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A rat like the participants in an experiment to measure
risk-taking. The probe can be used to measure or cause neural signals. Credit
Viviana Gradinaru, Murtaza Mogri, John Carnett and Karl Deisseroth
When
people make risky decisions, like doubling down in blackjack or investing in
volatile stocks, what happens in the brain?
Scientists
have long tried to understand what makes some people risk-averse and others
risk-taking. Answers could have implications for how to treat, curb or prevent
destructively risky behavior, like pathological gambling or drug addiction.
Now, a
study by Dr. Karl Deisseroth, a prominent Stanford neuroscientist and
psychiatrist, and his colleagues gives some clues. The study, published
Wednesday in the journal Nature, reports that a specific type of neuron or
nerve cell, in a certain brain region helps galvanize whether or not a risky
choice is made.
The
study was conducted in rats, but experts said it built on research suggesting
the findings could be similar in humans. If so, they said, it could inform
approaches to addiction, which involves some of the same neurons and brain
areas, as well as treatments for Parkinson’s disease because one class of
Parkinson’s medications turns some patients into problem gamblers.
In a
series of experiments led by Kelly Zalocusky, a doctoral student, researchers
found that a risk-averse rat made decisions based on whether its previous
choice involved a loss (in this case, of food). Rats whose previous decision
netted them less food were prompted to behave conservatively next time by
signals from certain receptors in a brain region called the nucleus accumbens,
the scientists discovered. These receptors, which are proteins attached to
neurons, are part of the dopamine system, a neurochemical important to emotion,
movement and thinking.
In
risk-taking rats, however, those receptors sent a much fainter signal, so the
rats kept making high-stakes choices even if they lost out. But by employing
optogenetics, a technique that uses light to manipulate neurons, the scientists
stimulated brain cells with those receptors, heightening the “loss” signal and
turning risky rats into safer rats.
“We know
from other work that this is all relevant to human addiction and gambling,”
said Trevor Robbins, the chairman of the psychology department at the
University of Cambridge, who was not involved in the new research. “This study
has zeroed in on the area precisely where this occurs. They’ve tried to show
that not having this signal biases you toward risky judgments in the future,
and they’ve done a lovely job on that.”
Step by
step, the researchers built evidence that neurons with a dopamine receptor
called D2 in the nucleus accumbens, a region integral to brain reward
circuitry, play a critical role in risky-or-not decision-making. Strikingly,
they found they could alter the message those neurons send.
Rats
were given a choice of two food levers. One released a consistent amount of
sucrose each time; the other often delivered a tiny amount, but in 25 percent
of presses, it unleashed a delicious sucrose flood. Over time, both levers gave
the same quantity, so rats did not go hungry and their choices came down to
whether or not they were gamblers.
Risky
rats gambled on the iffier lever more than half the time. Risk-averse rats were
strongly influenced by their last choice; if they picked the risky lever and
received a trickle, they picked the consistent lever next time.
“Some
are very sensitive to losing, and if they take a risky option and lose, they’re
very likely to not go back to it again,” said Paul Phillips, a professor of
psychiatry and pharmacology at the University of Washington and a co-author of
a commentary about the study. “That’s very common in human behavior. An analogy
is a slot machine in Vegas.”
To
identify the brain location involved in these decisions, the researchers gave
rats a drug used to treat Parkinson’s disease, pramipexole, marketed as
Mirapex, which acts on D2 receptors and seems to dampen some patients’ ability
to restrain risk-seeking behavior. Risk-averse rats receiving pramipexole
turned into risk-taking rats, but the drug had much greater effects when piped
directly into the nucleus accumbens than when it was administered to another
brain area researchers had thought might be involved.
The
scientists used a technique Dr. Deisseroth helped invent fiber photometry,
which uses light particles to track activity of neurons tagged with certain
proteins. They found that neurons in the nucleus accumbens with D2 receptors
transmitted a signal when rats were making their decisions. That signal was
much larger if the choice the rat had made had just had been a loser, yielding
just a dribble of sucrose. The signal only spiked in non-risky rats, however;
it was negligible in rats that always gambled for the sucrose windfall.
So, what
to do with those risky rats? Using optogenetics, which Dr. Deisseroth also
helped develop, the team stimulated nucleus accumbens neurons with D2 receptors
at the very moment of the fateful food-lever decision. That caused the
receptors to send strong loss signals to the rats, apparently making them weigh
recent losses more heavily, and prompting them to play it safe with their next
lever choice.
“It
turns out you can explain a large part of whether rats were risky or not by
this particular signal at this particular time,” Dr. Deisseroth said. “We saw
it happen, and then we were able to provide that signal, and then see that we
could drive the behavior causally.”
Human
brains are more complex, of course, and “are not only affected by immediate
recent losses,” Dr. Deisseroth said, but “your appetite for risk in many
circumstances might be at least possibly reducible to what a particular set of
cells in a particular brain area is doing.”
Dr.
Robbins said that might yield insights for drug addiction, since it “clearly
involves the dopamine system and these areas of the brain,” and in addicts, as
in risky rats, the same receptors produce weaker signals.
For
Parkinson’s patients, if versions of drugs like pramipexole could be developed
to skip the nucleus accumbens and focus on brain areas responsible for
movement, “it would be a much more effective therapy,” Dr. Phillips said. “It’s
because it gets to the nucleus accumbens that it has this gambling effect.”
He
added, “Now, not only do we know the part of the brain, but we know the
particular cells in the brain, and we know that if you manipulate them you can
change the behavior.”
Dr. Deisseroth
said optogenetic manipulation is too invasive to be done in humans, but
findings from optogenetic studies in animals are now being used to identify
brain areas to target with noninvasive brain stimulation for problems like
cocaine addiction.
Finding
the roots of risk in the brain also “helps us understand what might be making
people different in terms of their risk appetites,” he said. “It may help us
see them differently, maybe in a more tolerant way, to realize that there’s a
real biological basis for their behavior.”
Source:
nytimes.com
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