.,2009 ; Jones-Jordan et al., 2012 ; Jones et al., 2007 ; Mutti, 2010 ;Rose et al., 2008a ; Rosen eld and Gilmartin, 1998 ). Under theassumption that accommodation links near vision tasks and oculargrowth, the effect of the nonselective muscarinic antagonist atro-pine on myopia progression has been studied for two centuries(Wells, 1811 ). The vast literature on atropine as a therapeutic gen-erally supports a favorable effect against myopia progression inchildren ( Chua et al., 2006 ; Kennedy, 1995 ; Song et al., 2011 ) andagainst form-deprivation and lens-induced myopia in severalexperimental mammals ( Ganesan and Wildsoet, 2010 ; Stone,2008 ). Atropine s acute side effects of mydriasis and cycloplegiahave hampered clinical acceptance of this drug despite its osten-sible ef cacy. Reducing the usual clinical concentrations of 0.5% or1.0% in an effort to lessen these side effects has yielded variable

amounts of partial anti-myopia effects in clinical studies ( Chia et al.,2012 ; Shih et al.,1999 ). Several researchers have found that myopiaprogression resumes if atropine is stopped ( Brodstein et al., 1984 ;Tong et al., 2009 ). Thus, despite extensive study, further in-vestigations are warranted before recommending general clinicaluse of atropine.

Laboratory evidence suggests that the anti-myopia action of atropine is independent of the drug s inhibition of accommodation.For instance, the protective effect of atropine against experimentalmyopia in chick ( McBrien et al., 1993 ; Schmid and Wildsoet, 2004 ;Stone et al., 1991 ) contradicts the long-held view that atropine santi-myopia activity results from inhibiting accommodation.Atropine has been long-known to be inactive at avian iris and cil-iary muscles. In contrast to the smooth intraocular muscles of the

mammalianeye, the avian intraocular muscles are striated muscles,and are activated by nicotinic rather than muscarinic acetylcholinereceptors ( Glasser and Howland, 1996 ). Indeed, cycloplegia in birdsrequires a neuromuscular blocking agent like curare. Muscarinicreceptors of chicks are structured differently from those in mam-mals. Mammalian tissues express ve distinct muscarinic ace-tylcholine receptor subtypes ( Caul eld and Birdsall, 1998 ; Fischeret al., 1998a ); the m3-muscarinic acetylcholine receptor mediatescontraction of the iris and ciliary muscles in the mammal eye ( Gilet al., 1997 ; Poyer et al., 1994 ). Atropine is a potent inhibitor withsimilar af nity to all ve mammalianmuscarinic receptor subtypes,and a number of antagonists with relative selectivity for the dif-ferent muscarinic receptor subtypes have been evaluated in chickfor anti-myopia activity. Of these, the antagonist pirenzepine has

shown anti-myopia activity in chick, tree shrew and monkey

R.A. Stone et al. / Experimental Eye Research 114 (2013) 35 e 47 36


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(Cottriall and McBrien, 1996 ; Leech et al., 1995 ; Rickers andSchaeffel, 1995 ; Stone et al., 1991 ; Tigges et al., 1999 ). Only rela-tively selective, pirenzepine shows highest af nity in mammals forthe m1 and also the m4 muscarinic receptor subtypes; but it alsobinds with lower af nities to the other subtypes ( Caul eld andBirdsall, 1998 ). Although birds lack a receptor homologous to themammalian m1 receptor, pirenzepine binds with high af nity tothe avian cm2 as well as to the cm4 muscarinic acetylcholine re-ceptor subtypes ( Jakubik and Tu cek, 1994 ; Tietje and Nathanson,1991 ). Consistent with the binding af nities for pirenzepine inmammalian and avian tissues, other data suggest a role forboth m1and m4 muscarinic receptor subtypes in inhibiting experimentalmyopia ( Arumugam and McBrien, 2012 ; Cottriall et al., 2001b ;McBrien et al., 2011 ). Regardless of the comparative roles of m1 vs.m4 cholinergic receptor subtypes, pirenzepine was long used inhumans for gastrointestinal disease and, when tested topically inchildren, showed minimal effects on pupil sizeand accommodation(Bartlett et al., 2003 ), consistent with its comparatively low af nityfor the m3 muscarinic acetylcholine receptor subtype ( Caul eldand Birdsall, 1998 ). Accordingly, pirenzepine was studied in twomulticenter clinical trials and found to reduce myopia progressionin children by 40 e 50% (Siatkowski et al., 2004 , 2008 ; Tan et al.,2005 ). While supporting a presumptive role for muscarinic ace-tylcholine receptors in refractive development (see also Section 2.4 ,below), the pirenzepine data also suggest that the muscariniccholinergic pathway in uencing myopia progression does notinvolve the m3 receptor mechanism. As another line of evidence,squirrels lack accommodation; but atropine inhibits the develop-ment of form-deprivation myopia in these animals ( McBrien et al.,1993 ). Hence, atropine s anti-myopiaeffect occurs independently of accommodation in both laboratory animals and in children.

2.2. Nicotinic acetylcholine receptor mechanisms

The nicotinic acetylcholine receptors are a large and complexfamily of acetylcholine-gated non-selective cation channels, with

multiple subunits ( Liu et al., 2009 ; Miwa et al., 2011 ; Wu and Lukas,2011 ). Their name derives from the early observation that the plantalkaloid nicotine activates these receptors.

Several antagonists to the neural typesof nicotinic acetylcholinereceptors inhibit form deprivation myopia in chick ( Stone et al.,2001 ), with nonselective antagonists in that study showing thegreatest ef cacy. Two of the antagonists enhanced the myopicgrowth response at low doses but inhibited it at higher doses, thusrevealing multiphasic dose e response curves. These anti-myopiaeffects are consistent with action at neural acetylcholine re-ceptors based on the nature of the drugs, but the complexity of thedose e response curves precludes clear mechanistic interpretations.As examples, the complexities of the drug responses may followactions at multiple receptor subtypes with dissimilar af nities,

differential dose-related activation of speci c receptor subtypes orinvolvement of multiple neuronal structures.Nicotine is one of the prominent constituents of tobacco smoke.

The suggestion that neural nicotinic acetylcholine receptors mightin uence refractive development in an experimental animal raisedthe question of whether exposure to tobacco smoke might in u-ence refractive development of children. Several epidemiologicsurveys subsequently have associated speci c distributions of refraction with passive tobacco smoke exposure during childhoodand even in utero . While the magnitude of the effect varied be-tween studies, most investigations found reduced myopia preva-lence and an overall refractive shift toward hyperopia in childrenpassively exposed to environmental tobacco smoke, includingexposure from maternal smoking during pregnancy ( Borchert et al.,

2011 ; El-Shazly, 2012 ; Ip et al., 2008 ; Saw et al., 2004 ; Stone et al.,

2006 ). In addition to questionnaire data, one study included mea-surementsof urinary cotinine, a metabolite of nicotineand a widelyused biomarker for nicotine exposure; it found higher urinary co-tinine levels in hyperopic than myopic/emmetropic children, andurinary cotinine levels correlated positively with increasing hy-peropia ( El-Shazly, 2012 ). One study with detailed pregnancy his-tories found that maternal smoking throughout pregnancy was notassociated with myopia in the offspring, but that maternal smokingduring just the rst trimester was associated with high myopia(Rahi et al., 2011 ). Maternal smoking during pregnancy also hasbeen associated with a higher risk of astigmatism in preschoolchildren ( McKean-Cowdin et al., 2011 ).

It is not possible at present to propose a speci c mechanism toexplain the action of tobacco smoke or nicotine on refractivedevelopment in children because of the many nicotinic acetylcho-line receptor subtypes, the complexities of their signaling mecha-nisms, the uncertainty aboutpotentially involvedreceptor subtypeswith theirdifferent drug af nities, the unknowneffects of activatingreceptors during development and the potential biological effects of other constituents of tobacco smoke. Despite these mechanisticuncertainties, the clinical studies suggest that passive exposure totobacco smoke, as might occur from parental smoking, in uencesrefractive development in children. Based on both the initial labo-ratory ndings in experimental myopia and the subsequentepidemiological associations, a potential role of neural nicotinicacetylcholine receptors would seem to be a productive area forfuture mechanistically-based research.

2.3. Acetylcholinesterase inhibition

About 50 years ago in Japan, an increasing incidence of myopiaoccurred in parallel with increasing use of organophosphate pesti-cides that act by inhibiting acetylcholinesterase and elevating ace-tylcholine levels ( Dementi, 1994 ; Ishika wa and Miyata, 1980 ). Avariety of systemicalterations in autonomic and peripheral nervousfunction often accompanied the myopia, and the syndrome was

termed

Saku disease

after a Japanese district with many affectedsubjects.Based on bothepidemiologyand laboratory investigations,this disorder was believed to result directly from organophosphatepesticide toxicity. In chicks, however, systemic or ocular admin-istration ofan acetylcholinesterase inhibitordidnotalter thenormalrefractive development of eyes with intact visual input but insteadinhibited form deprivation myopia ( Cottriall et al., 2001a ; Gelleret al., 1998 ). It is not at present possible to reconcile the clinicaland laboratory effects of this drug class on refractive development.Because these drugs increase acetylcholine levels that can act ateither muscarinic or nicotinic acetylcholine receptors, it is also notpossible to relate these results directly to the clinical and laboratory

ndings that muscarinic or nicotinic acetylcholine receptor antag-onists exert anti-myopia effects. One acetylcholinesterase inhibitor

increased retinal levels of both acetylcholine and dopamine, and itwas suggested that these drugs might affect experimental myopiaindirectly by acting through retinal dopamine ( Cottriall et al.,2001a ), described below. As discussed elsewhere, however, localintra-retinal acetylcholine action, involvement of multiple ace-tylcholine receptors with different af nities or effects, or non-cholinergic drug effects might also provide the basis for theseseemingly inconsistent ndings.

2.4. The cholinergic conundrum

In addition to the con icting results related to nicotinic ace-tylcholine receptor pharmacology and acetylcholinesterase inhibi-tion already discussed, other puzzling results further hamper

formulating a direct mechanistic explanation for the breadth of the



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clinical and laboratory ndings supporting a cholinergic in uenceon refractive development.

The anatomical locus of a cholinergic mechanism regulatingrefraction is uncertain. Despite the general evidence implicatingthe retina in refractive control ( Stone, 1997 , 2008 ; Wallman, 1993 ;Wallman and Winawer, 2004 ) and the general developmental rolesfor cholinergic signaling ( Abreu-Villaa et al., 2011 ), form depriva-tion does not alter retinal levels of acetylcholine, its biosyntheticenzyme choline acetyltransferase or choline ( McBrien et al., 2001 ;Pendrak et al., 1995 ); and form deprivation also does not alter thenumber or af nity of cholinergic receptors in the retina ( Vesseyet al., 2002 ). These negative results, however, do not exclude reti-nal cholinergic involvement. Given the diversity of cholinergic cellsand targets in the retina, it is possible that reciprocal changesdevelop in different retinal cells with no net measurable effect ontotal retinal content of acetylcholine/choline, enzyme activity orcholinergic receptor properties. Alternatively, there may be noperturbation in these parameters from form deprivation. Whenretinal cholinergic neurons are lesioned with toxins, emmetrop-ization remains intact, form deprivation myopia continues todevelop and the anti-myopia activity of atropine persists ( Fischeret al., 1998b ). These latter results suggest that cholinergic ama-crine cells and muscarinic cholinergic receptors might not beessential for emmetropization or that a locus outside the neuro-sensory retina might account for cholinergic effects. However, theapplied toxins incompletely lesioned the retinal cholinergic system(Fischer et al., 1998b ); and any residual cholinergic network mightbe suf cient, e.g., if eye growth control operates through a lowspatial resolution system. Further, the rapid effect of atropine onthe retinal expression of the mRNA for the transcription factor ZENK in form-deprived chick eyes best conforms with a retinal, not anextra-retinal, site of action for the anti-myopia action of cholinergicdrugs ( Ashby et al., 2007 ).

In one study, there was marked variability in anti-myopia ef -cacy among a large series of muscarinic receptor antagonistsinjected into the vitreous cavity; some drugs showed partial or

even no anti-myopia activity ( Luft et al., 2003 ). The pertinent drugtargets might lie outside the retina or even outside the eye, orperhaps unde ned differences in drug penetration to the pertinentreceptor(s) may account for the puzzling ineffectiveness of theinactive muscarinic antagonist drugs. Another possible explan-ation, as suggested by the authors, is that drugeffects through non-muscarinic mechanisms may explain the limited anti-myopia ac-tion of some of the cholinergic antagonists ( Luft et al., 2003 ).However, many of the drugs studied are not well characterized,particularly against chick muscarinic acetylcholine receptors, andsome are well-known to bind to non-muscarinic receptors andmayhave opposing refractive effects to muscarinic antagonists; de ni-tive explanations for these results are not now possible.

Identifying a candidate extra-retinal pathway to explain chol-

inergic effects has been dif cult. Scleral cells in chick, for instance,do not express muscarinic cholinergic receptors by binding assay(Vessey et al., 2002 ). Consistent with this observation, muscarinicreceptor antagonists such as atropine alter proliferation andextracellular matrix production by scleral cells in culture ( Lindet al., 1998 ); but the required doses are high and may not act viaspeci c muscarinic receptor mechanisms. Ipsilateral to eyes withform deprivation myopia, choline acetyltransferase activity issuppressed in the ciliary ganglion and choroid ( Pendrak et al.,1995 ), suggesting that cholinergic signaling already is reduced inthese tissues. It is thus unclear why further reducing cholinergicactivity with antagonist drugs acts to suppress myopia in chick.While accommodation is regulated through the ciliary ganglion,the long-held supposition that accommodation induces myopia is

not supported by the contemporary research that casts doubt on

a role for visual near work in myopia pathogenesis (see above).Reviewed elsewhere ( Nickla and Wallman, 2010 ; Wallman andNickla, 2010 ), the thickness of the choroid is modulated under vi-sual and pharmacological conditions that in uence eye growth, andinvestigating in greater detail cholinergic signaling in the choroidmay be a productive future direction to understand the exper-imental and clinical roles of cholinergic signaling in refractivedevelopment.

Extensive clinical and laboratory research has repeatedlyimplicated cholinergic signaling in the mechanism governingrefractive development. How or even whether acetylcholine mod-ulates post-natal eye development at a molecular level and howcholinergic receptor mechanisms might be ef ciently exploited todevelop acceptable future therapies remains a challenge for clinicaland basic investigators.

3. Retinal dopamine, light and retinal rhythms

3.1. Retinal dopamine and refractive development

One of the rst non-cholinergic retinal neurotransmitter sys-tems implicated in refractive development ( Stone et al., 1989 ), thecatecholamine dopamine is synthesized by a subset of retinalamacrine/interplexiform cells. Retinal dopamine normally oscil-lates in a diurnal pattern with storage levels and release rateshigher during daytime than nighttime. Dopamine synthesis andrelease are stimulated by light and modulated by circadian clocksand melatonin ( Iuvone et al., 2005 ; Tosini et al., 2008 ; Witkovsky,2004 ). Reviewed elsewhere in greater detail ( Ganesan andWildsoet, 2010 ; Stone, 2008 ), uctuations in dopamine metabo-lism accompany conditions modulating eye growth. The wearing of an image diffusing goggle or negative spectacle lens, both of whichstimulate eye growth and induce myopia, reduces the daytimeincrease in dopamine metabolism; the wearing of a positive spec-tacle lens, that inhibits eye growth and causes hyperopia, has theopposite effect on retinal dopamine ( Guo et al., 1995 ; Iuvone et al.,

1989 , 1991 ; Stone et al., 1989 ). Ocular administration of dopamineagonists inhibits myopia from goggle or lens wear and also aug-ments the hyperopic response from positive lens wear ( Iuvoneet al., 1991 ; Schmid and Wildsoet, 2004 ; Stone et al., 1989 ). TheD2 subtype dopamine receptor seems to mediate the inhibitoryeffect on form deprivation myopia ( Rohrer et al., 1993 ). Brief pe-riods of unobstructed vision prevent form deprivation myopia, aneffect that can be blocked by antagonists of D 2-like dopamine re-ceptors ( McCarthy et al., 2007 ). These and other ndings supportthe hypothesis that retinal dopaminergic amacrine cells lie in thepathway linking visual input to eye growth regulation ( Ganesanand Wildsoet, 2010 ; Stone, 2008 ). Because of potential side ef-fects outside the eye in children, dopaminergicdrugs have not beeninvestigated clinically as anti-myopia agents.

Like other tissues, the retinahas an intrinsic clockmechanism toregulate itsphysiology to thedaily cycleof light anddark. Discussedbelow and illustrated in Fig. 1, retinal dopamine is a component of the retinal clock network, exertingan opposing role to melatonin inregulating retinal physiology ( Iuvone et al., 2005 ; Tosini et al.,2008 ). Dopamine has been implicated in retinal circadianrhythms of gene expression, protein phosphorylation, and visualprocessing ( Jackson et al., 2011 , 2012 ; Pozdeyev et al., 2008 ; Ruanet al., 2008 ).

In chick, a retinal dark e light switch model has been proposedthat links the circadian rhythm of melatonin secretion by photo-receptors to the light phase by reciprocal activity of dopaminergicamacrine cells and a second amacrine cell type co-expressingenkephalin-, neurotensin- and somatostatin-like immunoreactiv-

ities, the so-called ENSLI amacrine cells ( Morgan and Boelen,1996 ).



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ENSLI amacrine cells have not been identi ed in other vertebrates,and it is not established whether functional equivalents exist inother species. Nonetheless, some data suggest potential roles forenkephalin and neurotensin in refractive development in chick. Thelight:dark cycling of leu-enkephalin is reduced in the retina of form-deprived chick eyes, and patterns of restored vision or strobeillumination that independently reduce the myopic response toform deprivation also at least partly re-establish the diurnal cyclingof leu-enkephalin ( McKenzie et al., 1997 ; Megaw et al., 1996 ).Similarly in chicks, strobe lighting re-establishes the cycling of retinal dopamine metabolism of form-deprived eyes ( Rohrer et al.,

1995 ), and dopaminergic receptors contribute to the action of brief periods of unimpaired vision to inhibit form-deprivation myopia(McCarthy et al., 2007 ). The nonspeci c opiate antagonist naloxoneblocks form-deprivation myopia in chicks, but the opiate agonistmorphine has no effect. Of opiate drugs selective to oneof the threeopiate receptor subtypes, only kappa-selective drugs were active;but both an agonist and an antagonist inhibited form-deprivationmyopia ( Pickett Seltner et al., 1997 ). One report found increasedexpression of the mRNA for neurotensin in form-deprived chickeyes ( McGlinn et al., 2007 ), but no other data are available onneurotensin and refractive development. Thus, the few availablereports do not now provide conclusive evidence for a role of ENSLIamacrine cells in refractive development, but the possibility thatthey may interact with dopaminergic amacrine cells in regulating

refractive development remains an intriguing possibility.

While it is not yet established whether the refractive role of dopaminergic amacrine cells, or perhaps their interaction with theENSLI cells, relates to the retinal clock, evolving evidence suggeststhat there may be a connection. As perspective for the potentialinter-relation of dopamine, the retinal clock and refraction, recentevidence for daily rhythms in ocular dimensions and the role of light exposure in refractive development will be summarized.

3.2. Diurnal rhythms of eye length and growth

In laboratory animals with non-restricted vision ( Liu and Farid,

1998 ; Nickla et al., 2002 , 1998a ,b; Papastergiou et al., 1998 ; Weissand Schaeffel, 1993 ) and in humans ( Brown et al., 2009 ;Mapstone and Clarke, 1985 ; Read et al., 2008 ; Stone et al., 2004 ;Wilson et al., 2006 ), the axial dimensions of the eye uctuate indiurnal patterns. Ocular parameters that uctuate include axiallength, choroidal thickness, vitreous chamber depth and anteriorchamber depth. Most studied in chick, these uctuations in nor-mally developing eyes result in eye growth principally during thedaytime ( Nickla et al., 1998b ; Papastergiou et al., 1998 ; Weiss andSchaeffel, 1993 ). For chicks, these changes in ocular dimensionspersist in constant dark, indicating that eye length uctuationscomprise a true circadian rhythm ( Campbell et al., 2012 ; Nicklaet al., 2001 ). With form deprivation myopia, the overall growth isnot only accelerated but the rhythms also become shifted so that

daytime growth and nighttime growth are more equivalent ( Nickla

Fig. 1. Dopamine, melatonin and retinal physiology. Dopamine and melatonin play opposing roles in retinal physiology. Both are diffusible neuromodulators, but dopaminepromotes light adaptive retinal physiology and melatonin has dark-adaptive effects. The synthesis and release of dopamine and melatonin are modulated by circadian clocks, withdopamine released during the daytime and melatonin released at night. Light stimulates dopamine release and inhibits melatonin secretion. Both neuromodulators act on Gprotein-coupled receptors that are widely distributed in the retina. Melatonin inhibits dopamine release from amacrine/interplexiform cells and dopamine inhibits the release of melatonin from photoreceptor cells. Thus, the dopamine-secreting inner retinal neurons and melatonin-secreting photoreceptor cells form an intercellular feedback loop that

regulates circadian retinal physiology. The dopamine neurons also interact with intrinsically photosensitive melanopsin-containing ganglion cells, providing another link to cir-cadian physiology. Adapted from Tosini et al. (2008) 2008 Wiley Periodicals, Inc.



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et al., 1998b ; Papastergiou et al., 1998 ; Weiss and Schaeffel, 1993 ).Spectacle lens wear also shifts the uctuations of these rhythms inchicks in patterns that suggest that eye growth rates may beaffected by the phase relationshipbetween diurnal axial length andchoroidal thickness oscillations ( Nickla, 2006 ). In children, no dataat present exist on daily size uctuations in eyes developing ame-tropias or whether these daily eye size uctuations contribute tothe mechanism(s) responsible for ametropias.

3.3. Ambient lighting and refractive development

The introduction of arti cial lighting has dramatically alteredthe daily patterns of light exposure, especially in more developedregions of the world ( Cinzano et al., 2001 ). There is growing con-cern that arti cial lighting is now affecting human health ( Navaraand Nelson, 2007 ; Pauley, 2004 ) in such matters as cancer risk,endocrine function and metabolism ( Anisimov, 2006 ; Bartnesset al., 2012 ; Stevens and Rea, 2001 ; Wyse et al., 2011 ). Conform-ing in a general sense to this medical literature, ambient lightingin uences refractive development in laboratory animals andseemingly in children. In fact, there is a long history of efforts tounderstand and relate light exposure to clinical refractive devel-opment (e.g., Brown and Carris,1930 ; Cowan,1942 ; Foulds and Luu,2010 ; Rau, 1951 ; Zhilov, 1977 ). The available data on whether, oreven if, modern patterns of lighting exposure impact eye devel-opment are contradictory and controversial; and a general frame-workto understand the interaction of lightexposure with refractivedevelopment is needed.

Much studied in chick, altering the daily light:dark cycle in-uences the patterns of ocular growth. For example, rearing under

constant light enlarges the chick eye while attening the cornea( Jensen and Matson, 1957 ; Oishi and Murakami, 1985 ); hyperopiaresults because the marked corneal attening reduces corneal po-wer so much that the image plane is located behind the retinadespite the elongated eye ( Li et al., 1995 ; Stone et al., 1995 ). Con-stant light rearing of chicks modi es the ocular responses to goggle

or spectacle lens wear ( Bartmann et al., 1994 ; Guo et al., 1996 ;Padmanabhan et al., 2007 ; Stone et al., 1995 ). Rearing rhesusmonkeys under constant light with or without a spectacle lens alsoaffects refractive development, but the responses are much lesspronounced in monkey than those in chick ( Smith et al., 2001 ,2003 ). For both chicks and monkeys, the constant light effectspresent a conceptual inconsistency: focused visual images at theretina should permit appropriate growth responses, but somehowaltered lighting disrupts refractive development.

In mice, data on photoperiod effects on refraction are contra-dictory. Most investigators rear mice under a light:dark photo-period to assess developmental phenomena ( Pardue et al., 2008 ;Schaeffel, 2008 , 2010 ). When reared under a light:dark period,increasing length of the light phase promotes axial myopia ( Zhou

et al., 2010 ). However, one group nds that mice emmetropizewhen reared under constant light and that they display morerobust responses to goggles or minus lens wear under constantlight than mice reared under a light:dark cycle ( Tkatchenko et al.,2010 ). While more research is needed for a consensus on miceand the available data are dif cult to interpret particularly becausemost mice species are nocturnal, refractive development in micealso seems in uenced by photoperiod. The use of mice in myopiaresearch is reviewed elsewhere in this issue.

For humans, photoperiod length also may in uence refractivedevelopment. Some cross-sectional epidemiology surveys havefound a higher myopia prevalence among children when darknessat night was disrupted by nighttime lighting duringearly childhood(Fig. 2) (Chapell et al., 2001 ; Czepita et al., 2004 , 2005 ; Quinn et al.,

1999 ); the initial report showed the strongest effect ( Quinn et al.,

1999 ). This result, however, has not been observed in other pop-ulations ( Guggenheim et al., 2003 ; Gwiazda et al., 2000 ; Saw et al.,2001 ; Stone et al., 2006 ; Zadnik et al., 2000 ). Using the habitualtimes for sleeping/waking as a marker for light exposure, myopia inlaw students also was associated with less daily exposure to dark-ness ( Loman et al., 2002 ). In the only available report to includeultrasound measurements of the eye, no refraction effectwas foundin the overall population; but nighttime ambient light exposurewas associated both with more high myopia and with longer axiallengths ( Saw et al., 2002 ). Even though results differ betweenstudies, positive associations so far are in the same direction einterrupting the daily dark period with light is associated withmyopia in children. Reconciling these disparate ndings is spec-ulative, but they could relate to population differences or to theshortcomings of questionnaire-based epidemiology, such asreporting bias or unknown confounding variables.

More objective approaches to estimating in uences of photo-period length on human refractive development also suggest thatlight exposure may in uence human refraction. Surveys of armyconscripts in Finland, a country with marked variability in daylength as well as light intensity throughout the year, found a higherprevalence of myopia in subjects from the country s far north(Vannas et al., 2003 ). Similarly, the geographic latitude of origin of human skulls demonstrates a positive correlation with orbital size,a presumed index of eye size ( Pearce and Dunbar, 2012 ). Thesestudies conform to a hypothesis that light exposuremight affect eyedevelopment. Recent studies have now associated myopia withbirth month ( Fig. 3) (Deng and Gwiazda, 2011 ; Mandel et al., 2008 ;McMahon et al., 2009 ); this nding is consistent with an in uenceon refraction of perinatal day length or ambient light exposure inearly infancy, although other physiologic effects on the infant or thepregnant mother are possible.

Besides photoperiod length, lighting intensity also in uenceseye development. In chicks, rearing under high intensity illumi-nation modulates the effects of constant light ( Cohen et al., 2008 ;Oishi and Murakami,1985 ), inhibits the myopic response to diffuser

wear ( Ashby et al., 2009 ) and slows the compensation to minusspectacle lens wear ( Fig. 4) (Ashby and Schaeffel, 2010 ). In mon-keys, high ambient illumination also inhibits form-deprivationmyopia ( Smith et al., 2012 ). Rearing of chicks in low intensity

Fig. 2. In uence of nighttime lighting before age 2 years on subsequent refraction. Ahistory of increased nighttime light exposure during the rst two years of life wasassociated with increased prevalence of myopia and reduced prevalence of emme-tropia later in childhood ( P < 0.00001). Hyperopia prevalence was unaffected. Despitethe high statistical signi cance of these ndings, the positive results in subsequentstudies have been less strong; and they have not been replicated in other studies, as

discussed in the text. Modi ed from Quinn et al. (1999) .



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light for several months lengthens the eye, elongates the vitreouschamber and induces myopia, relative to those effects in chicksrearedunder higher light levels ( Fig. 5) (Cohen et al., 2011 ). Becausedecreasing light intensity reduces the rate of dopamine release inchick retina, retinal dopamine may comprise a link between day-time light intensity and refractive development in eyes with non-impaired visual input ( Cohen et al., 2012 ).

Clinically, intriguing ndings perhaps related to lighting in-tensity concern the relationship of refraction to outdoor activitiesduring childhood. A long-standing observation ( Cowan, 1942 ),modern clinical epidemiology has repeatedly con rmed associa-

tions of increased sports or outdoor activities during childhood orearly adulthood with reduced myopia ( Dirani et al., 2009 ; Jacobsenet al., 2008 ; Jones-Jordan et al., 2011 ; Jones et al., 2007 ; Mutti et al.,2002 ; Onal et al., 2007 ; Prssinen and Lyyra, 1993 ; Rose et al.,2008a ; Sherwin et al., 2012 ; Wu et al., 2010 ). Myopia progression

also is slower during the summer than during the winter ( Fulket al., 2002 ), perhaps because children are outdoors for moretime during the summer ( Deng et al., 2010 ). Not all contemporarystudies, however, substantiate this association between reducedmyopia and increased outdoor activity ( Lu et al., 2009 ; Saw et al.,2000 ; Zhang et al., 2010 ), including an assessment of myopiaonset in children age 5 years and below ( Low et al., 2010 ). Thenegative association of myopia and outdoor/sports activities nowseems related to time spent outdoors rather than physical activity per se (Rose et al., 2008a ). Children of Chinese ancestry in Singaporehave a higher prevalence of myopia than children of Chineseancestry living in Sydney, Australia; and the Singapore childrenspend less time in outdoor activities than those in Sydney ( Roseet al., 2008b ). Caucasian children living in Northern Ireland havea higher prevalence of ametropia than Caucasian children living inSydney, Australia, a difference the authors suggest may relate togeographic differences in sunlight exposure and time spent inbrighter outdoor light ( French et al., 2012 ). Annual hours of sun-shine also have been associated with blindness from malignantmyopia, in patterns modi ed by subject age and gender ( Daubs,1982 , 1984 ). Besides intensity, however, indoor and outdoor envi-ronments and activities differ in other complex ways that mightin uence the visual system, such as different chromatic propertiesof the lighting or different image characteristics; and it has beensuggested that systemic effects of outdoor lighting (e.g., on vitaminD metabolism) might account for the apparent refractive effects of outdoor exposures ( Mutti et al., 2012 ). Thus, a physiologic mecha-nism for these observations remains speculative. In the context of the effects of light intensity on eye development in laboratory an-imals, higher outdoor than indoor light intensity nonetheless isone hypothesized mechanism ( Guggenheim et al., 2012 ; Rose et al.,2008a ). Alternatively, an anti-myopia effect might follow improvedimage quality as a result of reduced pupil size in bright light. Thein uence of illumination intensity and/or the light:dark cycle onretinal dopamine release also has been proposed as a possiblephysiologic mechanism to explain the in uence of light on refrac-

tive development, via the effects of retinal dopamineon eye growth(Ashby et al., 2009 ; Ashby and Feldkaemper, 2010 ).

A conceptual dilemma, however, underlies much of the currentthinking about light intensity and refractive development. Indoorrearing of laboratory animals, including chicks, tree shrews,

Fig. 3. Myopia prevalence and birth month. The prevalence of moderate and severemyopia increased with increasing hours of daylight during the subjects birth monthamong over 275,000 Israeli army conscripts. The solid line shows the averaged dailyperiod of daylight for each month. From Mandel et al. (2008) with permission fromElsevier.

Fig. 4. The in uence of light intensity on the refractive response to spectacle lens wear. Illustrating an effect of light intensity on emmetropization in the chick, the rate of refractivecompensation of chicks wearing either a unilateral 7 diopter spectacle lens (in A) or a unilateral 7 diopter spectacle lens (in B) was altered by ambient daytime light intensityduring a 12 h light:dark cycle. Compared to chicks reared under 500 lux lighting (usual laboratory conditions), chicks that were exposed to 5 h of intense 15,000 lux lighting in themiddle of the day demonstrated a slowed response to minus lens wear (in A) and an accelerated response to plus lens wear (in B). The refractive development of the contralateraleyes with non-impaired visual input was not affected by light intensity in either group over this short rearing period. (Error bars: SEM; * P < 0.05; **P < 0.01.). From Ashby and

Schaeffel (2010) ; with permission from the Association for Research in Vision and Ophthalmology, the copyright holder.



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marmosets and monkeys,with non-impaired visual input results inemmetropia and presumed normal refractive development(Bradley et al., 1999 ; Norton et al., 2003 ; Troilo and Judge, 1993 ;Wallman et al., 1981 ). Yet, the lower intensity of indoor vs. outdoorlighting is postulated as an environmental parameter promotingmyopia in children. While bright light rearing inhibits form deri-vation myopia in chicks and monkeys ( Ashby et al., 2009 ; Smithet al., 2012 ), form deprivation per se is not the underlying causeof myopia in almost all affected children. More prolonged labora-tory rearing periods than typically used in laboratory studies may

be needed to demonstrate a refractive effect of indoor lighting(Cohen et al., 2011 ), or perhaps the mechanisms of experimentalmyopia in laboratory animals are not as closely related to themechanisms underlying common childhood myopia as generallyassumed.As other alternatives, the diverse observations about lighton refraction may depend on lighting qualities besides just in-tensity; or the underlying biological mechanism of the refractiveeffects of lighting may be more complex than simply retinal dop-amine release rates. Thus, how light in uences refraction remainsa conundrum, still not easily resolved.

3.4. Intrinsic retinal circadian rhythms

The retina has many endogenous circadian rhythms for signal

transduction, neurochemical activity, gene transcription, metabo-lism, retinal structure and even gross retinal function ( Golombekand Rosenstein, 2010 ; Storch et al., 2007 ). Entrainment is theprocess by which endogenous rhythms are synchronized to anenvironmental stimulus (the so-called Zeitgeber , from Germanfor time giver ) that in uences circadian rhythm timing andmaintains a stable phase relationship between biological rhythmsand environmental stimuli. For most vertebrates, the dominant Zeitgeber is environmental light, but the in uence of light on cir-cadian rhythms is complex ( Duffy and Czeisler, 2009 ; Johnsonet al., 2003 ) and involves retinal dopamine ( Jackson et al., 2011 ,2012 ; Yujnovsky et al., 2006 ). The light exposure patterns in u-encing refractive development (e.g., see above) often conform tothe light exposure patterns used to study and model circadian

rhythms.

Like other tissues with intrinsic circadian rhythms, the retinarelies on a clock to match its rhythms to the 24 h cycle of the day.Biological clocks are constructed of transcriptional and transla-tional feedback loops consisting of the clock genes and their proteinproducts ( Tosini et al., 2008 ). Besides in uencing its endogenousrhythms, an intact retinal clock even seems critical for processingvisual input ( Cameron et al., 2008 ; Storch et al., 2007 ).

3.4.1. Do circadian rhythms interface with refractive development?Seeking to clarify the retina s role in refractive development,

several investigators have assessed retinal gene expression (i.e.,mRNA expression) in eye growth models using microarrays ( Ashbyand Feldkaemper, 2010 ; McGlinn et al., 2007 ; Stone and Khurana,2010 ; Stone et al., 2011 ; Summers Rada and Wiechmann, 2009 ). Asrecently reviewed, proper interpretation of mRNA expressionstudies requires attention to methodologic details, including tissuepreparation, gene pro ling strategy, bioinformatics approach andsubsequent validations; for a complex tissue like retina, expressionpro lesprovidedata pertinent to the tissue actually sampled ( Stoneand Khurana, 2010 ). Despite the caveats needed in interpretingthese data, many potentially informative individual signaling mol-eculeshave emerged from these studies ( Stone and Khurana, 2010 ).

Potentially related to dopamine s effects on refractive develop-ment, an intriguing set of differentially expressed retinal genesdevelops in chicks with myopia from minus lens wear ( Stone et al.,2011 ). Lens-induced myopia alters the mRNA expression in theretina of a signi cant proportion of intrinsic clock genes, the geneto oneof the receptorsfor melatonin (itself a majorretinal output of the circadian clock), and a gene for melanopsin. Melanopsin isa light-sensitive pigment in non-photoreceptors of the vertebrateretina. In mammals, melanopsin is expressed by a subpopulation of intrinsically photosensitive retinal ganglion cells that project tobrain centers controlling circadian rhythms and pupil size ( Bailesand Lucas, 2010 ; Paul et al., 2009 ). In chick retina, melanopsin ex-ists in two forms ( Bellingham et al., 2006 ) and is expressed byhorizontal and bipolar cells as well as ganglion cells ( Tomonari

et al., 2005 ). Dopaminergic amacrine cells express clock genes atcomparatively high levels ( Ruan et al., 2006 ). Signi cantly,melanopsin-containing ganglion cells also provide input to dop-aminergic amacrine cells and in uence their diurnal activity; anddopaminergic amacrine cells and melanopsin-containing retinalganglion cells directly interact ( Sakamoto et al., 2005 ; Viney et al.,2007 ; Vugler et al., 2007 ; Zhang et al., 2008 ). Moreover, mela-nopsin modulates diurnal rhythms of visual processing through thecone pathway in mouse retina ( Barnard et al., 2006 ).

3.4.2. Refractive pharmacology and endogenous rhythmsIn this context, the evidence that the diurnal variation in the

biosynthetic and physiologic activity of dopaminergic amacrinecells modulates refractive development in both experimental

mammals and birds ( Iuvone et al., 1989 , 1991 ; Stone, 2008 ; Stoneet al., 1989 ) raises the possibility that endogenous rhythms mayprovide the link between image clarity, retinal pharmacology andrefractive development. The expression of clock genes in dop-aminergic amacrine cells and their interaction with melanopsinganglion cells, just discussed, supports this hypothesis for futureresearch. As indirect but further support for this hypothesis, otherretinal neurotransmitters/neuromodulators implicated in refrac-tive development (e.g., acetylcholine, GABA and VIP) ( Chebib et al.,2009 ; Pickett Seltnerand Stell,1995 ; Stone, 2008 ; Stone et al., 1988 ,2003 ; Tkatchenko et al., 2006 ) are already known to in uencecircadian rhythms in retina ( Golombek and Rosenstein, 2010 ; Ruanet al., 2008 ; Steenhard and Besharse, 2000 ; Yujnovsky et al., 2006 )or, if not yet studied in the eye, are known to modulate circadian

rhythms in brain ( Golombek and Rosenstein, 2010 ; Hut and Van der

Fig. 5. The effect of light intensity on refractive development in normal chickens withnon-impaired visual input. Chicks, reared from hatching under high (10,000 lux),medium (500 lux) or low (50 lux) illumination for 90 days, demonstrated differentpatterns of refractive development ( P < 0.0001). At 90 days, the chicks reared underlow intensity lighting were mildly myopic ( 2.4 diopters), and those reared under highintensity lighting were slightly hyperopic ( 1.1D), with intermediate refractions for thecohort reared under medium intensity lighting. (Error bars: SD). Modi ed from Cohenet al. (2011) , with permission from Elsevier.



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Zee, 2011 ; Mohawk and Tokahashi, 2011 ; O Hara et al.,1998 ; Welshet al., 2010 ).

Additional lines of evidence in chick also have suggested a po-tential role for circadian rhythms in refractive development. A shortperiod of daily darkness inhibits the constant light response,hinting toward a circadian explanation for theeffect( Li et al.,2000 ).Interrupting the dark period with three intermittent 5-min lightexposures/hour reduced the response to minus lens wear andinhibited contralateral eyes with intact visual input, and strobelighting just before the onset and just after offset of light inhibitedform-deprivation myopia; the authors speculated that their resultsare consistent with an in uence of circadian rhythms on refractivedevelopment ( Kee et al., 2001 ). Also, rearing chicks under con-tinuous light but reducing the light intensity during subjective

night inhibits this refractive response to constant light rearing,even when alternating between light levels that when held con-stant induce the constant light response ( Liu et al., 2004 ). The ac-tion of continuous light that oscillates in intensity within a 24 h dayto inhibit the response to rearing under constant intensity light alsocould be consistent with a circadian signal.

4. A hypothesis for emmetropization

Increasingly, studies suggest that endogenous retinal rhythmsmight interface with the mechanism(s) governing refractivedevelopment. These ndings include the in uence of dopaminerhythms on refractive development and endogenous retinalrhythms, the discovery of circadian rhythms in eye size and eyegrowth, the altered growth rhythms now known at least for chicksdeveloping myopia, the effects of defocus on shifting daily eyedimension rhythms in chick, the extensive literature describinglight effects on refractive development in laboratory animals andchildren and the microarray data identifying dysregulatedcircadian-rhythm related retinal genes in lens-induced myopia.While the observations do not yet provide a coherent molecular

explanation, the breadth of these data suggests the hypothesis thatintact intrinsic retinal circadian rhythms are fundamental to themechanisms controlling refractive development and that refractiveerrors might arise from disruptions of circadian control ( Fig. 6).

Establishing a central role for circadian retinal rhythms inrefractive development could reconcile and unify many seeminglydisparate observations. These include the increasing prevalence of myopia as societies become more economically advanced (perhapsfromcircadiandisruptions due to increased arti cial lighting), birthdate effects (perhaps from in uences of season on circadianrhythms of infants or pregnant mothers), the questions about in-door/outdoor activities with their varied lighting qualities, and the

direct role of light itself. Circadian biology may also reconcile theseemingly contradictoryobservations that both less light (e.g., fromindoor activities) and more light (e.g., from shorter or disrupteddaily dark periods) are associated with more myopia in populationsurveys. Interrupting or altering the light:dark photoperiod haslong been known to impact circadian rhythms ( Golombek andRosenstein, 2010 ); and dim lighting, including prior light expo-sures, can cause complex alternations of circadian physiology(Duffy and Czeisler, 2009 ; Turner and Mainster, 2008 ). Much futureresearch is needed, though, to determine if and how circadianbiology in uences refractive development.

5. Conclusion

Using well-de ned experimental eye growth models, the pastseveral decades have seen increasing application of pharmacologicmethods to learn the signaling mechanisms responsible for normalpostnatal eye growth and for refractive errors. The literature onrefractive development, laboratory and especially clinical, is vast;but understanding of the basic biological processes remains frag-mentary, hypothetical, and often quite speculative. The large num-ber of signaling molecules reported to be involved in this processalso arenot readily incorporated into a simpli ed eye growthmodelat present. Nonetheless, investigators are increasing applying basicpharmacology ndings to the design of clinical investigations.Evolving clinicaldatanowhighlightseveral signalingpathways thatmight be central to normal and abnormal refractive development,and two promising pathways are reviewed here: acetylcholine sig-naling through muscarinic and/or nicotinic acetylcholine receptorsand dopaminepharmacology. The extent towhichthe acetylcholineand dopamine/circadian pathways are distinct or interacting inmodulating refractive development requires future study. Becausedesigning clinical trials of drugs acceptable to patients and regu-latoryagencieshasprovedproblematic( Stone,2008 ),thein uencesofdopaminesignaling maybeproviding an importantlead.Basedonthe complex roles of retinal dopamine signaling on intrinsic retinal

rhythms, future research on refraction, ocular rhythms and endog-enous circadian retinal rhythms may provide means to modulaterefractive development through controlled light exposure ratherthan through drugs or optical manipulations.

Acknowledgments

The authors acknowledge the following sources of nancialsupport: NIH grants R01-EY018838 (RAS), R01-EY016435 (MTP),R01-EY004864 (PMI), R01-EY013862 (TSK), P30 EY001583 (U PA),P30-EY006360 (Emory); the Paul and Evanina Bell Mackall Foun-dation Trust (RAS), Research to Prevent Blindness (RAS, PMI),Rehabilitation Research and Development Service, Department of Veterans Affairs Research Career Scientist Award (MTP). PMI isa recipient of theSenior Scienti c InvestigatorAward from RPB. Theauthor acknowledge many years of productive scienti c in-teractions withy Josh Wallman, a pioneer in applying biologicalmethods to the problem of refractive development.

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Fig. 6. A hypothetical framework for the regulation of eye growth and refractivedevelopment. Proposed here is the possibility that intrinsic retinal circadian rhythmsmight be central to the signaling mechanism regulating refractive development. Thisscheme proposes that the neurotransmitter responses to visual input interact with theintrinsic retinal circadian clock. The clock also can be in uenced by light and possiblyother Zeitgebers (e.g., temperature, diet). The retinal clock presumably governs thedaily rhythms in eye growth and ocular dimensions and thus could modulate theoverall refractive development of the eye. While consistent with the diverse clinicaland laboratory data discussed in the text, much work is needed to con rm the com-ponents of this hypothetical pathway. While not necessarily required, parallel but

independent pathways might also contribute to the emmetropization process.



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Farmacología de La Miopía y El Papel Potencial de Los Ritmos Circadianos Intrínsecos de La Retina

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