Grant: Project Grant

30-50% of depressed individuals are unresponsive to commonly prescribed treatments and only 30% completely remit, suggesting that current therapies do not address important biological mechanisms involved. Increasing evidence support that inflammation and vascular dysfunction contribute to the development of depression. We showed that chronic stress induces blood-brain barrier (BBB)-related changes promoting depression vs resilience, in a sex-specific manner. Indeed, prevalence, symptoms, and treatment of depression all point toward major sex differences. Chronic stress is depression's main risk factor, and the BBB is a dynamic barrier preventing harmful signals to penetrate the healthy brain. Here, we propose to investigate if pericytes, mural cells maintaining BBB integrity and brain plasticity, play an active role in stress responses and establishment of depressive symptoms. We hypothesize that favoring neurovascular health via proper pericyte function may represent an innovative strategy to treat stress and mood disorders. Cutting-edge microscopy techniques will be combined to cell-specific transcriptomic analyses to characterize in detail how pericytes react to stress exposure or antidepressant treatments. All experiments will be conducted in both sexes to identify sex-specific mechanisms that could explain differences in symptomatology and treatment response. Next, we will confirm a causal role of pericyte function in depressive behaviors vs resilience using viral-mediated manipulations performed in transgenic mice. Finally, mouse findings will be validated on human samples including from men and women with depression. This multidisciplinary approach integrating morphological, molecular, functional, and pharmacological techniques performed on two mouse models and human samples will decipher the role of pericytes in stress responses and depression. It will advance knowledge on the biology underlying psychiatric disorders and identify novel therapeutic targets.