Researchers have identified a gene-regulating protein in the brains of mice that triggers the animals' ability to cope with stress-related behavioral despair.
The research was carried out by scientists at the University of Texas Southwestern Medical Center, the European Neuroscience Institute, the Centre National de la Recherche Scientifique, Universite Louis Pasteur, Strasbourg, the University of Innsbruck, and Harvard Medical School. In earlier studies, they showed that exposure to repeated stress caused an increase in the transcription factor deltaFosB in the brain. In the new experiments, the team sought to explore the role of deltaFosB in regulating adaptation to stress. Their approach involved first exposing mice to random shocks from which the animals could not escape. Such repeated exposure to inescapable stress tends to increase the lag time for mice to escape subsequent shocks when they are given the chance.
Measuring this lag time, or the complete failure to escape, gave the scientists a measure of behavioral despair. This experimental approach has long been used as an animal model of human affective disorders such as depression, post-traumatic stress disorder, and bipolar disorder. As in humans with such disorders, this behavioral despair in mice responds to antidepressants.
The researchers discovered that the mice that showed the smallest lag in escape times also had higher levels of deltaFosB in a brain region involved in processing of pain signals and defensive responses. In contrast, animals with either longer lag times or failure to escape showed lower deltaFosB levels.
Furthermore, when the investigators introduced higher levels of the gene for deltaFosB into mice, they found it reduced the level of behavioral despair. They also established that increased deltaFosB levels in the mice decreased the activity of the gene for a protein called substance Pi, known to regulate processes such as mood, pain sensitivity, anxiety, and stress.
The findings will be published in the July 19 issue of Neuron.