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Talk of the Gown

BJ Casey, PhD

JOHN ABBOTT

Nervous Condition
Transgenic mice enable a breakthrough
in the DNA of anxiety

W hat does a mouse huddled at


the edge of a field have in
common with wallflowers at
a school dance? More than you might think. A
study published in Science last winter tested the
behavior patterns of mice bred to have a human
neurologically predisposed to have trouble recov-
ering from stressful experiences. Their findings
may help clinicians determine which anxiety suf-
ferers will respond to traditional therapies and
which may require different, or simply longer-
term, courses of treatment. “One genetic alter-
genetic variant associated with anxiety. Led by ation isn’t the cause of the anxiety,” says
MD-PhD student Fatima Soliman, under the Soliman, who recently completed her PhD, “but
mentorship of Sackler Institute of Developmental it may be a contributor.”
Psychobiology director BJ Casey, PhD, and asso- In 2006, Lee created the transgenic mouse
ciate professor of psychiatry Francis Lee, MD, model, which replicates a human variant of
PhD, its results suggest that some people may be brain-derived neurotrophin factor, or BDNF. (The

14 WEILL CORNELL MEDICINE


BDNF-variant mice aren’t born anxious, but—like after physician and trying treatment after treat-
many human patients—begin to develop nervous ment. You could know in advance, ‘This is not
tendencies around adolescence.) The polymor- going to work, let’s think of something else.’ ”
phism, which is essentially a swap of two amino Further studies are under way on how the
acids, has long been associated with anxiety dis- BDNF variant affects specific anxiety disorders,
orders because of the major role neurotrophins such as PTSD with severe burn trauma.
play in development—but until now, no one has Researchers are also looking at how the trans-
been able to pin down exactly how. The new genic mice respond to different mood-altering
study determined that rather than causing anxi- medications, as well as exploring the potential to
ety, the BDNF variant affects the ability to recov- treat BDNF carriers even before they manifest
er from traumatic events. “It’s not really the anxiety. “If you can identify at-risk individuals, Can’t forget: Casey and her
learning of fear,” says Casey. “It’s the elimination there’s the possibility that one could intervene students have uncovered an
of that fear.” and prevent the disorder from emerging,” Casey imbalance between prefrontal
For the experiment, the researchers set up a says. “Psychiatry should be as much about men- cortical control regions (below
classic conditioning paradigm rooted in basic tal health as mental illness. When we wait until left) and subcortical emotional
Pavlovian techniques. Both the mice and human there’s a diagnosis, we’ve waited too long.” regions (below right) in individ-
volunteers were repeatedly exposed to a neutral — Liz Sheldon uals with the BDNF genotype.
stimulus (a color or inoffensive sound) paired
with an aversive one. For mice, that meant an
electric shock; for humans, a blaring noise. The
animals’ stress levels were measured by their ten-
dency to freeze (anxious mice immobilize them-
selves, prompting Casey’s wallflower analogy),
while the humans’ were monitored via sweat out-
put. The ability of each individual to suppress the
initial fear memory was evaluated by how long
they continued to display anxious responses to
the neutral stimulus after the unpleasant one was
removed.
Finally, the researchers scanned the brains of
human subjects as they underwent the tests.
They discovered that those who carried the BDNF
variant not only took longer to recover from the
aversive stimulus but displayed unusual brain
activity in the process. “They were not activating
an area in the prefrontal cortex that’s key to Brain power: Casey and colleagues are using diffusion tensor imaging (DTI) to
extinguishing fear memory,” says Casey. “What examine the strength of connections between distal regions. The image below
they were doing instead was activating this deep shows the direction of fiber tracts in the adult brain from superior to inferior
structure in the brain, the amygdala, that’s cen- (blue), right to left (green), and anterior to posterior (red).
tral to learning about fear.”
In other words, individuals with the variant
didn’t just have a harder time forgetting their
fears, they triggered a portion of the brain that
inhibits recovery—rendering conventional treat-
ments ineffective. The discovery could change
the way psychiatrists approach such disorders,
perhaps pointing the way to treatments that
could be tailored even to the youngest anxiety
sufferers. “Some of the most difficult sessions I’ve
experienced in my research have been with pedi-
atric patients,” Casey says. “When you hear how
so many treatments have been tried for children
PROVIDED BY DR. BJ CASEY

experiencing anxiety, it’s agonizing—not only for


the child who’s not getting better, but for the par-
ent as well. This could offer a reliable prediction,
so you could save them from going to physician

SUMMER 2010 15