Regenerating optic pathways from the eye to the brain

Laha, Bireswar; Stafford, Ben K.; Huberman, Andrew D.

doi:10.1126/science.aal5060

Cited by 128 publications

(102 citation statements)

References 48 publications

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“…This resilience makes sense in light of the adaptive nature of sensory-driven adaptive reflexes such as the PLR and optokinetic reflex (OKR). Developmental constraints such as those described here are critical for models of regeneration, which is essentially an attempt to recapitulate developmental wiring, albeit to varying degrees depending on the lesion size and location (Laha et al, 2017). The findings presented here are consistent with the re-establishment of retino-OPN and retino-AOS connectivity observed in RGCs stimulated to regenerate by combined mTOR enhancement and neural activity (Lim et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly

et al. 2017

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The use of sensory information to drive specific behaviors relies on circuits spanning long distances that wire up through a range of axon-target recognition events. Mechanisms assembling poly-synaptic circuits and the extent to which parallel pathways can "cross-wire" to compensate for loss of one another remain unclear and are crucial to our understanding of brain development and models of regeneration. In the visual system, specific retinal ganglion cells (RGCs) project to designated midbrain targets connected to downstream circuits driving visuomotor reflexes. Here, we deleted RGCs connecting to pupillary light reflex (PLR) midbrain targets and discovered that axon-target matching is tightly regulated. RGC axons of the eye-reflex pathway avoided vacated PLR targets. Moreover, downstream PLR circuitry is maintained; hindbrain and peripheral components retained their proper connectivity and function. These findings point to a model in which poly-synaptic circuit development reflects independent, highly stringent wiring of each parallel pathway and downstream station.

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Section: Discussionmentioning

confidence: 99%

Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly

et al. 2017

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“…In mammals, RGCs do not regenerate once they are lost; this is contrary to other classes of animals, such as fish and amphibians, where retina and optic nerve can regenerate naturally. A number of animal studies have shown that under the right circumstances, mammalian RGCs are able to regenerate their axons and connect to the proper targets within the brain, resulting in some functional recovery of eye sight . The replacement of lost RGCs and the regeneration of their axons are high priorities in glaucoma research, and our dog patients may also benefit from these efforts in the future.…”

Section: Novel Treatment Strategies For the Futurementioning

confidence: 99%

“…A number of animal studies have shown that under the right circumstances, mammalian RGCs are able to regenerate their axons and connect to the proper targets within the brain, resulting in some functional recovery of eye sight. 139,140 The replacement of lost RGCs and the regeneration of their axons are high priorities in glaucoma research, and our dog patients may also benefit from these efforts in the future. The National Eye Institute (NEI) within the National Institutes of Health (NIH) predicts that these goals are achievable within 10-15 years and has made them high priorities for research funding.…”

Section: Neuroregenerationmentioning

confidence: 99%

The future of canine glaucoma therapy

Komàromy

Bras²,

Esson

et al. 2019

Veterinary Ophthalmology

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Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO‐VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP‐lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.

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“…Vision loss in these patients is irreversible since humans and all mammals lack the ability to generate RGCs in adulthood (Jorstad et al, 2017). There is great interest in developing regenerative therapies to restore lost vision in these patients (Benowitz et al, 2017;Calkins et al, 2017;Crair and Mason, 2016;Laha et al, 2017;Marchetti et al, 2010;Roska and Sahel, 2018;Stern et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Regeneration of Functional Retinal Ganglion Cells by Neuronal Identity Reprogramming

Liu

Wei

Zhang

et al. 2020

Preprint

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Degeneration of retinal ganglion cells (RGCs) and their axons underlies vision loss in glaucoma and various optic neuropathies. There are currently no treatments available to restore lost vision in patients affected by these diseases. Regenerating RGCs and reconnecting the retina to the brain represent an ideal therapeutic strategy; however, mammals do not have a reservoir of retinal stem/progenitor cells poised to produce new neurons in adulthood. Here, we regenerated RGCs in adult mice by direct lineage reprogramming of retinal interneurons. We successfully converted amacrine and displaced amacrine interneurons into RGCs, and observed that regenerated RGCs projected axons into brain retinorecipient areas. They convey visual information to the brain in response to visual stimulation, and are able to transmit electrical signals to postsynaptic neurons, in both normal animals and in a diseased model. The generation of functional RGCs in adult mammals points to a therapeutic strategy for vision restoration in patients.

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Regenerating optic pathways from the eye to the brain

Cited by 128 publications

References 48 publications

Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly

Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly

The future of canine glaucoma therapy

Regeneration of Functional Retinal Ganglion Cells by Neuronal Identity Reprogramming

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