Any bully's victim knows the experience can cause lingering fear. Now scientists watching big mice intimidate small ones have discovered the stress spurs genetic changes in the brain, a finding that may help research into depression and other mental illnesses.
The experiment suggests a part of the brain linked to addiction also plays a previously unsuspected role in illnesses characterized by chronic anxiety and social withdrawal, Texas researchers report Thursday in the journal Science.
In fact, a substance produced in the brain, called BDNF, seems to be the culprit, controlling whether the bullied mice turned into fearful hermits or not.
"This is a fascinating observation," said Dr. Thomas Insel, director of the National Institute of Mental Health, which helped fund the work.
Neuroscientists at the University of Texas Southwestern Medical Center wanted to test the role of the brain's "reward pathway" in depression-like behavior. This brain circuitry is involved in emotional learning, and recognizing pleasure, and thus has a role in addiction. But people with major depression become almost numb, unable to experience pleasure, suggesting another role for the reward pathway.
Enter the mice, normally sociable creatures who quickly determine their pecking order, steering clear of aggressors in favor of friendlier company.
The Texas researchers subjected some small brown mice to intimidation more intense than they'd face in the wild: Each was placed for five minutes in the cage of a particularly aggressive, large white mouse, who battled the little one into a corner. Then, researchers divided the cage with a perforated, plexiglass divider for 24 hours so the little mouse was in no physical danger, but saw and smelled the aggressor. For 10 days, each little mouse met a new bully.
The bullied mice emerged drastically cowed. Four weeks later, they still fearfully withdrew from even presumably friendly little mice.
What was happening in their brains?
BDNF is a chemical important for the growth and maturation of nerve cells. Some antidepressants are thought to increase BDNF levels in the hippocampus, helpfully boosting neurons.
But in this different brain region, encompassing the so-called mesolimbic dopamine pathway, Dr. Eric Nestler, UT Southwestern's psychiatry chairman, found too much BDNF was bad: The bullied mice experienced marked BDNF increases, which in turn switched on several hundred genes located deep in the front part of the brain. That unusual gene activation paralleled the animals' social withdrawal.
Then Nestler's team injected mice with a virus that switched off BDNF production only in this one brain region, and repeated the bullying experiment. Mice lacking the BDNF didn't become cowed, they essentially couldn't learn how to respond to this emotional threat, evidence of BDNF's role in social stress.
"The ability of stress to induce BDNF in this reward circuitry is probably a good thing" from an evolutionary standpoint, Nestler said. "If you're constantly subjected to something bad like being beaten up, it makes sense to avoid what's beating you up."
But extreme stress can throw that normally protective system into overdrive, he explained.
That's similar to what can happen in people, when someone genetically predisposed to depression experiences a first bout after an emotionally stressful event.
Most antidepressant research has focused on overall levels of different brain chemicals, such as serotonin. But the new study suggests that's far too simplistic, since BDNF seems to have different effects in different brain regions, Insel said.
"We like to think about the brain like any other organ," he said. "It's much more complicated. ... We need to think about changes in specific circuits, not just whether something goes up or down in the brain."
Nestler agreed, saying the work points toward potential new targets for research into depression and other mental illnesses, such as posttraumatic stress syndrome or social phobias. Among his next steps is figuring out what those BDNF-controlled genes do, to better identify those targets.