Mechanism exposed for increased stress sensitivity

17 December 2019

Approximately seventy percent of the population carries a genetic variant of the so-called serotonin transporter gene. This genetic variant makes people more sensitive to stress and increases the risk of stress-related disorders, such as depression. How these two aspects relate to each other was still largely unknown. Researchers from the Radboudumc now show that the variation in this gene causes an excessive fear response in threatening situations.

The researchers looked at how subjects with and without the genetic variant responded to information that preceded a mild electric shock. If they were shown a yellow square, they could receive a mild shock on their finger. After a blue square they never got a shock.

Neuroscientist Marloes Henckens: “The test subjects learned this association in the MRI scanner, so that the response of their brain to the squares could be measured. In addition, their heart rate was measured while looking at the squares. Carriers of the genetic variant showed a stronger response to the yellow squares. Their heartbeat dropped more sharply in anticipation of the shock. The cognitive control centre, the frontal lobe, was also less active when the yellow squares were shown. Furthermore, communication increased between the brainstem and the fear centre in the brain, the amygdala. The stronger the communication between these brain structures, the stronger the decrease in heart rate.”

Fear and freezing

The researchers recorded a similar fear response in rats with a serotonin transporter switched off. The rats learned that a specific tone predicted a mild shock to their feet. Just like the people with the genetic variant, these rats showed a stronger fear response. Henckens: “Their heart rate went down more strongly and their ‘freezing response’ lasted longer. Freezing is a response that animals often show in a threatening situation. Just like the subjects, the rats showed a decrease in the activity of specific brain cells in the frontal lobe. They also showed increased activity in a specific type of brain cells in the amygdala, which is known to communicate with the brain stem. This enhanced communication predicted the behavioural fear response in the rats. The rat study thus provided a more detailed picture of the underlying mechanisms of the anxiety response.”
The enhanced communication between the amygdala and the brainstem appears to be the basis of the increased fear response among people with the genetic variant of the serotonin transporter. Henckens: “This link can explain why these individuals are more susceptible to stress-related disorders.”