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Untangling the tangled webs inside our brains: the different colors represent pathways involving different cells that instruct diverse behaviors. Using optogenetics and tissue clearing via PACT, Caltech scientists could extract specific pathways for locomotion and reward.
Credit: Ken Chan and Viviana Gradinaru Group at Caltech
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Mapping
Neurons to Improve the Treatment of Parkinson's
Because
billions of neurons are packed into our brain, the neuronal circuits that are
responsible for controlling our behaviors are by necessity highly intermingled.
This tangled web makes it complicated for scientists to determine exactly which
circuits do what. Now, using two laboratory techniques pioneered in part at
Caltech, Caltech researchers have mapped out the pathways of a set of neurons
responsible for the kinds of motor impairments—such as difficulty walking—found
in patients with Parkinson's disease.
The
work—from the laboratory of Viviana
Gradinaru (BS '05), assistant professor of biology and biological
engineering—was published on April 20 in the journal Neuron.
In
patients with Parkinson's disease, gait disorders and difficulty with balance
are often caused by the degeneration of a specific type of neuron—called
cholinergic neurons—in a region of the brainstem called the pedunculopontine
nucleus (PPN). Damage to this same population of neurons in the PPN is also
linked to reward-based behaviors and disorders, such as addiction.
Previously,
researchers had not been able to untangle the neural circuitry originating in
the PPN to understand how both addictions and Parkinson's motor impairments are
modulated within the same population of cells. Furthermore, this uncertainty
created a barrier to treating those motor symptoms. After all, deep brain
stimulation—in which a device is inserted into the brain to deliver electrical
pulses to a targeted region—can be used to correct walking and balance
difficulties in these patients, but without knowing exactly which part of the
PPN to target, the procedure can lead to mixed results.
"The
circuits responsible for controlling our behaviors are not nicely lined up,
where this side does locomotion and this side does reward," Gradinaru
says, and this disordered arrangement arises from the way neurons are
structured. Much as a tree extends into the ground with long roots, neurons are
made up of a cell body and a long string-like axon that can diverge and project
elsewhere into different areas of the brain. Because of this shape, the
researchers realized they could follow the neuron's "roots" to an
area of the brain less crowded than the PPN. This would allow them to more
easily look at the two very different behaviors and how they are implemented.
Cheng
Xiao, a senior research scientist at Caltech and first author on the study,
began by mapping the projections of the cholinergic neurons in the PPN of a rat
using a technique developed by
the Gradinaru lab called Passive CLARITY Technique, or PACT. In this
technique, a solution of chemicals is applied to the brain; the chemicals
dissolve the lipids in the tissue and render that region of the brain optically
transparent—see-through, in other words—and able to take up fluorescent markers
that can label different types of neurons. The researchers could then follow
the path of the PPN neurons of interest, marked by a fluorescent protein, by
simply looking through the rest of the
brain.
Using
this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons
as they extended into two regions of the midbrain: the ventral substantia
nigra, a landmark area for Parkinson's disease that had been previously
associated with locomotion; and the ventral tegmental area, a region of the
brain that had been previously associated with reward.
Next,
the researchers used an electrical recording technique to keep track of the
signals sent by PPN neurons—confirming that these neurons do, in fact,
communicate with their associated downstream structures in the midbrain. Then,
the scientists went on to determine how this specific population of neurons
affects behavior. To do this, they used a technique that Gradinaru helped
develop called optogenetics,
which allows researchers to manipulate neural activities—in this case, by
either exciting or inhibiting the PPN neural projections in the midbrain—using
different colors of light.
Using
the optogenetic approach in rats, the researchers found that exciting the
neuronal projections in the ventral substantia nigra would stimulate the animal
to walk around its environment; by contrast, they could stop the animal's
movement by inhibiting these same projections. Furthermore, they found that
they could stimulate reward-seeking behavior by exciting the neuronal
projections in the ventral tegmental area, but could cause aversive behavior by
inhibiting these projections.
"Our
results show that the cholinergic neurons from the PPN indeed have a role in
controlling both behaviors," Gradinaru says. "Although the neurons
are very densely packed and intermingled, these pathways are, to some extent,
dedicated to very specialized behaviors." Determining which pathways are
associated with which behaviors might also improve future treatments, she adds.
"In
the past it's been difficult to target treatment to the PPN because the
specific neurons associated with different behaviors are intermingled at the
source—the PPN. Our results show that you could target the axonal projections
in the substantia nigra for movement disorders and projections in the ventral
tegmental area for reward disorders, as addiction is," Gradinaru says. In
addition, she notes, these projections in the midbrain are much easier to
access surgically than their source in the PPN.
Although
this new information could inform clinical treatments for Parkinson's disease,
the PPN is only one region of the brain and there are many more important
examples of connectivity that need to be explored, Gradinaru says. "These
results highlight the need for brain-wide functional and anatomical maps of
these long-range neuronal projections; we've shown that tissue clearing and
optogenetics are enabling technologies in the creation of these maps."
These
results are published in a paper titled, "Cholinergic
mesopontine signals govern locomotion and reward through dissociable midbrain
pathways." In addition to Gradinaru and Xiao, other Caltech
coauthors include Jounhong Ryan Cho, Chunyi Zhou, Jennifer Treweek, Ken Chan,
Sheri McKinney, and Bin Yang. The work was supported by the National Institutes
of Health, the Heritage Medical Research Institute, the Pew Charitable Trust,
the Michael J. Fox Foundation, and the Sloan Foundation; the Beckman Institute
supports the Resource Center on CLARITY, Optogenetics, and
Vector Engineering (CLOVER) for
technology development and broad dissemination.
Written by Jessica
Stoller-Conrad
Contact:
Deborah Williams-Hedges
(626) 395-3227
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- See more at:
http://www.caltech.edu/news/mapping-neurons-improve-treatment-parkinsons-50521#sthash.dONHtLWX.dpuf
http://www.caltech.edu/news/mapping-neurons-improve-treatment-parkinsons-50521
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