|Mice Lacking Social Memory Molecule Take Bullying in Stride
The social avoidance that normally develops when a mouse repeatedly experiences
defeat by a dominant animal disappears when it lacks a gene for a memory molecule
in a brain circuit for social learning, scientists funded by the National Institutes
of Health’s (NIH) National Institute of Mental Health (NIMH) have discovered.
Mice engineered to lack this memory molecule continued to welcome strangers in
spite of repeated social defeat. Their unaltered peers subjected to the same
hard knocks became confirmed loners — unless the researchers treated them with
“For both mice and men, social status is important; for mice, losing to a dominant
mouse usually means that they avoid the dominant and they avoid social situations,” explained
NIMH director Dr. Thomas Insel. “These new findings add to a growing literature
on the molecular basis of social behavior, helping us to know where as well as
how social information is encoded in the brain.”
The results reveal neural mechanisms by which social learning is shaped by psychosocial
experience and how antidepressants act in this particular brain circuit. They
also suggest new strategies for treating mood disorders such as depression, social
phobia and post-traumatic stress disorder, in which social withdrawal is a prominent
symptom. Drs. Olivier Berton and Eric Nestler, University of Texas Southwestern
Medical Center (UTSMC), and colleagues, report on their study in the February
10, 2005 issue of Science.
Coursing from a hub in the center of the brain (ventral tegmental area), the
relevant circuit mediates responses to emotionally important environmental stimuli
via release of dopamine. Activity of this neurotransmitter is regulated in the
circuit by brain derived neurotrophic factor (BDNF), which is known to play a
key role in memory (http://www.nimh.nih.gov/Press/prbdnf.cfm). Berton, Nestler
and colleagues suspected that BDNF plays a similarly pivotal role in social learning.
To find out, they first subjected mice to a different dominant mouse daily for
10 days. Even 4 weeks later, the “socially defeated” animals vigorously avoided
former aggressors or unfamiliar mice. BDNF increased markedly in their social
memory circuit. Yet, the social avoidance behavior was reversible by giving the
Next, borrowing a page from gene therapy, the researchers injected mice with
a kind of molecular magic bullet (using transgenic techniques and a virus) that
selectively turned off BDNF expression in the social learning circuit. This exerted
an antidepressant-like effect; the mice were spared from developing social avoidance
behavior following repeated social defeat.
“Without BDNF in the circuit, an animal can’t learn that a social stimulus is
threatening and respond appropriately,” explained Nestler.
He and his colleagues also discovered that social defeat triggered an upheaval
in gene expression in the target area of the circuit, the nucleus accumbens,
located deep in the front part of the brain — 309 genes increased in expression
while 17 decreased. This pattern persisted even 4 weeks later, with 127 genes
still increased and 9 decreased, paralleling the changes seen in social behavior.
The researchers suggest that this alteration in gene expression encodes the motivational
changes induced by aggression. When BDNF was deleted, or the animals were given
antidepressants, most of the changes in gene expression reversed.
Identification of the products of the genes turned on and off by social defeat,
BDNF and antidepressants revealed the workings of the molecular pathways involved
in dopamine regulation of social motivational processes. The results suggest
that chronic treatment with antidepressants restores social approach behaviors
partly by interfering with the cascade of activity triggered by BDNF as the organism
adapts to experience.
The researchers say the study “suggests new directions for antidepressant drug
Also participating in the study were: Colleen McClung, Vaishnav Krishnan, William
Renthal, Scott Russo, Danielle Graham, Nadia Tsankova, Lisa Monteggia, David
Self, UTSMC; Ralph Dileone, Yale University; Carlos Bolanos, Florida State University;
Maribel Rios, Tufts University.
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 Human Services.
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