 |
November 18, 2005
Loss of Fear Factor Makes Timid Mouse Bold
Researchers have identified a fear factor - a protein the brain uses
to generate one of the most powerful emotions in humans and animals.
The molecule is essential for triggering both the innate fears that
animals are born with - such as the shadow of an approaching predator -
as well as fears that arise later in life due to individual
experiences. Eliminating the gene that encodes this factor makes a
fearful mouse courageous. The finding, the researchers say, suggests
new approaches for drugs designed to treat conditions such as phobias,
post-traumatic stress disorder, and anxiety.
Working in mice, the scientists, led by Howard Hughes Medical
Institute investigator Eric R. Kandel at Columbia University, found
that the protein stathmin is critical for both innate and learned fear.
Mice without stathmin boldly explore environments where normal mice
would be hesitant, and, unlike their normal counterparts, fail to
develop a fear of cues that have been associated with electric shock.
The scientists also found physiological changes in the brains of mice
lacking stathmin that correlate to the behavioral changes they
observed.
“It was localized not only in the pathway of the learning process, but also in the pathway of instinctive fear.”
Eric R. Kandel
The work, published in the November 18, 2005 issue of the journal
Cell, was carried out by lead author Gleb Shumyatsky, a
postdoctoral fellow from Kandel's lab who is now at Rutgers University,
and other scientists from Columbia, Rutgers, Harvard Medical School,
and Albert Einstein College of Medicine.
Both humans and animals are born with an innate fear of certain
threatening stimuli. As an example, Kandel said, “If you see a
train heading right at you, you get scared and run away. This is built
into the genome - the capability to respond to natural threat.”
Furthermore, when researchers pair a naturally frightening stimulus,
such as an electric shock, with a neutral signal, such as a tone,
animals develop fear of the neutral tone. “That is called learned
fear - that's acquired, it's a form of learning,” Kandel
explained. In humans, stage fright, phobias, and post traumatic stress
disorders are examples of learned fear.
In previous work, Kandel and his colleagues set out to determine the
underlying mechanisms that encode fear in the brain. “We knew
from other people's work about the neural pathways involved,”
Kandel said, “but there was little knowledge of the key genes or
the detailed neural circuitry involved. So we thought we would tackle
that problem.”
The researchers began their studies by searching for genes that were
particularly active in the amygdala, a region deep within the brain
known to contribute to fear and other emotions. They zeroed in on the
lateral nucleus, the portion of the amygdala that receives information
from the rest of the body about fearful stimuli. They dissected out
individual pyramidal cells, the principal cells in the lateral nucleus,
and found two genes, known as gastrin-releasing peptide (GRP) and
stathmin, that were much more active in the lateral nucleus than in a
part of the brain not thought to be involved in fear, which the
researchers analyzed for comparison.
Several years ago, Kandel, Shumyatsky, and their colleagues studied
the first of these genes, GRP, in detail and found that it encodes a
protein that inhibits the fear-learning circuitry in the brain. GRP
does not, however, play a role in innate fear — demonstrating that the
two fear pathways are genetically distinct.
When the scientists moved on to study stathmin, they had few clues
as to what role it might play in fear - if it was involved at all.
“When you go after a gene like this, you have no idea what
behavior or biological process it may be involved in,” Kandel
said. “I think it's the mystery of the thing that creates part of
the excitement. Except for thinking that the amygdala was very likely
to be involved, we had no way of knowing what the outcome would
be.”
An indication that stathmin might contribute to fear came when they
mapped the parts of the brain where the gene was most active. They
found that stathmin was highly expressed not only in the amygdala, but
also in other parts of the brain's fear circuitry. “It was
localized not only in the pathway of the learning process, but also in
the pathway of instinctive fear,” Kandel noted.
To investigate stathmin's role in more detail, the researchers
created mice lacking that gene, and examined the brain activity in the
lateral nucleus of their amygdalas. Recent work from other labs had
shown that during fear learning, the connections between the neurons in
this part of the brain strengthen. In stathmin-deficient mice, however,
the connections between these neurons remained virtually unchanged,
despite repeated stimulation.
These results were good indications that stathmin might play a role
in learned fear. To determine whether a lack of stathmin actually
altered animals' behavior in situations likely to trigger fear, the
scientists used several standard laboratory tests. Mice were trained to
associate an electric shock with either an auditory tone or a
particular location in a cage. After the training period, normal mice
would freeze when they encountered the tone or location that they'd
learned was likely to accompany a shock. Stathmin-deficient mice, on
the other hand, seemed unnerved by those stimuli, carrying on their
normal activities boldly, without fear.
From these experiments, it was clear to the scientists that stathmin
was needed for fear learning. To find out whether it might also
contributed to innate fear, the scientists took advantage of mice's
natural fear of open spaces. Unlike normal mice, which cower on the
edges of an open field and stay near the center of a plus-shaped maze,
mice without stathmin were much more adventurous, readily exploring
exposed areas.
The authors concluded from their experiments that stathmin is
required for both innate and learned fear. Together with his lab's
previous work on GRP, Kandel said, the work advances the understanding
of learned fear versus instinctive fear in several ways. “It
shows genetically there's a fundamental difference between the two; it
gives you some insight into the neural circuitry; it shows that there's
an inhibitory constraint to fear; and it gives you the potential of
thinking of therapeutic targets.”
As drug targets, Kandel said, GRP and stathmin each present unique
opportunities. “One would be for learned anxiety, the other would
be for instinctive. They both, I think, are reasonable - no one has
worked on those as targets before.” While drugs targeting
stathmin would likely affect both types of fear, Kandel expects that
with further work, researchers should also be able to identify genes
that act exclusively on instinctive fear.
|
|
Versión en español
|
|
Jim Keeley
