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Neural activity promotes long-distance, target-specific regeneration of adult retinal axons

Nature Neuroscience volume 19, pages 1073–1084 (2016)Cite this article

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Abstract

Axons in the mammalian CNS fail to regenerate after injury. Here we show that if the activity of mouse retinal ganglion cells (RGCs) is increased by visual stimulation or using chemogenetics, their axons regenerate. We also show that if enhancement of neural activity is combined with elevation of the cell-growth-promoting pathway involving mammalian target of rapamycin (mTOR), RGC axons regenerate long distances and re-innervate the brain. Analysis of genetically labeled RGCs revealed that this regrowth can be target specific: RGC axons navigated back to their correct visual targets and avoided targets incorrect for their function. Moreover, these regenerated connections were successful in partially rescuing a subset of visual behaviors. Our findings indicate that combining neural activity with activation of mTOR can serve as powerful tool for enhancing axon regeneration, and they highlight the remarkable capacity of CNS neurons to re-establish accurate circuit connections in adulthood.

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Figure 1: Visual stimulation triggers regeneration of RGC axons.
Figure 2: Neural activity regulates regeneration of RGC axons.
Figure 3: Combining biased visual stimulation and enhancement of mTOR signaling with cRheb1 overexpression triggers long-distance regeneration of RGC axons.
Figure 4: Combining biased visual stimulation and enhancement of mTOR signaling with cRheb1 overexpression allows RGCs to regenerate their axons back to their targets.
Figure 5: Specificity of axon regeneration from distinct RGC types to their visual targets.
Figure 6: Removing one eye and enhancement of mTOR signaling with cRheb1 overexpression trigger RGC regeneration to correct visual targets in the brain.
Figure 7: Combined daily visual stimulation and enhancement of mTOR signaling with cRheb1 overexpression partially rescues visually guided behaviors.

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Acknowledgements

The authors would like to thank T. Seabrook, O. Dhande, R. El-Danaf and other members of the Huberman laboratory for comments on earlier versions of this manuscript. This work was supported by grants from the National Institutes of Health National Eye Institute R01, NIH/NEI R01EY026100 (ADH), The Pew Biomedical Foundation, The McKnight Foundation and The Glaucoma Research Foundation Catalyst for a Cure Initiative.

Author information

Authors and Affiliations

  1. Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.,

    Jung-Hwan A Lim & Brian V Lien

  2. Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, California, USA.,

    Benjamin K Stafford & Phong L Nguyen

  3. Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Chen Wang & Zhigang He

  4. Dairy and Veterinary Sciences Department, Animal, Utah State University, Logan, Utah, USA

    Katherine Zukor

  5. Department of Neurobiology, Stanford University School of Medicine, Stanford, California, USA

    Andrew D Huberman

  6. Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA

    Andrew D Huberman

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Contributions

J.-H.A.L. carried out all experiments, imaging, analysis of the data, and figure preparation. B.K.S. performed recordings from RGCs and the analysis of activity in response to chemical genetic manipulations. P.L.N. assisted with the visual stimulation experiments and tissue collection, and provided technical assistance. B.V.L. contributed to the visual stimulation experiments and tissue collection. C.W. prepared AAV-cRheb1 viruses. K.Z. provided technical assistance for optic nerve crush surgery and AAV-cRheb1. Z.H. provided AAV-cRheb1 virus. A.D.H. supervised the project and data analyses. J.-H.A.L., Z.H., B.K.S. and A.D.H. wrote the paper.

Corresponding author

Correspondence to Andrew D Huberman.

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Lim, JH., Stafford, B., Nguyen, P. et al. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci 19, 1073–1084 (2016). https://doi.org/10.1038/nn.4340

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