photoreceptors are intimately connected to the rest of the retina through intercellular communication and cell support mechanisms . the two main photoreceptor types are rods , which are highly sensitive to light and are needed for vision in low light conditions ; and cones , which are less sensitive to light and are utilized in the bright light of daytime . cones are further divided into subtypes based on maximal wavelength sensitivity ; combinations of inputs from multiple cone types enable colour discrimination . for vision restoration the fovea is an important target - it is a region of human and other primate retinas containing exclusively cones , and is responsible for daytime , high acuity , and colour vision . therefore , the ultimate goal is to restore or preserve function of the fovea and surrounding macula , which requires not just a sufficient number of cones , but also their survival , integration , and function within this unique retinal environment . hence in modeling vision disease , regeneration , and restoring function , more emphasis must be placed on the effects of 1 ) the surrounding retinal environment , and 2 ) the photoreceptor type , specifically cones and cone subtypes . in these endeavours , we suggest that diverse vision models would prove powerful complements to existing ones . the zebrafish retina especially can mimic the macula , because it contains a dense , even distribution of cones . zebrafish have numerous additional advantages such as conserved eye development , genetic tools , and robust regeneration ( bibliowicz et al . , 2011 ; gemberling et al . , 2013 ) . the retina is specialized to suit the unique visual environment of an organism , based on factors like circadian activity ( e.g. , diurnal , nocturnal ) and vital visual stimuli ( e.g. , color sensitivity , motion detection ) . the composition and connectivity of photoreceptor populations are complex and variable among vertebrates , necessitating the study of multiple models . in this regard , the nocturnal rod - dominated mouse retina , a relevant system for mammalian genetics and retinal biology ( but insufficient in cones ) , should be complemented with others such as the diurnal cone - dominated zebrafish retina , which mimics the human macula ( figure 1 ) . furthermore , the retinal environment 's response to photoreceptor loss is an emerging question relevant to photoreceptor biology , including disease . the murine and zebrafish retinas have several intriguing contrasts , including genetic regulation of photoreceptor specification ( kim et al . , 2016 ) , responses to degeneration , and synaptic plasticity , which differentially influence rods and cones during photoreceptor loss and re - introduction . thus we are interested in how cone subtypes regenerate , and how the retinal environment influences them . indeed , established and emergent data indicate the retinal environment influences photoreceptor fate and survival . the diversity of retinal responses to photoreceptor loss and/or introduction can be appreciated in the contexts of disease or damage , and of an organism 's life history . in many of these cases , the retina is a thin neural tissue that lines the inside of the eye , as shown through a cutaway in a schematized eyeball . in humans , the macula is a region of the retina that is very rich in cones , including blue- , green- , and red - sensitive cone types . the cones of the macula are responsible for daytime photopic vision , color discrimination , and visual acuity , thus the macula is an important target for vision restoration . the zebrafish and murine retinas are well - studied examples of cone rich and rod rich respectively , exemplary of a spectrum of retinal environments . zebrafish have a high and even density of cones across the entire retina , with rods dispersed throughout . zebrafish cones are arranged in a row mosaic where rows of ultraviolet and blue cones ( colored purple and blue ) alternate with rows of red and green cones ( red and green , shown in double cone morphology ) . mouse cones express green - sensitive opsin in the dorsal retina , blue - sensitive opsin in the ventral retina , and co - express both in the central retina . rods are depicted as long grey bodies ; cones depicted as stout bodies . in photoreceptor schematics across vertebrate species , diversity in photoreceptor development and composition ( e.g. , variation in rod - to - cone population ratios ) underlines how photoreceptors are influenced by their environments . surveying multiple vision models , one quickly develops an appreciation that different retinas show biases toward the development , survival , and integration of certain photoreceptor types ( often comparing rods and cones , but also subtypes of cones ) , and have different responses to damage and disease ; therefore the context of the environment should be considered when investigating photoreceptor loss and regeneration . photoreceptor biology has been extensively studied in murine and zebrafish retinas , two complex and complementary vision models . the mouse retina is biased to the survival and integration of primarily rods from donor precursors , suggesting mechanisms to maintain a rod - dominated milieu . implantation of crx photoreceptor precursors ( which have potential to become either rods or cones ) into wildtype retinas results in the majority becoming rods . however , cone fate adoption is slightly higher when crx precursors are implanted into cone - deficient gucy2e retinas , though not above cone : rod population ratios seen in wild type retinas ( lakowski et al . , 2010 ) . in other words , the murine retina strongly regulates photoreceptor populations toward a rod majority and a cone minority , suggesting , essentially , that environmental context matters . the zebrafish promises to expand on this hypothesis because zebrafish retinas have both a high density of cones and a large variety , with four major cone types organized in a precise mosaic pattern ( compared to two types in mice and three in humans ) ( figure 1 ) . the zebrafish retina is especially attractive for its regenerative capacity ; the coordination of inflammation , neuroprotection , and latent pluripotency of mller glia is fascinatingly effective and robust , though these topics are beyond the scope of this paper ( ahmad et al . adding to the wealth of literature documenting zebrafish retinal regeneration , we reported differential responses based on the photoreceptor type ablated , implicating a regeneration process that is responsive to context . following ultraviolet ( uv ) cone - specific ablation the regenerative response is shifted to produce proportionately more uv cones ( fraser et al . , 2013 ) , perhaps in order to restore cone subtype ratios ( figure 2 ) . thus in contrast to the rod - permissive / cone - restrictive murine retina , the zebrafish retina promotes a large and strictly - proportioned cone population in development and regeneration . effects of photoreceptor identity on retinal regeneration and functional vision restoration . both cellular regeneration and the kinetics of synaptic plasticity loss of ultraviolet ( uv ) cones in zebrafish via pharmacogenetic ablation biases the retina to regenerate uv cones , resulting in restoration of their position and abundance . alternatively when blue cones are ablated , a robust and rapid restoration of visual function occurs through synaptic plasticity . meanwhile , the remaining photoreceptor types survive , likely through many pro - survival mechanisms . thus multiple mechanisms act in response to cone loss , and the identity of the cone type lost ( or perhaps the type[s ] that remain ) affects the mechanisms employed for regeneration and restoration of function . based on these inferences , the need to consider photoreceptor types during regeneration strategies is apparent : regeneration , survival , and re - wiring of cones into the cone - rich human macula obliges use of appropriately cone - dominant model systems . in zebrafish , ablation of uv cones results in regeneration with increased production of uv cones , indicating the retina ( or a subset of cells therein ) can , in some manner , detect the loss of specific photoreceptor types and drive pluripotent cells toward that identity ( fraser et al . , 2013 ) . in rainbow trout a similar process occurs as part of their life history ; elevated thyroid hormone levels cause uv cones to disappear during preparation for migration . the subsequent return and reintegration of uv cones later in life suggests that the retinal environment retains the capacity to generate new uv cones and functionally integrate them ( allison et al . 2006a , b ) . both fish systems also support the notion that the cell types lost , or the types that remain in the retinal environment , influence what photoreceptor types regenerate ( sherpa et al . , 2014 ) . teleosts regenerative capacity and precise response to loss of specific neural types continue to be a source of keen investigation and hope for use in the therapeutic realm . recent insightful work , such as material transfer between donor and host photoreceptors in mouse models of retinal degenerations , suggests unforeseen influences of the retinal environment ( ortin - martinez et al . , 2016 ; pearson et al . , 2016 ; santos - ferreira et al . , 2016 ; singh et al . , 2016 ) . exchanging material such as rna between cells may be a pro - survival mechanism , possibly explaining past implantations of donor cells that resulted in vision improvements , despite low integration rates . 2016 ) suggest that donor cells may transfer vital components , helping host photoreceptors survive and thus preserving function ( in contrast to restoring it ) . if so , implanting healthy cells may instead prove valuable for photoreceptor survival as part of overall therapeutic strategy . recovery of visual function without photoreceptor replacement in zebrafish may be another mechanism to preserve function independently of regeneration , possibly through altering inputs from remaining cones or other forms of synaptic plasticity ( hagerman et al . , 2016 ) . moving forward , experiments that compare different environments , rods to cones , and cone subtypes the establishment , patterns , and plasticity of synaptic connections are critical for visual function and are just beginning to be described . in our and others work comparing blue and uv cones in zebrafish , we can already see that retinal interneuron synaptic development is influenced by photoreceptor identity . we also see synaptic plasticity in photoreceptor degeneration and regeneration , and that it is subject to influences of the retinal environment within these contexts . after blue cone ablation in zebrafish , blue cone - dependent colour discrimination is restored before regeneration , but this is not seen when uv cones are ablated ( figure 2 ) ( hagerman et al . , 2016 ) . horizontal cells display a preference to synapse with uv more than blue cones , and do not synapse with red or green cones . this preference persists when uv cones are specifically ablated h3 cells preferentially synapse with newly - generated uv cones ( though this response can be modified under certain conditions again , the environment matters ! ) ( yoshimatsu et al . , 2014 , 2016 ) . again , from these findings we infer that the zebrafish retinal environment is biased toward re - establishing a cone - rich population with specific ratios of subtypes . next , we infer that retinal plasticity occurs to integrate new cones , and restores a connectivity pattern that discriminates among subtypes . the plasticity of the retina can restore function before regeneration depending on the cone type lost , apparently using multiple mechanisms to correct for different insults . these differential responses to cone loss underpin the need to conduct focused studies on cones and each cone subtype in turn . among other considerations , the retinal environment affects both surviving and new photoreceptors , including their connections to interneurons . the teleost retina responds to photoreceptor damage using both regeneration and synaptic plasticity , based on such information as the identities of lost cells and the availability of remaining ones . these responses sharply contrast the mammalian retina , in which regeneration is not found , and photoreceptor degeneration causes diverse changes in synaptic plasticity , often with deleterious results ( jones et al . moving forward , studying visual function and restoration will require rigorous examination of underlying cellular mechanisms . showing , via electroretinogram and visual behavioral assays , the successful preservation or recovery of visual function is a powerful measure of efficacy . more often though , little or ambiguous change may be found on these assays , leaving investigators without indication where , on the road to visual function , any changes may have occurred . interrogating , at the cellular level , changes in photoreceptor death , survival , replacement , function , and connectivity would bridge this gap . we showed that the optimized optomotor response can be sensitive enough to detect changes in synaptic function following loss of specific photoreceptors in zebrafish , but the mechanisms require further investigation ( hagerman et al . , 2016 ) . characterization of h3 horizontal cells provides important starting points for interrogating connectivity and plasticity among cone subtypes ( yoshimatsu et al . , 2016 ) . a non - exhaustive list of approaches to assess photoreceptor function is provided here as food for thought . methods to measure neuronal activity , used successfully in other neuron types , could be utilized in the retina . calcium - sensitive compounds and genetic tools to measure in vivo activity , such as campari , offer a peek into active , intact neuronal systems ( grienberger and konnerth , 2012 ; fosque et al . , 2015 ) . functional photoreceptors respond to changes in light stimuli , which may be measurable by exploiting well - known processes such as byproducts of phototransduction . additionally , photoreceptors must communicate with downstream neurons via synaptic transmission . the preservation or novel formation of synapses and the release of neurotransmitters with tools like genetically encoded transmitter indicators ( getis ) ( lin and schnitzer , 2016 ) can provide context for changes on scotopic or photopic erg , or alterations in colour sensitivity . additionally , changes in the release of neuromodulators in response to changes in photoreceptor types or numbers would be of great interest . horizontal cells mediate lateral inhibition and exhibit plasticity in response to changes in the environment , such as light conditions and low availability of a preferred photoreceptor type ( yoshimatsu et al . , 2014 ) . to expand our understanding of vision biology , and to develop effective vision restoration therapies , it is becoming increasingly important to study diverse retina types . the retinal environment shapes the composition and function of the photoreceptors , and it influences regenerative capacity and synaptic plasticity . therefore , as we learn more about photoreceptor death , survival , and regeneration , it is important to include 1 ) the retinal environment , and 2 ) the photoreceptor type as two important contexts in which to frame questions and experiments . to develop effective therapies for restoring human sight , clinical outcomes for models should especially emphasize repairing photopic vision , colour vision , and visual acuity , all of which are mediated by cones . to these ends a diversity of photoreceptor models is powerful , and to advance cone biology in particular , we need to work with cone - rich models such as the zebrafish .
retinal regeneration is a promising central nervous system ( cns ) target amongst the various stem cell therapy pursuits , due to its accessibility for manipulation and its disposition towards longitudinal monitoring of treatment safety and efficacy . 
 we offer our perspective on current hurdles towards functional regeneration of cone photoreceptors . 
 cones are key : for patients suffering vision loss , cone photoreceptors are a required cellular component to restoring daytime vision , colour vision , and high acuity vision . 
 the challenges of regenerating cones contrast with logistic challenges of regenerating rod photoreceptors , which underlines the importance of evaluating context in degeneration and regeneration studies . 
 foundational research is required to delineate the factors required to generate a diversity of cones in the human macula , and to coax both remaining and newly regenerating cones to rewire towards restoring daytime colour vision . 
 a complex interplay between cell - intrinsic factors and the retinal environment determine both the specification of cone fates and the synaptic plasticity enabling their functional integration . 
 recent revelations that cellular materials are transferred amongst photoreceptor progenitors further emphasize the critical role of neighbouring cells in directing stem cell fates . from our vantage point , 
 translation of stem cell therapies to restore the cone - rich human macula must be borne upon foundational research in cone - rich retinas . 
 research frameworks centered on patient outcomes should prioritize animal models and functional outputs that enable and report functional restoration of cone - mediated vision .