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
BRONX TIMES REPORTER, J 22 ANUARY 25-31, 2019 BTR
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 socalled
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 break-
throughs 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.