Grant: Operating Grant

The goal of this research project is to understand how people get depressed, and to find new and better treatments. Depression is an illness in which people feel very sad all the time, to the point that many commit suicide. Depression causes more disability than any other disease in developed countries like Canada, so it is a very important public health problem. Psychological and social stress, like abuse or neglect in childhood, the death of a loved one or being fired from work, increase the risk of getting depressed. In this proposal we want to examine a special kind of DNA modification that can change the amount or timing of gene expression. This is a powerful mechanism to regulate the function of the genome, which is influenced by various environmental inputs such as stress, and early life experience. While this general phenomenon is known, it is not known how psychosocial stress can directly cause biological changes leading to depression. That is what we hope to find out. We plan to study a large set of human identical twins, who have the same DNA sequence as their co-twins, and a set of mice, who respond with depression-like behavior to emotionally stressful situations, much like humans do. In the human twins, we will compare stress exposure, and depression-related measures to the DNA modification patterns. Although we expect to find some particular correlations, we can't tell whether the depression-related changes are actually caused by the DNA modifications. This is where the mouse experiments can help. In mice, we can check the DNA modifications immediately after stressful experiences, before the depressive behaviors have emerged. This will allow us to determine the cause of the depressive behaviors at a molecular level. We will also test some new drugs that target these DNA modifications, and we think that this strategy will lead to antidepressant medications that are more effective than those currently available.