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 antidepressants.
"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. 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 and an indicator of gene expression increased markedly in their social memory circuit. Yet, the social avoidance behavior was reversible by giving the animals antidepressants.
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 discovery."
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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