Grant: Project Grant

Major depressive disorder (MDD) is a devastating disorder affecting over 3.2 million Canadians and current antidepressants are effective in only half of the treated patients. Anxiety is one of the most common MDD's comorbidities. Patients with anxiety disorders in early life are more likely to develop MDD and be treatment-resistant. Understanding how chronic stress and chronic anxiety can lead to depression is of utmost importance for the field. A common feature of anxiety, depression and stress-related disorders is hyperactivity of the amygdala, a key brain region involved in emotion processing. A lot is known about amygdala activity and its role in acute stress response, fear and anxiety; however the effects of sustained amygdala hyperactivity and its role in chronic stress at the behavioral or functional level are unclear. Taking advantage of growing advances in small animal brain imaging, we recently showed that chronic stress in mice increases amygdala structural connectivity at the detriment of overall brain structural synchrony. A similar shift is found in people with history of childhood trauma. In mice and humans increased amygdala connectivity correlated with depressive behaviors. Here we aim to determine: 1) if chronic stress-induced amygdala structural changes appear first and induce brain-wide changes, following a trajectory that maps onto the development of specific behavioral deficits, 2) if artificial (via transgenic tools) chronic amygdala hyperactivation causes depressive-like behavioral and structural changes, 3) if anxiolytic or antidepressant treatment can reverse the behavioral and structural deficits induced by chronic stress or hyperactivated amygdala. Considering the central role of amygdala in stress-related illnesses, this work will shed light on the direct contribution of chronic amygdala dysfunction to stress-induced behavioral and brain connectivity deficits, while determining which deficits are not targeted by current pharmacotherapy.