Electronic Poster | Session 1

024 – Sex-specific effects of chronic stress on neurovascular health: implication for sex differences in depression

Laurence Dion-Albert (1) – Alice Cadoret (1) – Fernanda Neutzling Kaufmann (1) – Charles Gora (1) – Katarzyna Dudek (1) – Manon Lebel (1) – Martin Lévesque (1) – Caroline Ménard (1)
CERVO Brain Research Center, Université Laval, Québec, Canada (1)

Major depressive disorder (MDD) is now considered the leading cause of disabilities worldwide and women have a roughly twofold higher risk for MDD than men. Only 30% of patients completely remit, suggesting the neuron-centric traditional treatments do not address important causal biological factors. Clinical studies report higher prevalence of MDD in patients suffering from cardiovascular diseases or stroke, indicating that increased inflammation and vascular dysfunction may contribute to depression pathogenesis. Compared to men, women experience higher rates of autoimmune diseases and inflammation, both of which could elevate depression risk. The great majority of basic and clinical studies on MDD explored biological mechanisms exclusively in males, leading to causal biological factors being omitted. Recent evidence shows that chronic social stress induces blood-brain barrier (BBB) leakiness in a critical structure for stress response in male mice, the nucleus accumbens. This promotes infiltration of harmful peripheral immune signals into the brain leading to establishment of depressive behaviors. Interestingly, not all stressed mice display depressed phenotype and loss of BBB integrity, suggesting that neurovascular adaptations may contribute to stress resilience. However, this has not yet been studied in female mice. Based on this data, I hypothesize that higher rates of inflammation observed in women exacerbate stress-induced BBB leakiness, which would explain heightened vulnerability for MDD. Therefore, I investigate BBB function under a 10-day chronic social defeat stress paradigm, a mouse model of depression mimicking human bullying. Comparison of stress-induced transcriptional pattern of key BBB genes suggests region-specific adaptations in the BBB of stressed males vs females. In parallel, by drawing blood from mice at different time points, I aim to establish a peripheral blood profile correlated with behavioral and transcriptional findings, in order to find promising BBB-related biomarkers of depression and resilience. Mouse findings will be confirmed in human brain and blood samples. It is imperative to study depression as whole-body disorder, as well as considering sex differences as a variable to develop innovative therapeutic strategies to improve women and men’s health worldwide.