Delineating neural circuitry of STress REsilience and Stress Susceptibility using DREADD combined with fMRI technique (STRESS-DREADD)

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Depression has become the second leading cause of illness-induced disability with 300 million people affected. Suicide due to depression is the second leading cause of death in 15-29-year-olds. Chronic stress exposure greatly raises depression risk. However, there is a degree of inter-individual variation in the way people respond to severe stress, with a spectrum ranging from vulnerability to resilience. Since no current antidepressant is effective for more than 50% of patients, a new frontier in psychiatry could be an induction of natural mechanisms of resilience to treat depression. Our aim is to understand the phenomenon of stress resilience in currently non-explored longitudinal perspective, i.e. to study brain before and after stress in order to separate trait and state-dependent markers of resilience and susceptibility, and also to separate maladaptive from pro-adaptive stress response. The understanding of what makes individuals more resistant to the deleterious effects of stress could suggest new path for the development of treatments. Once we know the key regions and projections discerning resilience and susceptibility, we aim to chemogenetically excite/inhibit these brain projections to find out whether it induces stress resilience in stress-susceptible rats, and vice versa.We will perform a longitudinal study using chronic mild stress model, one of the most realistic and extensively validated animal models of depression, and will use high-field functional magnetic resonance imaging (fMRI) to identify: (1) brain imaging endophenotypes of predisposition to resilience and susceptibility, i.e. trait markers (stress-free environment), (2) state-dependent endophenotypes of resilience and susceptibility (post-stress). Next, we will use a cutting-edge combination of high-field fMRI and a recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technique, to experimentally probe the effects of focal modulation of key regions and projections discerning resilience and susceptibility, in order to find out whether this manipulation would result in imaging endophenotype and behavior characteristic for stress resilience in stress-susceptible rats, and vice versa.