A study in mice funded by the National Institutes of
Health shows for the first time that high-contrast
visual stimulation can help damaged retinal neurons
regrow optic nerve fibers and re-wire visual system
partially restoring sight.
Regenerating mouse retinal ganglion cell axons
(magenta and green) extending from site of optic
nerve injury (left). Andrew D. Huberman
In combination with chemically induced neural
stimulation, axons grew further than in strategies
tried previously. Treated mice partially regained
visual function.
The study also demonstrates that adult regenerated
central nervous system (CNS) axons are capable of
navigating to correct targets in the brain. The
research was funded through the National Eye
Institute (NEI), a part of NIH.
“Reconnecting neurons in the visual system is one of
the biggest challenges to developing regenerative
therapies for blinding eye diseases like glaucoma,”
said NEI Director Paul A. Sieving, M.D., Ph.D. “This
research shows that mammals have a greater capacity
for central nervous system regeneration than
previously known.”
The optic nerve is the eye’s data cable, carrying
visual information from the light-sensing neurons of
the retina to the brain. Like a bundle of wires, it
consists of about a million axons that each extend
from an individual retinal ganglion cell.
A variety of optic neuropathies, such as glaucoma,
cause vision loss when they destroy or damage these
axons. In adults, retinal ganglion cell axons fail
to regrow on their own, which is why vision loss
from optic neuropathies is usually permanent.
The researchers induced optic nerve damage in mice
using forceps to crush the optic nerve of one eye
just behind the eyeball. The mice were then placed
in a chamber several hours a day for three weeks
where they viewed high-contrast images—essentially
changing patterns of black lines. The mice had
modest but significant axonal regrowth compared to
control mice that did not receive the high-contrast
visual stimulation.
Prior work by the scientists showed that increasing
activity of protein called mTOR promoted optic nerve
regeneration. And so they wondered if combining
visual stimulation with increased mTOR activity
might have a synergistic effect.
Two weeks prior to nerve crush, the scientists used
gene therapy to cause the retinal ganglion cells to
overexpress mTOR. Optic nerve crush was performed
and mice were exposed to high-contrast visual
stimulation daily.
After three weeks, the scientists saw more extensive
regeneration, with axons growing through the optic
nerve as far as the optic chiasm, a distance from
the eye of about 6 millimeters. Encouraged by these
results, the researchers again increased mTOR
activity but then forced mice to use the treated eye
during visual stimulation by suturing shut the good
eye. This combined approach of increasing mTOR
activity with intense visual stimulation promoted
regeneration down the full length of the optic nerve
and into various visual centers of the brain.
“We saw the most remarkable growth when we closed
the good eye, forcing the mice to look through the
injured eye,” said Andrew Huberman, Ph.D., associate
professor, Stanford University School of Medicine’s
department of neurobiology, and lead author of the
report, published online in Nature Neuroscience. In
three weeks, the axons grew as much as 12
millimeters, a rate about 500 times faster than
untreated CNS axons.
The regenerating axons also navigated to the correct
brain regions, a finding that Huberman said sheds
light on a pivotal question in regenerative
medicine: “If a nerve cell can regenerate, does it
wander or does it recapitulate its developmental
program and find its way back to the correct brain
areas?”
Using transgenic mouse lines designed to express
fluorescent proteins only in specific retinal
ganglion cell subtypes (about 30 exist), the
investigators traced where regenerating axons went.
“The two types of retinal ganglion cells that we
looked at — a-cells and melanopsin cells — seemed
fully capable of navigating back to correct
locations in the brain, plugging in and forming
synapses,” said Huberman. “And just as interesting,
they didn’t go to the wrong places.” Fluorescent
axons appeared in brain regions where a-cells and
melanopsin cells would be expected but were absent
in other regions.
Visual function was partially restored in animals
that received visual/mTOR combination therapy. The
investigators used four tests to assess four types
of visual perception: ability to track moving
objects, pupillary reflex, depth perception, and
ability to detect an overhead predator — a stimulus
that normally causes mice to freeze or flee for
cover.
Mice treated with combination therapy performed
significantly better than untreated mice in two of
the four tests.
“This study’s striking finding that activity
promotes nerve regrowth holds great promise for
therapies aimed at degenerative retinal diseases,”
noted Thomas Greenwell, NEI program director for
retinal neuroscience research. Greenwell said the
research has great relevance to the NEI Audacious
Goals Initiative (AGI), a sustained effort to
develop regenerative medicine for retinal diseases.
For future therapies that preserve optic nerve
axons, Huberman envisions the development of filters
for virtual reality video games, television
programs, or eyeglasses designed to deliver
regeneration-inducing visual stimulation.
A drawback of the optic nerve crush model is that it
does not mimic typical blinding diseases or
injuries. The investigators are therefore currently
examining the effect of intense visual stimulation
in a mouse glaucoma model. Going forward, they are
homing in on the specific qualities of visual
stimulation that drive retinal regeneration.
For more information
Lim JA, et al. Neural activity promotes
long-distance, target-specific regeneration of adult
retinal axons.
Nature Neuroscience. Published online June 11, 2016.
DOI 10.1038/nn.4340.
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