DNA's moody temperament: gene variant linked to depression-ready brain.

Scientists have for the first time seen what a genetic predisposition to depression looks like in the brain. Brain images show that people who inherit a short version of a particular gene have poor control over neural reactions to threats and stress.

The short gene's protein, known as the serotonin transporter protein, may degrade connections in the brain's mood-regulation system by fostering intense serotonin activity, propose psychiatrist Daniel R. Weinberger of the National Institute of Mental Health in Bethesda, Md., and his colleagues. Serotonin plays a pivotal role in assembling the brain's emotion circuitry, especially during fetal development.

Bearers of the truncated gene reported high levels of daily anxiety and concern with avoiding potential dangers, which are temperament measures that researchers had previously linked to a propensity for developing depression.

In contrast, brain imaging showed that the mood-related circuitry is well connected in nondepressed people who carry the same gene's long version, which spurs moderate serotonin activity, Weinberger's group reports in the June Nature Neuroscience. These individuals also have relatively anxiety-free temperaments, the team reports.

The researchers were inspired to conduct their study by prior investigations revealing that people who possess two copies of the short version of the serotonin-transporter gene often become depressed after experiencing traumas such as childhood neglect and abuse (SN: 11/20/04, p. 323).

Weinberger and his coworkers studied 114 adults, none of whom had any psychiatric disorder. Of that number, 35 carried two copies of the long version of the gene and 79 possessed at least one copy of the short version.

In participants with the short gene, magnetic resonance imaging revealed low numbers of neurons, and relatively sparse connections among them, in brain areas already implicated in handling negative emotions. The most prominent of these regions were the amygdala, which triggers fear responses, and the cingulate, which reins in amygdala activity.

The researchers then used functional magnetic resonance imaging to monitor blood flow in the brains of volunteers as they matched pairs of angry and fearful trees shown on a computer screen. Those volunteers with the short gene displayed little coordination between amygdala and cingulate activity, a sign of a communication breakdown. Moreover, volunteers showing the weakest connections between these brain areas reported the highest levels of daily anxiety.

In participants with the long-gene variant, amygdala activity consistently declined as cingulate activity rose. That pattern reflects the cingulate's quelling of amygdala responses to negative facial expressions, the researchers hold.

The short version of the gene doesn't cause depression, Weinberger emphasizes. Rather, it boosts a person's sensitivity to stressful events, which can lead to depression. "This gene variant interferes with the brain's ability to shut off [emotional] responses to threats," Weinberger says.

It makes sense that roughly half of the general population carries at least one copy of this gene's short variant, writes psychologist Stephan Hamann of Emory University in Atlanta, in an editorial accompanying the new report. Sensitivity to fear and threat would have proved valuable throughout our species' evolution, he asserts. There was also a need for optimistic and more-fearless types bearing the gene's long version, Hamann notes. "But a blunted response to aversive stimuli carries its own risks," he says.