Optogenetic therapy for spinal cord injury
Category: Neuroscience
Posted on: November 18, 2008 12:18 PM, by Mo
Optogenetics is a recently developed technique based on microbial proteins
called channelrhodopsins (ChRs), which render neurons sensitive to light
when inserted into them, thus enabling researchers to manipulate the
activity of the cells using laser pulses.
Although still very new - the first ChR protein was isolated from a species
of green algae in 2002 - optogenetics has already proven to be extremely
powerful - it can be used to switch neurons on or off in an extremely
precise manner and so to control simple behaviours in small organisms such
as the nematode worm.
Earlier this year, ChR was used to restore vision to blind mice lacking the
light-sensitive photoreceptor cells in the retina. And now researchers from
Case Western Reserve University in Cleveland, Ohio have used the technique
to restore motor function in rats paralysed by spinal cord injuries.
Among the most common types of spinal cord injuries in humans are those
involving damage to the cervical area of the spine, which begins at the base
of the skull and extends down through the neck. The cervical spinal cord
gives rise to the nerves which control the head, neck, arms, upper body and
diaphragm, so serious damage to this area leads to complete paralysis, and
is often fatal, due to paralysis of the muscles required for breathing.
Jerry Silver and his colleagues used an animal model of cervical spinal
cord injury in their study. They sectioned one half of the cord at the upper
cervical level, leaving their rats paralysed down on side of the body, and
with breathing difficulties because of the half-paralysed diaphragm. During
the procedure, they also injected a modified Sindbis virus, containing the
genes encoding channelrhodopsin and green fluorescent protein, directly into
the ventral grey matter of the spinal cord, where the cell bodies of motor
neurons are located. Some of these motor neurons form the phrenic nerve,
which innervates the diaphragm and controls breathing
Four days later, the animals' spinal cords were exposed again. The motor
neurons were stimulated with blue light from a fibre optic cable, and the
electrical activity of the diaphragm recorded. Brief episodic bursts of
light were found to induce first erratic and then rhythmic activity, which
became synchronised with the respiratory activity recorded from the other
side of the diaphragm, aso that the rats could breathe normally. Remarkably,
a longer repeating patteren of light was found to induce recovery of
breathing which persisted for 24 hours.
Somehow, the spinal cord circuitry had adapted so that it could continue to
generate the rhythmic patterns of activity required for respiratory
movements long after the light stimulation had ceased. Analysis of the GFP
expression pattern in the spinal cord showed that an average of 650 neurons
in each experimental animal had been successfully infected with the virus
carrying the channelrhodopsin gene. It also revealed that both motor neurons
and interneurons had taken up the virus, and that some of the infected cells
had processes which extended across to the opposite side of the spinal cord.
The researchers suggest that swiching on the infected motor neurons with the
pulses of light had initiated a novel form of synaptic plasticity in the
"crossed phrenic pathway". This pathway contains the projections of motor
neurons which cross the midline and form connections with their mirror image
counterparts on the other side of the spinal cord. Normally, these synapses
are weak, so motor neuron activity on one side does not elicit activity on
the other., but the strengthening of these crossed pathways seems to have
been sufficient to generate rhythmic respiratory activity.
This and other research could one day lead to the development of optical
neuroprosthetic devices consisting of remote-controlled light sources
(perhaps light-emitting diodes) implanted into the body. Eventually though,
optogenetics-based treatments for various neurological diseases seems
plausible. The ability to use ChR proteins to both excite and inhibit
neurons would have advantages - activating spinal motor neurons or neurons
in the brain would be benficial in conditions such as amyotrophic lateral
sclerosis or stroke and Parkinson's Disease, respectively, while inhibiting
the activity of spinal neurons could prove to be an effective treatment for
chronic pain.
Such treatments would of course involve first infecting patients with a
genetically engineered virus, which poses major problems. In the meantime,
Silver and his colleagues are using the same method to try to restore
bladder function to the paralysed rats. They are also looking for ways to
prolong ChR expression in the spinal motor neurons, and planning similar
experiments in monkeys.
Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
rbrown@xxxxxxxxx
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