It is well established that interactions between genes and the environment contribute to psychiatric disorders. However, the way in which this is translated into changes in the brain has long been elusive. Now, a multimodal imaging study led by Turhan Canli, in collaboration with Klaus-Peter Lesch, shows that the variants of the serotonin transporter gene (5-HTT), which is involved in depression, have different effects on brain function depending on the level of stress that individuals have in their lives.

People carrying a short allele of 5-HTT tend to have increased anxiety-related temperaments and are more vulnerable to depression compared with people who have two long alleles of the gene. Canli and colleagues set out to test whether this is due to heightened responses of the amygdala and hippocampus to negative emotional stimuli, as suggested by the phasic activation model. If this theory is correct, short-variant carriers with higher levels of stress in life should show more brain activity in response to stimuli such as fearful or sad faces. By contrast, the tonic activation model posits that the presence of the short allele and higher levels of stress increases the resting activity of the amygdala and hippocampus, rather than elevating brain reactivity to emotional stimuli or stress.

In support of the tonic activation model, the researchers found that in participants with a short allele of 5-HTT there was a negative correlation between the reactivity of the amygdala and hippocampus — as measured by functional MRI — and the level of stress, regardless of the emotional nature of the stimuli. By contrast, a positive correlation was identified in people with two long alleles of the gene.

To further investigate the significance of these findings, Canli et al. used the perfusion scanning technique to measure the absolute cerebral blood flow — an indicator of the level of resting activity — in those brain regions. The resting activity of the amygdala and hippocampus was higher in subjects with a short 5-HTT allele than in those with two long alleles. Interestingly, the more stress short-variant carriers have in their lives, the higher the resting activity. The opposite was observed in people with two long alleles.

The researchers also uncovered similar correlations between self-reported levels of rumination — a form of dysfunctional cognitive reappraisal of negative life events — and stress. So, short-allele carriers with high levels of stress tended to ruminate a lot, which might increase their risk for depression and anxiety disorders.

These intriguing findings lend support to the tonic activation model, and further suggest that short-variant carriers might be in a chronic state of vigilance, threat or rumination, which makes them more vulnerable to mental illnesses.