Central Nervous System Reprogramming of the Control of Blood Pressure Induced by Early Life Stress

早期生活压力引起的血压控制的中枢神经系统重新编程

• 批准号: 10555126
• 负责人: ALAN Kim JOHNSON
• 金额: $ 38.91万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555126
• 关键词: Acute; Address; Adult; Affect; Animals; Anti-Inflammatory Agents; Behavioral; Blood Pressure; Blood Vessels; Brain; Butyrates; Cardiovascular system; Cell Nucleus; Central Nervous System; Cerebrovascular system; Clinical; Collaborations; Consumption; Diet; Dietary Factors; Dietary Fats; Dietary Intervention; Disease; Eating; Epidemiology; Epigenetic Process; Etiology; Exercise; Exposure to; Fatty acid glycerol esters; Female; Foundations; Genetic; Glean; Hypertension; Immune system; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Knowledge; Laboratories; Life; Macrophage; Macrophage Activation; Mediating; Mediator; Mental disorders; Methods; Modeling; Molecular; Mothers; Mus; Nervous System; Neural Pathways; Neuroanatomy; Neuronal Plasticity; Oxidative Stress; Pathogenesis; Pathology; Pharmaceutical Preparations; Physiological; Play; Process; Psychological Stress; Rattus; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Rodent; Rodent Control; Role; Sex Differences; Site; Stimulus; Sympathetic Nervous System; Testing; Vascular Diseases; Weaning; Work; adverse childhood events; blood pressure control; blood pressure elevation; blood pressure regulation; brain pathway; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; comparison control; cytokine; design; dietary; dietary salt; early life stress; experimental study; high salt diet; hypertensive; innovation; insight; male; maternal separation; neural network; neuroinflammation; novel; pharmacologic; postnatal; pre-clinical; prevent; programs; psychologic; psychological stressor; pup; resilience; response; sexual dimorphism; stressor; synergism; translational pipeline

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 understanding the etiology and pathogenesis of essential HT and will provide valuable insights into intervention strategies for preventing high blood pressure.

项目二总结