The overall goal of this research program is to understand how to regenerate mammalian central visual pathways. This proposal specifically focuses on the question of how to regenerate projections from output neurons of the eye, retinal ganglion cells (RGCs) to their targets in the brain (collectively referred to `retinofugal pathway')- a circuit absolutely essential vision. Significant progress has recently been made in identifying molecular programs capable of triggering some RGC axon regeneration. The next crucial milestones for the field are to discover ways to increase the number RGC axons that regenerate and the distance they regro. It is also crucially important to determine whether regenerating RGCs can find and reconnect to the correct targets, such visual capacities return. The three major aims of this proposal are to: 1) test the hypothesis that specific forms of visual stimulation can enhance the number and distance of RGC regenerating axons 2) test the hypothesis that combining visual stimulation with molecular triggers of RGC axon growth can cause RGC axons to regrow long distances back into the brain and 3) determine whether regenerating RGCs are capable of pathfinding back to and re-connecting to their appropriate targets, as well as avoiding targets incorrect for their function. Results from these experiments should lead to new understanding of how mammalian visual circuits can be replenished in response to injury and pave the way for the cultivation of tools applicable to humans suffering from vision loss.

Public Health Relevance

The long-term objective of our research is to understand how to regenerate functional retinofugal and other central visual pathways in response to diseases or injuries that degenerate them. Knowledge gained from the studies in this proposal will be particularly relevant to understanding and treatment of visual system diseases that impact retinal connections with central targets such as glaucoma and various optic neuropathies, and may have general relevance to restoration of other CNS circuits such as spinal cord, cortical and deep brain structures, such as those impacted in Alzheimer's dementia.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Greenwell, Thomas
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Stanford University
Schools of Medicine
United States
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Seabrook, Tania A; Burbridge, Timothy J; Crair, Michael C et al. (2017) Architecture, Function, and Assembly of the Mouse Visual System. Annu Rev Neurosci 40:499-538
Laha, Bireswar; Stafford, Ben K; Huberman, Andrew D (2017) Regenerating optic pathways from the eye to the brain. Science 356:1031-1034
Seabrook, Tania A; Dhande, Onkar S; Ishiko, Nao et al. (2017) Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly. Cell Rep 21:3049-3064
Lim, Jung-Hwan A; Stafford, Benjamin K; Nguyen, Phong L et al. (2016) Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci 19:1073-84