SUMMARY FOR PROJECT 1 Psychosocial stress has a major impact on cardiovascular health. Over the last 5 years of this PPG, we have identified tissue, cellular, and molecular pathways that connect nervous, immune, and vascular systems during stress. In this renewal, we will focus on identifying specific nodes of communication that link brain regions with the vessel wall during the progression of cardiovascular disease. We will broaden our studies to explore how neuroimmune and neurovascular connections are altered in the context of different stress perceptions. Specifically, we will first seek to identify brain circuits and peripheral pathways linking psychosocial stress with cardiovascular disease and then elucidate how resilience vs susceptibility to social defeat stress shapes communication between brain and periphery in cardiovascular disease and its resolution. We will build on preliminary data showing that acute stress elicits a profound spatial reorganization of four major leukocyte classes, characterized by a mass migration of lymphoid and myeloid cells known to be important in cardiovascular disease and noting that there is important difference in atherosclerosis progression between resilient and susceptible mice. We hypothesize that distinct brain regions dynamically regulate monocyte, neutrophil, and lymphocyte function and spatial distribution, influencing the development, progression, and complications of atherosclerosis and that one or more of these pathways is critical during social defeat stress. We will use sophisticated approaches and models, including optogenetics and chemogenetics. Together, we will elucidate the communication network linking the brain with the vasculature and atherosclerosis during resilience and susceptibility to social stress.