January 31, 2018, Columbia University
 |
| In mice, activating dopamine-releasing neurons for half a second is enough to initiate movement. |
From morning til night, we never stop executing
movements at the right time and speed. But patients suffering from Parkinson's
disease lose this natural control over their voluntary movements.
Parkinson's is caused by the death of the neurons that make a
neurotransmitter, dopamine, in a region of the brain called the substantia
nigra. Now a new study, published by scientists from the Champalimaud Centre
for the Unknown (Portugal) and Columbia University's Mortimer B. Zuckerman Mind
Brain Behavior Institute in the journal Nature,
represents an important step towards better understanding the precise normal
function of these neurons.
Experts have long worked to understand why the absence of these
so-called dopaminergic neurons (and therefore, the lack of dopamine) leads to
the motor dysfunctions that are the hallmarks Parkinson's, such as stiffness,
slow movements and tremors. The more widely accepted explanation has been that,
in order to move normally, our brain constantly needs a certain level of
dopamine - something that Parkinson's patients progressively lose.
However, as
psychiatrist and neuroscientist Joaquim Alves da Silva, first author of the new
study, explains, people with Parkinson's disease actually "do not have a
global motor problem." As incredible as it may seem, they can even ride a
bicycle—a rather complex motor task—if pushed at the right time.
The motor problems
that Parkinson's patients experience are more specific, and this was the
observation that motivated the new study. "The patients' problem is in the
difficulty to initiate movement and in the slowness of movement,"
adds Alves da Silva.
In fact, as these
authors now showed in mice not afflicted by Parkinson's disease, for a movement
to unfold correctly it only takes a "puff" of dopamine—or more
precisely, a peak of dopaminergic cell activity—right before the movements
starts. In other words, dopamine (or, in this case, the activity of the cells
that produce it) is just a "trigger" for voluntary movements.
"Our most
important result is that we showed, for the first time, that the change in
neural activity is necessary to promote movement," says Alves da Silva.
"And also for the first time, we showed that the dopamine peak that
precedes movement initiation does not only regulate initiation, but also
regulates movement vigor."
Previous results
already pointed in this direction. "Our laboratory and others had shown
that, in normal conditions, there is a transient increase in the activity of
dopamine-producing neurons, and that this increase seems to precede movement
initiation," says Alves da Silva. "But we still had to determine whether
that neural activity was mostly important to initiate movement or if it was
also important during movement execution," he adds.
The
scientists performed their experiments by using optogenetics, a technique that
allowed them to turn neurons on and off very quickly with laser light.
"In
this way, we were certain that we were only recording the activity of the
animals' dopaminergic cells" in the substantia nigra,
explains Alves da Silva.
The mice
were placed in an "arena" where they could roam freely. By using
motion sensors, the authors then measured whether the animals were moving or
not at any given moment. They recorded identified dopamine neurons and were
able to observe a transient peak of activity in many of these cells before the
movements.
In the next
phase, the scientists activated or inhibited the dopamine cells with a laser.
And they could then see that when the mice were not moving, "activating
the neurons for half a second was enough to promote movement—and with more
vigor—than without these neurons' activity," says Alves da Silva.
However, if
the neurons were activated when the mice were already moving, the animals
"just went on doing whatever they were doing" in terms of movement
and movement vigor, as measured by acceleration. Moreover, inhibiting the neurons' activity during
an ongoing movement did not have any effect on its normal execution.
"These
results show that the activity of dopamine neurons
can act as a gate to permit or not the initiation of movements," says Rui
Costa, DVM, PhD, associate director of Columbia's Zuckerman Institute who led
the study. "They explain why dopamine is so important in motivation, and
also why lack of dopamine in Parkinson's disease leads to the symptoms that it
does."
The authors
say the new study could pave the way for the development of treatments for
Parkinson's disease with fewer side-effects.
Currently,
Parkinson's is usually treated with the drug levodopa, which works by boosting
dopamine in the body and alleviating symptoms. "But levodopa elevates
dopamine all the time, not just when we want to move" says Costa, who is
also professor of neuroscience and neurology at Columbia University Irving
Medical Center. And indeed, the long-term use of levodopa often causes other
motor disorders—mainly, erratic and involuntary body movements known as
dyskinesia. "Our study suggests that strategies that would boost dopamine when there is a
desire to move would work better," adds Costa.
When
patients do not respond to or cannot take the drug, there is an alternative
treatment, called "deep brain stimulation" (DBS). For this, patients
are implanted with a high-frequency pacemaker that blocks the abnormal electric
signals generated in the brain areas that control movement and make it
difficult for the patients to initiate movement.
It is known
that DBS substantially improves parkinsonian symptoms—but it can also have
adverse effects. This study suggests that it may be better to stimulate the
brain only when patients want to initiate movement, promoting not only
initiation but also controlling the vigor of the movement. If this possibility
were to be confirmed, it could render DBS more physiological, more natural, so
decreasing unwanted side-effects.
The paper
is titled "Dopamine neuron activity before action initiation gates and
invigorates future movements." Additional contributors include Fatuel
Tecuapetla and Vitor Paixão.
More
information:
Dopamine neuron activity before action initiation gates and invigorates future
movements, Nature (2018). nature.com/articles/doi:10.1038/nature25457
Journal reference: Nature
Provided by: Columbia University
https://medicalxpress.com/news/2018-01-body-movements-puff-dopamine.html
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