Gene may trigger depression by affecting fear response

A gene variation previously linked to depression and anxiety affects brain regions involved in processing fear and 'dampening' negative emotions, US scientists say. The short version of the serotonin transporter , 5-HTT (5-hydroxy- tryptamine) gene, is linked to an increased risk of depression following stress. Researchers at the National Institute of Mental Health (NIMH) have now shown that this gene variant could exert its effects by altering a key 'mood-regulating' circuit in the brain. Their findings, published in the journal Nature Neuroscience, suggest that this in turn predisposes people to 'persistent bad moods and eventually depression as life's stresses take their toll'.

A team based at Kings College in London showed two years ago that people who inherit two short versions of the 5-HTT gene, one from each parent, are more likely to develop serious depression after a stressful life event. The 5-HTT gene makes the serotonin transporter protein, which affects levels of the brain chemical serotonin - low levels of which are linked to depression. In the latest study, the researchers looked at the relationship between the two different versions of the 5-HTT gene, and a person's fear response.

The scientists used a scanning technique called magnetic resonance imaging (MRI) to look at the brains of 114 healthy people. They found that those with at least one copy of the short 5-HTT gene had less 'grey matter' (neurons and their connections) in parts of the brain responsible for processing fear. The two parts of this brain circuit are the amygdala, which triggers the fear response, and the cingulate, which controls this response.

Next, the team used another technique, called functional MRI, to monitor the brain activity of 94 healthy people while they looked at pictures of scary faces. They found that those with the short 5-HTT gene had a weaker fear processing circuit - that is, the response from the amygdala was dampened down less by the cingulate than in people with the long gene variant.

Study author Andreas Meyer-Lindenberg said that until now, it had been hard to relate the activity of the amygdala to temperament and the genetic risk for depression. 'This study suggests that the cingulate's ability to put the brakes on a runaway amygdala fear response depends on the degree of connectivity in this circuit, which is influenced by the serotonin transporter gene', he concluded. Since serotonin plays a key role in wiring up the brain's emotional circuits during early development, the researchers propose that the short version of the 5-HTT gene could lead to 'stunted coupling' in this circuit, leaving the individual at increased risk of anxiety and depression in adult life.