Grant: Project Grant

Depression is the leading cause of disability worldwide and existing antidepressant therapies have limited efficacy. It is well known that chronic stress can lead to depression, yet not all those who encounter stress will become depressed. Understanding what makes some people especially vulnerable to depression is essential for developing proper treatment and for possibly even preventing the disorder. Stress experienced in early life is one factor known to increase risk for depression but key questions remain unanswered. What are the enduring changes in brain function that are induced by early life stress to mediate life-long susceptibility to depression? Can neural signatures of aberrant brain function be detected before depression is observed? To answer these questions, we will employ a multi-disciplinary approach integrating advanced neuroscience techniques with robust mouse models to probe the enduring effects of early life experience on neuronal activity and the underlying changes in gene expression in a key brain circuit implicated in depression, the ventral hippocampus projection to the nucleus accumbens. We will use ex vivo measurements of neuronal connectivity, in vivo imaging of neuronal activity and post-mortem assays of genome-wide gene expression to examine how maternal separation in mice, a form of early life stress, shapes neuronal function and gene networks in the ventral-hippocampus to nucleus accumbens circuit to increase susceptibility to chronic stress in adulthood. Elucidating both the alterations in brain circuit function and the underlying gene networks that render an individual susceptible to depression will provide the knowledge necessary to develop treatments to treat and even prevent depression. This research will open the door to new interventions to regulate brain activity to mitigate susceptibility before depression emerges, reducing the enormous societal costs and improving the lives of millions of Canadians struggling with depression