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Lessons Learned—Or Overlearned: It Makes All the Difference in How the Brain Copes

Study may offer a new therapeutic target for counteracting post-traumatic stress disorder and depression by switching coping methods



© ISTOCKPHOTO/JUSTIN HORROCKS

The neural activity and physical behavior of mice recovering from several stressful encounters may illustrate alternative ways that mammals respond to traumatic events.

Researchers at the University of Texas (U.T.) Southwestern Medical Center at Dallas noticed that mice used two primary methods to cope with defeat after being repeatedly pummeled by larger, more aggressive foes: Some of the weaker members withdrew, avoiding all types of social interaction for more than a month, whereas others rolled with the punches, so to speak, quickly bouncing back to their normal behavior.

The observation of different coping mechanisms led the team to probe the animals' brains, where they discovered that the level of a certain protein in its reward circuitry determines whether the mice will be traumatized for several weeks or only temporarily down. Researchers found that levels of neurotrophic factor (BDNF) nearly doubled in the brains of vulnerable mice, a finding that could point to a therapeutic target in humans for combating post-traumatic stress disorder and depression.

In an earlier study, the research team, led by U.T. Southwestern psychiatry professor Eric Nestler, found that levels of BDNF—which is implicated in learning because of its role in creating stronger connections between neurons—increase in the nucleus accumbens in response to chronic stress. (The nucleus accumbens is a region in the rear of the forebrain that plays a role in determining whether a stimulus is rewarding or negative.) This rise in BDNF concentration, the scientists say, results from increased activity of neurons in the ventral tegmental area, a midbrain structure that sends signals to the nucleus accumbens via the chemical messenger dopamine.

"Vulnerability is caused by an increase in the frequency of dopamine impulses; a side-effect of that is an increase in the levels of BDNF," says study co-author Vaishnav Krishnan, a graduate student in Nestler's lab. "Resilient mice overcome this change by counteradapting their gene expression [the suite of genes that act on the nucleus accumbens that are either turned on or off] to clamp down the levels of activity in the ventral tegmental area."

Because the mice involved in the study were genetically similar, researchers ruled out a genetic link to the different responses. "These two end points," Krishnan explains, "are really the manifestations of two different types of coping styles."

According to the researchers, as they plunged into despair, mice that experienced the increase in BDNF levels showed symptoms similar to those of human depression: they interacted less with other mice, lost weight and were not interested in sugar or sexual activity, both of which they naturally find rewarding.

"The increase in BDNF may have an adaptive role normally, allowing an animal to learn that a situation is bad and [to] avoid it in the future," Nestler says. "Under conditions of extreme social stress, susceptible animals may be 'overlearning' this principle and generalizing it to other situations."

The U.T. Southwestern team, in an effort to get a clearer parallel between the animal and human condition, conducted autopsies on the brains of depressed and normal individuals. The group suffering from depression had BDNF levels that were as much as 40 percent higher than their counterparts.

"If we can understand how to promote resilience to [chronic] stress," Krishnan says, "we can find new ways of treating depression…. Off the top of my head, a drug that would decrease the amount of BDNF that's released in response to [dopamine] activity would be a good antidepressant." He cautions, however, that such therapy would have to be localized, so that it did not interfere with the protein's role in learning in other brain regions.

The neural activity and physical behavior of mice recovering from several stressful encounters may illustrate alternative ways that mammals respond to traumatic events.

Researchers at the University of Texas (U.T.) Southwestern Medical Center at Dallas noticed that mice used two primary methods to cope with defeat after being repeatedly pummeled by larger, more aggressive foes: Some of the weaker members withdrew, avoiding all types of social interaction for more than a month, whereas others rolled with the punches, so to speak, quickly bouncing back to their normal behavior.

The observation of different coping mechanisms led the team to probe the animals' brains, where they discovered that the level of a certain protein in its reward circuitry determines whether the mice will be traumatized for several weeks or only temporarily down. Researchers found that levels of neurotrophic factor (BDNF) nearly doubled in the brains of vulnerable mice, a finding that could point to a therapeutic target in humans for combating post-traumatic stress disorder and depression.

In an earlier study, the research team, led by U.T. Southwestern psychiatry professor Eric Nestler, found that levels of BDNF—which is implicated in learning because of its role in creating stronger connections between neurons—increase in the nucleus accumbens in response to chronic stress. (The nucleus accumbens is a region in the rear of the forebrain that plays a role in determining whether a stimulus is rewarding or negative.) This rise in BDNF concentration, the scientists say, results from increased activity of neurons in the ventral tegmental area, a midbrain structure that sends signals to the nucleus accumbens via the chemical messenger dopamine.

"Vulnerability is caused by an increase in the frequency of dopamine impulses; a side-effect of that is an increase in the levels of BDNF," says study co-author Vaishnav Krishnan, a graduate student in Nestler's lab. "Resilient mice overcome this change by counteradapting their gene expression [the suite of genes that act on the nucleus accumbens that are either turned on or off] to clamp down the levels of activity in the ventral tegmental area."

Because the mice involved in the study were genetically similar, researchers ruled out a genetic link to the different responses. "These two end points," Krishnan explains, "are really the manifestations of two different types of coping styles."

According to the researchers, as they plunged into despair, mice that experienced the increase in BDNF levels showed symptoms similar to those of human depression: they interacted less with other mice, lost weight and were not interested in sugar or sexual activity, both of which they naturally find rewarding.

"The increase in BDNF may have an adaptive role normally, allowing an animal to learn that a situation is bad and [to] avoid it in the future," Nestler says. "Under conditions of extreme social stress, susceptible animals may be 'overlearning' this principle and generalizing it to other situations."

The U.T. Southwestern team, in an effort to get a clearer parallel between the animal and human condition, conducted autopsies on the brains of depressed and normal individuals. The group suffering from depression had BDNF levels that were as much as 40 percent higher than their counterparts.

"If we can understand how to promote resilience to [chronic] stress," Krishnan says, "we can find new ways of treating depression…. Off the top of my head, a drug that would decrease the amount of BDNF that's released in response to [dopamine] activity would be a good antidepressant." He cautions, however, that such therapy would have to be localized, so that it did not interfere with the protein's role in learning in other brain regions.

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