BRONX W www.BXTimes.com EEKLY January 27, 2019 12
St. Raymond students participate in RPI Engineering event
Brain’s cerebellum found to infl uence addictive/social behavior
In a study published online
in the journal Science, researchers
at Albert Einstein College of
Medicine, part of Montefi ore,
prove for the fi rst time that
the brain’s cerebellum—long
thought to be mainly involved
in coordinating movement—
helps control the brain’s reward
circuitry. The surprising fi nding
indicates that the cerebellum
plays a major role in reward
processing and social behaviors
and could potentially lead to
new strategies for treating addiction.
Previous studies had hinted
that the talents of the cerebellum—
a fi st-sized structure
located just above the brainstem—
were under-appreciated.
For example, several functional
MRI studies (which measure
blood-fl ow changes that occur
with brain activity) assessed
the brain activity of people recovering
from addiction who
were shown images associated
with their addiction, such as
a syringe. Unexpectedly, the
cerebella of these individuals
glowed on MRI scans, indicating
heightened activity; in addition,
the intensity of the glow correlated
with a person’s risk of relapse.
This and other evidence
suggested that the cerebellum
is somehow involved in triggering
release of the feel-good
neurotransmitter dopamine in
brain areas that receive rewarding
stimuli.
“The notion that the cerebellum
did much beyond controlling
movement was met with a
lot of skepticism—and no one
had any real clues as to how the
cerebellum might affect dopamine
release,” said study leader
Kamran Khodakhah, Ph.D., professor
and chair of the Dominick
P. Purpura Department of Neuroscience
and the Florence and
Irving Rubinstein Chair in Neuroscience.
Ilaria Carta, a Ph.D.
student at Einstein, and Christopher
Chen, Ph.D., are co-fi rst
authors on the study.
Dr. Khodakhah, who is also
professor of psychiatry and behavioral
sciences and professor
in the Saul R. Korey Department
of Neurology, suspected that the
cerebellum directly connected
with and activated the ventral
tegmental area (VTA), a nearby
structure known to play a role in
addiction. (VTA neurons synthesize
and release dopamine into
the mesolimbic pathway, which
mediates pleasure and reward.)
In studies designed to test this
hypothesis, his lab showed that
stimulating cerebellar neurons
activates the VTA and leads to
“addictive” behaviors in mice.
Opting for Optogenetics
To conduct these studies, Dr.
Khodakhah used optogenetics,
which involves inserting genes
that produce light-sensitive proteins
into select neurons. The
researchers are then able to selectively
activate or inactivate
the treated neurons by exposing
them to light.
In an initial experiment, Dr.
Khodakhah’s team inserted the
genes into cerebellar neurons,
some of which connected with
the VTA via long fi bers called
axons. When the cerebellar axons
extending into the VTA
were selectively stimulated with
light, about one third of the VTA
neurons increased their fi ring.
Since only the cerebellar axons
contained the light-sensitive
proteins and could be activated
by the light, this experiment
proved for the fi rst time that
cerebellar neurons form working
synapses (connections) with
VTA neurons.
Triggering the Reward
Center
Do those connections have
any infl uence on behavior? To
answer that question, Dr. Khodakhah
conducted a so-called
open-fi eld chamber test, in which
mice were free to explore any corner
of a square enclosure. Each
time a mouse reached a particular
corner (randomly chosen for
each mouse), cerebellar neurons
linked to the VTA were optogenetically
stimulated. If the mice
found this stimulation pleasurable,
they’d be expected to preferentially
return to this corner
(to get another rewarding fl ash
of light) instead of to the other
corners—and they did, much
more often than occurred with
control animals.
Could stimulating cerebellar
projections to the VTA trigger
“addiction” in mice? To fi nd out,
Dr. Khodakhah and colleagues
put mice in a chamber that was
half dark and half brightly lit.
Since mice prefer dark areas—
the better to avoid becoming
a predator’s next meal—they
spent more time exploring the
dark part of the chamber. The
researchers then repeated the
experiment—except this time,
every other day for six days,
mice were confi ned to the bright
side for 30 minutes while cerebellar
axons with connections
to the VTA were optogenetically
stimulated. After that initial
conditioning period, the mice
were allowed to freely explore
the entire chamber.
“Even though mice normally
shun bright areas, now they
preferentially ran toward the
light, because that’s where they
remembered getting a reward,”
said Dr. Khodakhah. “This suggests
that the cerebellum plays a
role in addictive behaviors.” He
notes that the results were “very
similar” to fi ndings in other
studies in which mice confi ned
to the bright part of chambers
received addictive drugs such
as cocaine instead of cerebellar
stimulation.
Cerebellum abnormalities
have been implicated in autism
spectrum disorder (ASD),
although how the cerebellum
contributes to ASD isn’t clear.
Because the VTA is required
for social behavior, Dr Khodakhah
and colleagues tested
whether the cerebellum-VTA
pathway may be involved. They
placed mice in a three-chambered
box in which they were
free to travel to an inanimate
object, another mouse or an
empty chamber. The activity of
cerebellar axons within their
VTA was monitored.
The mice being studied
typically spent most of their
time socializing with another
mouse—and when they did,
cerebellar axons in their VTA
were most active, consistent
with the idea that the cerebellum
relays information relevant
to social behavior to the
VTA. Intriguingly, when the
researchers optogenetically
silenced cerebellar axons projecting
into the VTA, the mice
no longer preferred interacting
with other mice. This fi nding
suggests that social behavior
requires a functioning cerebellum
VTA pathway and that
interference with this pathway
may be a glitch through which
cerebellar dysfunction contributes
to ASD.
Next Steps
In future studies, Dr. Khodakhah
will test whether the
cerebellum-VTA pathway can
be manipulated, using drugs or
optogenetics, to treat addiction
and prevent relapse after treatment.
He will also investigate
whether cerebellar neurons affect
the prefrontal cortex and
the nucleus accumbens, two
other brain regions that are
targeted by the VTA and are intimately
associated with addictive
behavior and mental disorders.
“Cerebellar abnormalities
are also linked to a number of
other mental disorders such as
schizophrenia,” said Dr. Khodakhah,
“so we want to fi nd out
whether this pathway also plays
a role in those disorders.”
The study is titled, “Cerebellar
Modulation of the Reward
Circuitry and Social Behavior.”
The other contributors
are Amanda Schott, formerly of
Einstein and now a Ph.D. student
at University of Pennsylvania,
and Schnaude Dorizan,
formerly of Einstein, and now a
Ph.D. student at Northwestern
Medical School. Dr. Chen is a
post-doctoral fellow at Harvard
Medical School. The authors report
no confl icts of interest.
This work was supported
by grants from the National
Institutes of Health (NS050808,
DA044761, MH115604, and
RR027888).
Dr. Khodakhah’s lab inserted
genes for an opsin called
channelrhodopsin (which activates
neurons) into particular
cerebellar neurons of mice.
Since only neurons containing
opsins could have been activated
by the light, this experiment
proved that cerebellar
neurons form working synapses
(connections) with VTA
neurons.
For the third year, Rensselaer
Polytechnic Institute Engineering
Ambassadors have joined
with St. Raymond High School
for Boys and St. Raymond’s Girls
Academy to share their message,
‘Find your passion and Engineer
It.’ To aid in the cost of the RPI
visit, St. Raymond was able to
secure a grant of $1,500 from the
New Yankee Stadium Community
Benefi t Fund.
The RPI Engineering Ambassadors
are student engineers
devoted to inspiring younger students
to explore STEM fi elds by
showing them the newest technological
breakthroughs in their
fi elds and the obstacles yet to be
overcome. The RPI Engineering
Ambassadors spoke about applications
of engineering including
chemical engineering processing,
nanotechnology use in drug
delivery, biomedical applications
of biosensors, civil engineering
focusing on the design of concrete,
aerospace engineering
focusing on the importance of
space exploration, electrical engineering
focusing on energy
sources with the smart grid,
mechanical engineering focusing
on the laws of physics, and
manufacturing polymers, which
reviews the chemical structure,
properties, and applications of
polymers. Each presentation began
with a 10-minute engaging
overview and was followed by
complimentary hands-on activities.
RPI Engineering Ambassadors
begun the partnership with
St. Raymond in 2016 when Vladimir
Ramos-Vasquez, St. Raymond
alumnus and 2018 graduate
of Rensselaer, initiated and
helped plan the fi rst school visit.
The partnership also included an
invitation for the students to join
a fully scholarship 1-week enrichment
program in the summer
2018, ‘Delve into Engineering.’
Participants in the RPI Engineering event.
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