PROJECT 2 SUMMARY Early life stress (ELS) acts as a strong etiological factor establishing conditions for subsequent stressors to trigger many psychological and physiological disorders. There is a strong association between adverse childhood experiences and cardiometabolic pathologies, including hypertension. When studying the role of the central nervous system (CNS) in the long-term regulation of blood pressure (BP), we discovered that the hypertensive response can be sensitized by exposure to mild stressors present earlier in life. Both Dr. Pollock’s laboratory (Project 1) and our laboratory (Project 2) have found that the psychological stress produced by repeated brief periods of maternal separation of rodent pups from their mothers (MaSep) will produce hypertensive response sensitization (HTRS). Our studies suggest that CNS inflammatory mechanisms play a key role in inducing and maintaining HTRS and therefore increased risk for cardiovascular disease. The central hypothesis of Project 2 is that the psychological stress of MaSep produces inflammatory mediators that reprogram the central neural network controlling sympathetic tone and BP and thereby exacerbates hypertension when new stressors are encountered in adulthood. Unfortunately, there are critical gaps in our understanding of exactly how ELS acts to induce the reprogramming of the CNS and maintain HTRS especially when it is expressed by ecologically relevant stressors such as eating high fat and high salt diets. Furthermore, we do not know what specific interventions can reverse the effects of ELS. The Specific Aims of Project 2 are designed to address these issues. Specific Aim 1 studies will determine whether the dietary risk factors of high dietary fat or salt (i.e., “second hits”) consumed after weaning exacerbate the hypertensive response in adult MaSep animals. Also, key brain nuclei controlling sympathetic tone and BP will be analyzed to identify molecular changes mediating HTRS. Specific Aim 2 will test the role of CNS inflammatory mechanisms in MaSep induction of HTRS and investigate strategies to reverse the effects of MaSep ELS and produce resilience. Project 2 is conceptually and technically innovative in that it tests an original hypothesis of how ELS sensitizes the hypertensive response to elicit frank HT in adults by using an experimental paradigm developed by the Johnson laboratory to separate the effects of HTRS induction from HTRS expression. Project 2 findings will provide important new information that will be relevant for directing the interpretation of results from other projects. Projects 1 and 2 enhance one another by both investigating the role of brain macrophages and inflammation in ELS-specific vascular dysfunction and HTRS. Project 2 will provide key mechanistic insights to both clinical projects (3 and 4) by clarifying involvement of dietary metabolites, exercise, and inflammation. New knowledge gained about mechanisms involved in HTRS will contribute to un...