|Gene Knockout Scores a Fearless Mouse
Knocking out a gene in the brain’s fear hub creates mice unperturbed by situations
that would normally trigger instinctive or learned fear responses, researchers
funded in part by the National Institutes of Health have discovered. The findings
may lead to improved treatments for anxiety disorders (http://www.nimh.nih.gov/healthinformation/anxietymenu.cfm),
The scientific team, led by National Institute of Mental Health (NIMH) grantee
and Nobel Laureate Dr. Eric Kandel, Columbia University, Dr. Vadim Bolshakov,
Harvard University, a grantee of the National Institute of Neurological Disorders
and Stroke (NINDS) and the National Institute on Drug Abuse (NIDA), and Dr. Gleb
Shumyatsky, Rutgers University, report on their study in the November 18, 2005
issue of Cell.
Fear memories are so essential for survival that they are easily formed and
rarely lost. The workings of fear circuitry, centered in the amygdala, an almond-shaped
structure deep in the brain, are well understood. But relatively little is known
about fear’s molecular basis, note the researchers.
The gene in the current study codes for stathmin, a protein that appears to
be critical for the amygdala to rearrange connections and form fear memories.
Stathmin normally controls this process by regulating the supply of microtubules,
building materials that amygdala cells use to make structural adaptations that
encode the memories. Runaway production of these building materials stymied construction
of fear memories in a mouse strain molecularly engineered to lack stathmin, the
They first showed that circuitry on the side of the amygdala known to be critical
for fear learning is rich in stathmin. They then demonstrated that a cellular
process critical for memory formation, long-term potentiation, is impaired there
in stathmin knockout mice, due to the excess production of microtubules.
Compared to control animals, the stathmin knockout mice showed less anxiety
(freezing) when they heard a tone that had previously been associated with a
shock, indicating less learned fear. The knockout mice also were more prone to
explore novel open space and maze environments, a reflection of less innate fear.
“Stathmin knockout mice can be used as a model of anxiety states of mental disorders
with innate and learned fear components,” propose the researchers. “As a corollary,
these animal models could be used to develop new anti-anxiety agents.”
This and related studies with other knockout mouse models suggest that subclasses
of anxiety disorders will ultimately emerge, “each of which is likely to have
a unique molecular signature and require distinctive pharmacological approaches,” they
“Whether stathmin is similarly expressed and pivotal for anxiety in the human
amygdala remains to be confirmed,” noted NIMH director Dr. Thomas Insel. “Yet,
this surprising discovery in the mouse hints at the potential for new treatment
strategies likely still hidden in the vast uncharted territory of brain genetics.”
Also participating in the study: Shuichi Takizawa, Jamie Joseph, Rutgers University;
Gael Malleret Stanislav Zakharenko, Svetlana Vronskaya, DeQi Yin, Columbia University;
Keith Tully, Evgeny Tsvetkov, Harvard University; Ulrich Schubart, Albert Einstein
College of Medicine.
In addition to the NIH, the research was also supported by NARSAD, NAAR, The
Cure Autism Now Foundation, the New Jersey Governor’s council on Autism, the
G. Harold and Leila Y. Mathers Charitable Foundation, the Whitehall Foundation,
and the Esther A. & Joseph Klingenstein Fund.
NIMH, NINDS and NIDA are parts 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 Human Services.
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Agency — includes 27 Institutes and Centers and is a component of
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agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.