Grant: CIHR Fellowship

Stress-related illnesses, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), affect 1 billion people worldwide and are a leading cause of disability. Women are disproportionately affected, with 2-3 times higher incidence vs men. High resistance rates to pharmacotherapies suggest that neuron-centric approaches may not fully address underlying biological causes. Increasing evidence links stress and trauma to immune activation and vascular dysfunction, but the biological processes driving these sex differences remain poorly understood. Chronic stress causes neurovascular alterations and blood-brain barrier (BBB) leakiness in brain regions critical to emotional processing and social behaviors. We revealed that these changes occurred in different mood-regulating brain regions in depressed men and women, possibly explaining differences in clinical presentation, symptomatology and treatment response. The pathophysiology of PTSD remains elusive, but emerging evidence suggests shared and distinct inflammatory and vascular mechanisms between MDD and PTSD. I hypothesize that sex-specific neurovascular dysfunction underlies stress-related disorders and targeting these alterations represents a promising therapeutic avenue. I will generate the first sex- and brain region-specific single-cell vascular atlas of stressed mice and compare hits to human datasets in collaboration with Harvard Medical School to identify molecular signatures of stress susceptibility vs resilience. Then, I will validate these molecular targets in preclinical models using advanced whole-brain 3D imaging to map BBB dysfunction and magnetic resonance imaging to investigate neurovascular coupling. These findings will be cross-referenced to human neuroimaging datasets. This multidisciplinary approach could lead to novel treatments for stress-related psychiatric disorders by revealing the neurovascular basis of sex differences in MDD and PTSD.