REVIEW

Regenerating optic pathwaysfrom the eye to the brainBireswar Laha,1 Ben K. Stafford,1 Andrew D. Huberman1,2,3*

Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connectthe eyes to the brain, fail to regenerate after damage, eventually leading to blindness.Here, we review research on regeneration and repair of the optic system. Intrinsicdevelopmental growth programs can be reactivated in RGCs, neural activity canenhance RGC regeneration, and functional reformation of eye-to-brain connections ispossible, even in the adult brain. Transplantation and gene therapy may serve to replaceor resurrect dead or injured retinal neurons. Retinal prosthetics that can restore visionin animal models may too have practical power in the clinical setting. Functionalrestoration of sight in certain forms of blindness is likely to occur in human patientsin the near future.

Sight is crucial for humans to navigate theworld. Under normal, healthy conditions,our eyes and brain create sight so automat-ically that only when our visual pathwaysare damaged do we fully appreciate the ex-

tent towhich eyesight defines our experience. Forthe many who suffer visual impairments, it is ur-gent that we discover strategies to regenerate ret-inal neurons and convert those strategies intoclinically viable therapeutics.Vision begins in the retina, the thin trilayered

neural tissue at the back of the eye (Fig. 1); there,photoreceptors transform light information intoelectrical signals that the rest of the visual systemcan understand. The retinal interneurons—thehorizontal, bipolar, and amacrine cells—then passthat information to the retinal ganglion cells(RGCs), the output neurons of the eye. There are~30 different types of RGCs, each firing actionpotentials depending on the quality and locationof visual stimuli in the environment (1). Thoseaction potentials propagate down the optic nervesand into the brain, where they are translatedinto perceptions and light-mediated behaviors.

The importance of retinal ganglion cells

RGCs are a bottleneck for vision. Even when therest of the visual system is healthy, if RGCs aredead or dysfunctional, vision is impossible. RGCsare protected by the sclera, the thick, durabletissue that encompasses the back of the eye. How-ever, the path that RGC axons take to reach thebrain renders them vulnerable to damage in re-sponse to impacts to the head or eye. Glaucoma,with its attendant elevated eye pressure, is themost common cause of irreversible blindness (2).Research on visual repair has therefore focusedon sustaining RGCs after injury, encouraging axonregrowth down the optic nerve, and reestablish-

ing their correct synaptic relationships. Un-fortunately, mammalian RGC axons do notregenerate after damage and damaged RGCseventually die, never to be replaced. So prevalentis this cause for blindness that the U.S. NationalEye Institute has set forth as their “Audacious

Goal” to discover means to repair RGC con-nections with the brain (https://nei.nih.gov/audacious).The major questions that drive research on

visual restoration and RGC repair are simplebut challenging: What strategies support RGCaxon regeneration after damage?Can regeneratingRGC axons form functional synapses with theirtargets in the brain?

Extrinsic factors unique to the CNSlimit optic nerve regeneration

Various environmental influences limit RGCregeneration. Although neurons with cell bodiesin the peripheral nervous system (PNS) avidlyregenerate, neurons such as RGCs, whose cellbodies reside in the central nervous system(CNS), fail to reextend after injury (3, 4). Evenif the rodent optic nerve is completely tran-sected, a peripheral nerve graft allowsRGC axonsto regenerate and form synapses with theirtargets in the brain (5, 6). Thus, the damage en-vironment constrains the regeneration ofmaturerodent RGCs. Unfortunately for humans, the PNSnerve graft approach holds limited therapeuticpotential because it involves massive neuro-surgeries. Nevertheless, these studies underscore

Laha et al., Science 356, 1031–1034 (2017) 9 June 2017 1 of 4

1Department of Neurobiology, Stanford University School ofMedicine, Stanford, CA 94305, USA. 2Department ofOphthalmology, Stanford University School of Medicine,Stanford, CA 94305, USA. 3BioX, Stanford University Schoolof Medicine, Stanford, CA 94305, USA.*Corresponding author. Email: adh1@stanford.edu

Retina

Light responseAction potentials

Myelin

Myelinatedoptic nerve

Intact optic nerve Optic nerve damage

Photoreceptors

Horizontal cells

Bipolar cells

Amacrine cells

Retinal ganglion cells (RGCs)

Light pathway

Signal outputpathway

Fig. 1. Visual information is transmitted from the eye to the visual centers in the brain via theoptic nerve. (Top) Light reaching the retina is converted into electrical potentials that eventually causeaction potentials in the ganglion cells (RGCs). (Middle) The myelinated optic nerve transmits actionpotentials (Bottom left) to the visual processing centers in the brain. (Bottom right) After damage,RGC axons degenerate. In the absence of therapeutic interventions, blindness ensues.G

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the principle that RGCs can regen-erate if given the appropriatemilieu.

Inhibitory effects ofmyelin proteins

Normally, myelin insulates axons,increasing conduction velocity ofelectrical signals (Fig. 1). In thePNS, where regeneration is inher-ent to the system, Schwann cellsprovide myelination. In the CNS,Oligodendrocytes are themyelinat-ing glial cells and have an inhib-itory effect on axon regeneration.Oligodendrocytes present a varietyof proteins inhibitory to axon re-growth, includingmyelin-associatedglycoprotein, the neurite-outgrowthinhibitor “Nogo,” oligodendrocyte-myelin glycoprotein, and semaphor-ins (7, 8). Neutralization of theseproteins has been shown to enhanceRGC axon regeneration in vitro (7).However, experiments assessing the consequencesof removing these proteins in vivo reveal littleor no regeneration (9), challenging whetherthese proteins actually constitute major brakeson regeneration. Neutralizing Nogo can enhanceregeneration if RGCs are shifted into a growthstate (10), but overall, the effects of reducingmyelin-associated proteins on RGC regenerationare subtle. Thus, attention has expanded to con-sider other extrinsic influences that might un-derlie RGC regenerative failure and that mightconstitute targets for enhancing regeneration inthe clinic.

Reactive scarring and inflammation

As with any injury, damage to the optic pathwayrecruits cellular and molecular processes to buf-fer the injury response, some of which affect theregenerative potential of RGCs (11). Astrocytes—the glial cells that support synapse development,transmission, and plasticity (12)—create physi-cal and molecular barriers after injury that canprevent RGC axons from regrowing. Some ofthese include chondroitin sulfate proteoglycans(CSPGs) and tenasins (11, 13). Lesions of the ro-dent spinal cord induced in a context of minimalastrocyte reactivity allow for robust axon re-generation, even through myelin (14), under-scoring the extent to which astroglial scarringmight limit RGC regeneration. Other work shows,however, that glial scars can actually promoteregeneration in the rodent spinal cord (15). Thefield of visual repair awaits studies that evaluatethe role of scar-related factors in the optic nervein vivo. This needs to be addressed directly inthe visual system because the wiring architec-ture of the eye-to-brain pathway differs vastlyfrom that of the spinal column. Spinal lesionstypically injure axons at locations that allowfor collateral (side-branch) sprouting around thelesion, something not possible for RGC lesionslocated near the optic nerve head (Fig. 1).Lesions can cause local production of inflammation-

related cytokines such as interleukin-6, leuke-

mia inhibitory factor, and ciliary neurotrophicfactor (CNTF) from glia and other non-neuralcells (16, 17). In the adult, CNTF up-regulates atranscriptional pathway involving suppressionof cytokine signaling factor 3 (SOCS3) in RGCs,thus limiting axon regeneration (18). In the ab-sence of SOCS3, CNTF can, however, enhanceregeneration by activating gp130-dependent ki-nase signaling (19). Thus, the pathways that af-fect RGC regeneration depend on the signalingcontext, which imposes complexity on potentialtherapeutic strategies.Zinc released from amacrine interneurons af-

ter injury is internalized byRGCs and limits theirregeneration (20). Other extrinsic factors, how-ever, canpromote regeneration: Lens injury causesmacrophages to release oncomodulin, which sup-ports RGC axon extension via a Ca++/calmodulinpathway (21). Lesion-reactive cells and proteinsin both the eye and in the optic nerve can eitherhelp or hurt regeneration. The key is to discoverwhen and why.

Intrinsic factors that limitRGC regeneration

RGC axons down-regulate their axon growthspeed more than 1000-fold as they transitionfrom embryonic to postnatal ages, likely becauseof molecular programs intrinsic to RGCs (22). AsRGCs mature, they down-regulate expression ofphosphorylatedmammalian target of rapamycin(phosphor-mTOR), a growth-promotingmolecule.Deletion of anmTOR inhibitor, phosphatase andtensin homolog (PTEN) in RGCs, greatly enhancestheir axonal regeneration capacity after injury(23). Some regenerated axons even extend fromthe lesion site located just behind the eye all theway to the optic chiasm, a distance of many mil-limeters. This degree of regeneration representsa triumph for the field, andwhen combined withknockdownof SOCS3,mTOR enhancement causeseven more RGCs to regenerate (24).Combining mTOR activation and SOCS3 inhi-

bition is promising, but caveats pertain when

considering their clinical applications. First, theincrease in phosphor-mTOR has to be in placebefore axon injury in order for regeneration tooccur (25). Second, mTOR broadly affects cellgrowth (26) and thus may cause retinal tumorformation (27). Any therapeutic approach thatrelies on enhancing mTOR signaling thus wouldhave to include safeguards. Third, mTOR en-hancement alone (or mTOR plus SOCS3 dele-tion) triggers regeneration of RGC axons only asfar as the chiasm (23–25). This suggests thatthere are inhibitory cues at the optic chiasm andthatmorepotent stimulators ofRGC regenerationmay be needed to inspire RGC axon growthinto the brain. In some mice, axons regenerateto the optic chiasm but then turn away from thebrain and grow into the other optic nerve, towardthe contralateral eye (28). Thus, not all regener-ation is productive. Other manipulations such asknockdown of the growth-inhibiting transcrip-tional repressor KLF4 can also encourage RGCsregeneration (29), but again, not the full distanceback into the brain.

Reconnection to targets in the brain

A few studies show regeneration of RGC axonsbeyond the optic chiasm into the brain. En-hancement of mTOR combined with augmen-tation of adenosine 3′,5′-monophosphate (cAMP)and injections of oncomodulin promoted long-range regeneration of RGC axons (30) to brainstructures, including the dorsal lateral genic-ulate nucleus (dLGN), which relays visual in-formation to the cortex. Mice that received thecombined treatment of PTEN-knockdown/cAMP-increase/oncomodulin also recovered some visualfunction, although the connections eventuallyregressed.Therefore, strategies must support both RGC

regeneration and long-term survival of circuits.Some of the same factors that can promote regen-eration also can promote degeneration of RGCsafter injury. Removal of dual leucine zipper ki-nase (DLK) from RGCs enhances their survival

Laha et al., Science 356, 1031–1034 (2017) 9 June 2017 2 of 4

Site of opticnerve damage

Injured RGCsmade active

Injured RGCs

RGCs

Retina

Fig. 2. Electrical activity can promote RGC axon regeneration. Increasing the activity of RGCs after opticnerve damage can facilitate the repair of degenerating axons in the optic nerve (25, 33), with many extending pastthe site of damage into the brain and partially restoring sight in animal models (25).

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after optic nerve injury by altering apoptoticpathways but also limits PTEN-knockdown–basedenhancement of axon regeneration (31).

Neural activity facilitatesRGC axon regeneration

During development, spontaneous and visuallydriven electrical activity refine RGC connec-tions (32) and enhance RGC axon outgrowth byincreasing responsiveness to trophic factors (22).In the adult animal, increasing RGC firing per-mits their axons to regenerate through opticnerve lesions (Fig. 2) (25, 33) and boosts the im-pact ofmolecular stimulants of axon growth suchasmTOR (25). Conversely, reducing activity levelsof RGCs inhibits their survival after damage (25).Increasing RGC firing alone was not sufficient tosupport RGC axon regeneration into the brainunless phosphor–mTOR was increased (25).RGC axons that regenerate back to their tar-

gets apparently fail to undergo myelination andtherefore suffer slower conduction of electricalpotentials (34). RGC firing induces myelinatingoligodendrocytes during development (35) butapparently not during adulthood. This informsus that only some of the mechanisms that ini-tially establish visual circuitry are available forreactivation in adulthood; others may need tobe replaced.

Target and cell-type specificity ofregenerated connections

Can regenerating RGC axons rewire appropri-ately in the brain? One idea is that adult mam-malian CNS circuits avoid regeneration becauseit is better to have no regeneration than incorrectregeneration. Evidence, however, indicates thatregenerated RGCs form correct connections andavoid targets incorrect for their function (25).

Similarly, in the spinal cord the central branchof dorsal root neurons (DRGs) regenerates in atopographic- and laminar-specificmanner, unlessmyelin-associated factors such as Nogo are per-turbed (36). Axon-guidance molecules that serveindevelopment todirectRGCaxons to their targetsmay thus get up-regulated after injury, a featureknown to occur in cold-blooded vertebrates thatnaturally add newRGCs across their life span (37).

Thresholds for reversing blindnessRegeneration of axons is only part of the story;restoration of functional visual capacity is re-quired. The mere presence of regenerated RGCaxons at a target in the brain does not predictvisual function (25, 34). For example, combiningRGC activity with mTOR enhancement led tothe recovery of the mice’s visual reflex to avoidoverhead looming stimuli (25), but even whenRGC axons regenerated to the dLGN, thoseconnections failed to lead to enhanced depthperception—a well-established property of theretino-dLGN-cortical pathway (25). The fact thatsome visual functions are restored whereas oth-ers are not, even in the presence of structural

regeneration, may reflect the lack of axon mye-lination or perhaps failure of correct proteins toreaccumulate at retino-dLGN synapses (38). Thegood news is that withmodern approaches suchas single-cell RNA-sequencing that enable thegenetic makeup of specific sets of neurons to beevaluated, one can now compare the molecularattributes of normal and regenerated CNS neu-rons and synapses.

Transplantation of RGCs

Therapeutic intervention with regeneration-inducing stimuli should be successful only dur-ing a limited period after injury, when RGCsare still alive. Although the mammalian retinamay harbor a stem cell population in the ciliarymargin (39), there is no evidence they replaceRGCs damaged by injury or disease. The lack ofendogenous RGC replacement in mammals isin stark contrast to the scenario in fish andamphibians, which add new RGCs throughouttheir life span, a feature thought to arise at leastin part from the presence of a specific proneuraltranscriptional factor, Ascl1, made by retinalMüller glia in cold blooded vertebrates but notby mammalian Müller glia (40).Three general approaches to replace RGCs

include (i) syngeneic transplantation of adultinduced pluripotent stem cells (iPSs) that havebeen programmed to assume RGC-phenotypes,(ii) allogeneic transplantation of RGCs fromhealthy eyes into host eyes, and (iii) possiblereprogramming of endogenousMüller glia intoRGCs (40). iPS cells with RGC-like characteristicshave been created in vitro (41) but not yet usedto rebuild functional eye-to-brain circuitry.Allogeneic transplantation of RGCs led to sub-

stantial integration of RGCs into existing ret-inal circuitry in rats (42). The transplanted RGCs

Laha et al., Science 356, 1031–1034 (2017) 9 June 2017 3 of 4

Transplanteddonor RGCs

Intrinsic signalsdrive initial neuriteand axonal outgrowth

Complete integrationinto retina and axon grows into optic nerve

Site of opticnerve damage

Allogeneic transplantationRGCs from healthy eyes into host eyesmay represent a viable strategy for curing irreversible forms of blindness

Fig. 3. Transplantation of RGCs to restore vision. (Left and top) Injected donor RGCs (red) differentiate and integrate into the retina after nervedamage, whereas endogenous RGCs (blue) degenerate. (Bottom right) A subset of the transplanted RGCs extend axons (red cables) down the opticnerve and ultimately reach the brain (41).

“What strategies supportRGC axon regeneration afterdamage? Can regeneratingRGC axons form functionalsynapses with their targetsin the brain?”

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adopted on-type or off-type or on-off-type photicresponses to light signals and extended axon pro-jections from the eye and to central visual targetsin the brain (Fig. 3) (42). Thus, the isolation ofRGCsfrom the retinas of recently deceased humans fortransplantation into recipient humans may ac-tually represent a clinically viable strategy forcuring otherwise irreversible forms of blindness.

Synthetic materials for replacinglight-driven electrical responses

When blindness results from disabled retinallight sensing, two approaches are likely to provehelpful: (i) prosthetic devices that directly stim-ulate the RGCs or (ii) gene therapy to activatequiescent remaining photoreceptors. Flexiblemicroarrays could be implanted into the hu-man eye to convert light to electrical signals andthen passed to RGCs (Fig. 4, A and B). The effici-ency of some of the modern implantable electrodearrays is comparable with light stimulation interms of generation of action potentials in theinner retina of animal models (43). The preci-sion with which these devices can stimulate thevisual pathways is impressive; some are startingto move them from the laboratory to the clinic.Introduction of light-sensitive ion-gated chan-

nels such as channelopsins to restore light sen-sitivity to sick photoreceptors (Fig. 4C) is beingvalidated in mouse models of retinitis pigmen-tosa and in ex vivo human retinas. This approachhas been shown to be capable of driving RGCfiring in response to light and can activate visualcircuits sufficiently well to drive visually guidedbehaviors in mice (44). Work in humans andnonhuman primates also suggest that such ap-proaches can lead to recovery of the ability todetect motion, read words, and recognize high-contrast objects (45, 46). Although diseases thatmainly affect the photoreceptorsmay leave RGCsintact, they may also indirectly alter RGC wiring(47). Therefore, therapeutic restoration of lightsensitivity to degenerated photoreceptors mayalso require steps to enhance RGC regenera-tion and central plasticity in order to restore ac-curate vision.

Paths forward

The potential to stave off and reverse certainforms of blindness is starting to emerge as a re-alistic goal for the next 5 to 10 years, and perhapseven sooner. The phase in which replacement ofdamaged eye-to-brain circuits has proven pos-sible has arrived, albeit in animal models. Thethree categories of approaches used to producethese effects—gene therapy for intrinsic growth-enhancing pathways, increasing RGC electricalactivity, and cell transplantation—in theory areall clinically feasible. The goal now is to deter-mine which specific molecular pathways are safeto trigger in humans and how to combine thosewith protocols that support RGC survival andregrowth. Research will determine whether thesemethods enhance visual function in humans, andwhether that function derives from RGC axonregeneration, from central plasticity or both (48).Meanwhile, prosthetic implants or gene therapy

with light-activated channels are both now readyfor testing in humans. It seems likely that a combi-nation of therapies may be needed to get full re-covery of visual function. Regardless, the idea ofregenerating eye-to-brain connections in humansis becoming an exciting and realistic possibility.

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ACKNOWLEDGMENTS

Work in the laboratory of these authors was supported by theNational Eye Institute, the Glaucoma Research Foundation, theMcKnight Foundation, the Pew Charitable Trusts, and the E. MatildaZiegler Foundation for the Blind.

10.1126/science.aal5060

Laha et al., Science 356, 1031–1034 (2017) 9 June 2017 4 of 4

Intact horizontal cells

Intact bipolar cells

Intact amacrine cells

Intact RGCs

580 nm light Light response

AAV-introduced halorhodopsin

A

B

C

Degenerated photoreceptorsexpressing halorhodopsin

Light stimulation

Pulse generator

Electrical signal

Spiking response

Fig. 4. Retinal prostheses and virallyintroduced light-sensitive ion channels canpotentially restore sight. (A) Electrodearrays can be surgical implanted in the retina.(B) Incoming light is converted into electricalsignals by electrodes, which generate spikingin RGCs, restoring eye-to-brain communicationand, potentially, sight. (C) Adeno-associatedviruses (AAVs) can be used to deliver light-sensitive ion channels (halorhodopsin) todegenerated photoreceptors, allowing lightstimulation at the appropriate wavelength togenerate spiking in the RGCs.G

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(6342), 1031-1034. [doi: 10.1126/science.aal5060]356Science 2017) Bireswar Laha, Ben K. Stafford and Andrew D. Huberman (June 8,Regenerating optic pathways from the eye to the brain

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