Scientists at the UCSF-affiliated Gladstone
Institutes have determined how specific circuitry in the brain controls not
only body movement, but also motivation and learning, providing new insight
into neurodegenerative disorders such as Parkinson’s disease — and psychiatric
disorders such as addiction and depression.
Previously,
researchers in the laboratory of Gladstone Investigator Anatol Kreitzer, PhD,
discovered how an imbalance in the activity of a specific category of brain
cells is linked to Parkinson’s.
Now, in
a paper published online today in Nature Neuroscience, Kreitzer, who is also an
assistant professor of physiology at UCSF, and his team used animal models to
demonstrate that this imbalance may also contribute to psychiatric disorders.
These findings also help explain the wide range of Parkinson’s symptoms — and
mark an important step in finding new treatments for those who suffer from
addiction or depression.
“The
physical symptoms that affect people with Parkinson’s — including tremors and
rigidity of movement — are caused by an imbalance between two types of medium
spiny neurons in the brain,” said Kreitzer, whose lab studies how Parkinson’s
disease affects brain functions. “In this paper we showed that psychiatric disorders — specifically
addiction and depression —might be caused by this same neural imbalance.”
Normally,
two types of medium spiny neurons, or MSNs, coordinate body movements. One
type, called direct pathway MSNs (dMSNs), acts like a gas pedal. The other
type, known as indirect pathway MSNs (iMSNs), acts as a brake. And while
researchers have long known about the link between a chemical in the brain called dopamine and Parkinson’s,
Gladstone researchers recently clarified that dopamine maintains the balance
between these two MSN types.
But
abnormal dopamine levels are implicated not only in Parkinson’s, but also in
addiction and depression. Kreitzer and his team hypothesized that the same
circuitry that controlled movement might also control the process of learning
to repeat pleasurable experiences and avoid unpleasant ones—and that an
imbalance in this process could lead to addictive or depressive behaviors.
Kreitzer
and his team genetically modified two sets of mice so that they could control
which specific type of MSN was activated. They placed mice one at a time in a
box with two triggers — one that delivered a laser pulse to stimulate the
neurons and one that did nothing. They then monitored which trigger each mouse
preferred.
“The
mice that had only dMSNs activated gravitated toward the laser trigger, pushing
it again and again to get the stimulation — reminiscent of addictive behavior,”
said Alexxai Kravitz, PhD, Gladstone postdoctoral fellow and a lead author of
the paper. “But the mice that had only iMSNs activated did the opposite. Unlike
their dMSN counterparts, the iMSN mice avoided the laser stimulation, which suggests
that they found it unpleasant.”
These
findings reveal a precise relationship between the two MSN types and how
behaviors are learned. They also show how an MSN imbalance can throw normal
learning processes out of whack, potentially leading to addictive or depressive
behavior.
“People
with Parkinson’s disease often show signs of depression before the onset of
significant movement problems, so it’s likely that the neural imbalance in
Parkinson’s is also responsible for some behavioral changes associated with the
disease,” said Kreitzer, who is also an assistant professor of physiology at
UCSF.. “Future research could discover how MSNs are activated in those
suffering from addiction or depression—and whether tweaking them could reduce
their symptoms and improve their quality of life.
Graduate
student Lynne Tye was also a lead author on this paper. Funding came from a
variety of sources, including the W.M. Keck Foundation, the Pew Biomedical
Scholars Program, the McKnight Foundation and the National Institutes of
Health.
Gladstone
is an independent and nonprofit biomedical-research organization dedicated to
accelerating the pace of scientific discovery and innovation to prevent, treat
and cure cardiovascular, viral and neurological diseases.
UCSF is
a leading university dedicated to promoting health worldwide through advanced
biomedical research, graduate-level education in the life sciences and health
professions, and excellence in patient care.
No comments:
Post a Comment