Peripheral effectors in alcohol-induced stress-susceptibility and blood-brain barrier permeability - Project Summary Individuals who chronically use alcohol have higher rates of psychological and biological perturbations including a higher incidence of mood-related disorders, inflammatory diseases, and cancers. Although we often focus on heavy drinking as being a cause for concern, problematic drinking patterns evolve from recreational use where repeated alcohol consumption alters homeostatic central and peripheral mechanisms. Recent work has suggested that the blood-brain barrier (BBB) is a critical interface that supports appropriate reactions to stress- eliciting stimuli, but how alcohol impacts BBB integrity and the subsequent peripheral/central interactions, remains largely understudied. Using a rodent model of volitional binge-drinking, I have found that chronic exposure to alcohol increases peripheral inflammation and promotes stress-susceptibility, even after a protracted withdrawal period. Moreover, mice with a history of alcohol have increased circulating levels of neutrophils at baseline and show an exaggerated release of the serine protease, neutrophil elastase, in response to a mild social stressor. Given the proteolytic nature of neutrophil elastase, I will use novel approaches to identify region- specific alcohol-induced BBB permeability and characterize the underlying mechanisms contributing to BBB breakdown with a focus on understanding neutrophil: endothelial cell interactions and how they contribute to complex mood-related behavioral alterations. Importantly, I have begun to investigate how inhibition of neutrophil elastase can promote adaptive responses to stress-eliciting situations. The data I have collected thus far support a novel peripheral mechanism by which alcohol exposure mediates stress-susceptibility and offers insight into managing peripherally-mediated CNS dysfunction. I am confident that this multifaceted approach will provide the scientific community with novel insights that can help guide the development of innovative therapeutic approaches targeting the immune system, which are desperately needed in the field of comorbid substance use and mood disorders.
