Brain's Reward Circuitry Revealed in Procrastinating Primates
Using a new molecular genetic technique, scientists have turned
procrastinating primates into workaholics by temporarily suppressing
a gene in a brain circuit involved in reward learning. Without the
gene, the monkeys lost their sense of balance between reward and
the work required to get it, say researchers at the NIH's National
Institute of Mental Health (NIMH).
"The gene makes a receptor for a key brain messenger chemical,
dopamine," explained Barry Richmond, M.D., NIMH Laboratory
of Neuropsychology. "The gene knockdown triggered a remarkable
transformation in the simian work ethic. Like many of us, monkeys
normally slack off initially in working toward a distant goal. They
work more efficiently make fewer errors as they get closer to
being rewarded. But without the dopamine receptor, they consistently
stayed on-task and made few errors, because they could no longer
learn to use visual cues to predict how their work was going to
get them a reward."
Richmond, Zheng Liu, Ph.D., Edward Ginns, M.D., and colleagues,
report on their findings in the August 17, 2004 Proceedings of the
National Academy of Sciences, published online the week of August
Richmond's team trained monkeys to release a lever when a spot
on a computer screen turned from red to green. The animals knew
they had performed the task correctly when the spot turned blue.
A visual cue a gray bar on the screen got brighter as they progressed
through a succession of trials required to get a juice treat. Though
never punished, the monkeys couldn't graduate to the next level
until they had successfully completed the current trial.
As in a previous study (http://www.nimh.nih.gov/Press/prrewardsignal.cfm)
using the same task, the monkeys made progressively fewer errors
with each trial as the reward approached, with the fewest occurring
during the rewarded trial. Previous studies had also traced the
monkeys' ability to associate the visual cues with the reward to
the rhinal cortex, which is rich in dopamine. There was also reason
to suspect that the dopamine D2 receptor in this area might be critical
for reward learning. To find out, the researchers needed a way to
temporarily knock it out of action.
Molecular geneticist Ginns, who recently moved from NIMH to the
University of Massachusetts, adapted an approach originally used
in mice. He fashioned an agent (DNA antisense <http://www.nhgri.nih.gov/glossary.cfm?key=antisense>
expression construct) that, when injected directly into the rhinal
cortex of four trained monkeys, spawned a kind of decoy molecule
which tricked cells there into turning-off D2 expression for several
weeks. This depleted the area of D2 receptors, impairing the monkeys'
reward learning. For a few months, the monkeys were unable to associate
the visual cues with the workload to learn how many trials
needed to be completed to get the reward.
"The monkeys became extreme workaholics, as evidenced by a
sustained low rate of errors in performing the experimental task,
irrespective of how distant the reward might be," said Richmond.
"This was conspicuously out-of-character for these animals.
Like people, they tend to procrastinate when they know they will
have to do more work before getting a reward."
To make sure that it was, indeed, the lack of D2 receptors that
was causing the observed effect, the researchers played a similar
recombinant decoy trick targeted at the gene that codes for receptors
for another neurotransmitter abundant in the rhinal cortex: NMDA
(N-methlD-aspartate). Three monkeys lacking the NMDA receptor in
the rhinal cortex showed no impairment in reward learning, confirming
that the D2 receptor is critical for learning that cues are related
to reward prediction. The researchers also confirmed that the DNA
treatments actually affected the targeted receptors by measuring
receptor binding following the intervention in two other monkeys'
"This new technique permits researchers to, in effect, measure
the effects of a long-term, yet reversible, lesion of a single molecular
mechanism," said Richmond. "This could lead to important
discoveries that impact public health. In this case, it's worth
noting that the ability to associate work with reward is disturbed
in mental disorders, including schizophrenia, mood disorders and
obsessive-compulsive disorder, so our finding of the pivotal role
played by this gene and circuit may be of clinical interest,"
"For example, people who are depressed often feel nothing
is worth the work. People with OCD work incessantly; even when they
get rewarded they feel they must repeat the task. In mania, people
will work feverishly for rewards that aren't worth the trouble to
most of us."
Also participating in the research were: Drs. Elisabeth Murray,
Richard Saunders, Sara Steenrod, Barbara Stubblefield, Deidra Montague,
NIMH is part of the National Institutes of Health (NIH), the
Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and