A Close Look At Rat Brains Under Stress

Stress-related disorders, such as anxiety and depression, are, in part, genetic. Evidence suggests that people whose brains have lower levels of transporters for the neurotransmitter serotonin are particularly vulnerable to such disorders. But a new study in rats suggests that this genetic difference might confer a benefit in certain stressful situations: Researchers found that rats lacking serotonin transporters handled stressful stimuli better than wild-type rats—in situations where the rodents had control (ACS Chem. Neurosci. 2015, DOI: 10.1021./acschemneuro.5b00126).

Stress can be a good thing, says Judith R. Homberg of Radboud University Medical Centre, in the Netherlands—motivating, for example, a person to escape danger. However, stress due to factors outside of a person’s control—like the bus running behind schedule and making a person late for work—is linked to stress disorders. Some people have the mental makeup to handle such uncontrollable stressors, while others develop stress-related disorders when such stressors accumulate. Homberg’s team wants to understand the genetic basis for these differences.

The researchers compared the behavior of rats genetically engineered to lack serotonin transporters with wild-type rats in two stressful situations, one controllable and the other uncontrollable. In the first scenario, the rats’ feet were shocked, but the rodents could learn to stop the shocks with a well-placed nose poke. In the second scenario, rat behavior had no impact on foot shocks.

The results showed that the genetic knockout rats learned to avoid foot shocks faster and used the nose-poke foot shock avoidance strategy more frequently than the wild-type rodents, suggesting they coped better with controllable stress. This was a surprise, because when faced with uncontrollable stress, the knockout rats exhibit depression-like behaviors and tend to “freeze up,” says study coauthor Pieter Schipper, a graduate student in Homberg’s laboratory.

The researchers also found that controllable stress, but not uncontrollable stress, activated the dorsal raphe nucleus, a part of the brain that produces serotonin, in wild-type rats. However, in the knockout rats, dorsal raphe nucleus activation was the same regardless of stress controllability. These data “strongly suggest that the role of serotonin might be different” in the knockouts versus the wild-type rats, Schipper says. That’s important, Homberg says, because antianxiety and antidepression medications are developed in “wild-type” humans, while the people who actually develop stress-related disorders may be more like the knockout rats.

Sayamwong E. Hammack of the University of Vermont says that the knockout rats’ improved learning in response to a controllable stressor is indeed “counterintuitive.” However, Hammack wonders whether this counterintuitive behavior is related to factors beyond the deletion of the serotonin transporter. He says that when rats grow up without a gene, unanticipated compensatory changes may occur during development that muddle the interpretation of data. Schipper acknowledges these limitations and, in future work, plans to disable the serotonin transporter in adult rats, which should remove the developmental ambiguity.