Validation of Immune Dysfunction in Model of Social Stress: Implications for Major Depression Disorder in Veterans

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Project Summary/Abstract At least 30% of Afghanistan and Iraq veterans are affected by Major Depressive Disorder (MDD) and 20% are affected by post-traumatic stress disorder (PTSD) and other stress-related mood disorders. Currently existing pharmacological treatments elicit temporary remission in <50% of patients; thus, there is an urgent need for novel therapeutic approaches to target MDD and psychological stress-related mood disorders. The prevalence of MDD is two- to threefold higher in patients with cardiovascular disease and MDD is associated with 80% increased risk of cardiovascular morbidity and mortality. Clinical studies report higher levels of circulating pro- inflammatory cytokines in patients with MDD and has been replicated in preclinical animal studies of depression. Individual differences in the modulation of cytokine release (most notably IL-6) are associated with susceptibility vs. resilience to chronic social stress in mice. Chronic inflammation and increases in circulatory pro-inflammatory cytokines associated with stress-induced depression is linked with atherosclerotic plaque formation, progression, and rupture, likely contributing to the pathogenesis of cardiovascular disease. Indeed, immune modulatory approaches to neutralize inflammatory cytokines in the periphery produce antidepressant- like behavioral effects following Chronic Social Defeat Stress (CSDS) in mice as well as in humans with depression and chronic inflammation. The concept of resilience, the ability to maintain normal psychological and physical functioning to avoid serious mental illness has topic of significant interest in Veterans during and post-deployment after exposure to psychological stress.Recently, CSDS-associated depression has been linked to impairment of the blood brain barrier (BBB), a series of protective layers including endothelial cells and astrocytes that plays a critical role in maintaining vascular impermeability between the periphery and brain parenchyma. The proposed validation studies implicate that impairment of the BBB may be causally associated with stress-induced mood disorders. In particular, we will validate and expand our understanding how stress influences the region-dependent impairment of the BBB in stress-induced mood disorders, as previously reported by our collaborators Scott Russo, Anne Schaefer, and Miriam Merad in their publication “Social stress induces neurovascular pathology promoting depression”. Using a well-characterized CSDS model of psychological stress in mice that recapitulates many of the symptoms of MDD including social withdrawal, anhedonia, and anxiety, we will explore through novel technological approaches how chronic psychological stress impairs the BBB. In particular, we will utilize a novel endothelial-specific Translating Ribosome Affinity Purification (TRAP) mouse to explore stress-induced transcriptional patterns in multiple mood-related brain regions to determine transcriptomic patterns to psychological stress. To further explore how psychological stress impairs the BBB, we will utilize an innovative mass cytometry (CyTOF) to determine the immune cell profiles in the periphery and brain tissue of susceptible vs. resilient mice and understand how psychological stress mobilizes the innate immune system and causes infiltration of cytokines into the brain. In summary, the proposal in this Merit Review Award for Validation Studies is of importance to Veteran Health. This VA Merit Review Award is to validate recent findings by our collaborators showing that psychological stress in a model of depression impairs BBB permeability and expand our knowledge into how stress induces region-specific endothelial gene expression changes, leading to vascular damage and depression-linked chronic inflammation. The findings of our studies will provide evidence for preclinical studies for novel therapeutic approaches for treating stress-related MDD for Veterans.