Depression is a chronic, remitting syndrome which exacts devastating consequences on humanity. Yet, our understanding of depression and our ability to treat it remain limited. We propose to use sophisticated mouse models of depression and postmortem brain tissue from depressed humans to define the molecular mechanisms in brain that control susceptibility versus resilience to depression over the lifetime of the individual. This knowledge will then be used to identify and validate new targets for antidepressant treatment. We will work in a highly collaborative manner with all other DTF members.