Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

研究缓解压力的神经回路以减轻心血管疾病

• 批准号: 9893161
• 负责人: Eric Gerald Krause
• 金额: $ 73.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9893161
• 关键词: Angiotensin Receptor; Angiotensin Type 1a Receptor; Angiotensins; Attenuated; Blood Pressure; Brain region; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Corticosterone; Coupled; Development; Disease; Energy Metabolism; Etiology; Event; Functional disorder; Gene Transfer; Genes; Genetic; Heart Rate; Human; Intervention; Laboratory mice; Life; Link; Mediating; Modeling; Modernization; Mus; Nervous system structure; Neurons; Neurosciences; Neurosecretory Systems; Nodose Ganglion; Perception; Pharmacology; Physiology; Population; Predisposition; Pressoreceptors; Psychological Stress; Research; Stress; Structure; System; Techniques; Treatment Efficacy; Type 2 Angiotensin II Receptor; United States; Viral; anxiety-like behavior; behavioral response; blood pressure reduction; cardiovascular health; experimental study; genetic technology; improved; in vivo; indexing; insight; neural circuit; neural patterning; novel therapeutics; optogenetics; preclinical study; receptor; recombinase-mediated cassette exchange; relating to nervous system; resilience

Project Summary Stressful life events are linked to the etiology of cardiovascular disease (CVD), which is the leading cause of death in the U.S. The mechanisms by which stress causes pathophysiology contributing to CVD are poorly understood and effective therapeutics that relieve stress and improve cardiovascular health are lacking. A premise of this proposal is that exploration of the neural circuits controlling the perception of stress may provide insight towards mechanisms underlying CVD and interventions aimed at its reversal. Causally-linking patterns of neural activity to stress and the development of CVD in humans is challenging. However, preclinical studies using laboratory mice that implement modern neuroscience and genetic technologies to excite or inhibit specific neural circuits make causally-linking neural activity and indices of stress responsiveness achievable. Using genetically-modified mice, we revealed that the activity of neurons that express genes encoding particular angiotensin receptor subtypes is coupled to cardiovascular, neuroendocrine and behavioral responses to stress. Specifically, we discovered that neurons expressing the angiotensin type-2 (AT2R) and Mas receptor (MasR) densely populate cortical and limbic brain regions controlling the perception of psychological stress and that excitation of these neurons decreases blood pressure, heart rate, circulating levels of corticosterone and anxiety- like behavior. In the periphery, we discovered that the nodose ganglion is densely populated by neurons expressing the angiotensin type 1a receptor (AT1R). These neurons function as primary baroreceptor afferents and excitation of these neurons lowers blood pressure, heart rate and energy expenditure. Collectively, these observations have led to the overall hypothesis that excitation of particular neuronal populations that express the AT1R, AT2R or MasR alters the perception of stress to protect against CVD. Experiments will use the Cre-LoxP system in mice with a cadre of modern neuroscience techniques and classical systems physiology to confirm or refute this hypothesis. Initial experiments utilize Cre-diver mice with virally-mediated gene transfer and in vivo optogenetics to determine whether the excitation or inhibition of neurons that express AT1R, AT2R, or MasR attenuates or exacerbates stress responding. Subsequent experiments use a model of stress-induced pathophysiology to evaluate how the structure and function of neurons that express the AT1R, AT2R or MasR is altered by disease. The final experiments attempt to alleviate stress-induced pathophysiology with optogenetic, genetic or pharmacological manipulations that alter the excitability of neurons that express the AT1R, AT2R or MasR. We anticipate that the proposed research will reveal, at a detailed and mechanistic level, neural circuits that provide stress relief, thereby guiding development of novel therapeutics for CVD.

项目摘要 压力性生活事件与心血管疾病（CVD）的病因有关，这是 在美国死亡，压力导致病理生理学的机制造成CVD的差异很差 缺乏缓解压力并改善心血管健康的有效治疗剂。一个 该提议的前提是，探索控制压力感知的神经回路可能会提供 对CVD和干预措施的基础机制的洞察力。因果关系模式 在人类中为压力和CVD的发展的神经活动具有挑战性。但是，临床前研究 使用实施现代神经科学和遗传技术的实验室小鼠来激发或抑制特定 神经回路使可因果关系的神经活动和应激反应能力的指标可实现。使用 遗传改性的小鼠，我们揭示了表达编码特定基因的神经元的活性 血管紧张素受体亚型与心血管，神经内分泌和对压力的行为反应耦合。 具体而言，我们发现表达血管紧张素2（AT2R）和MAS受体（MASR）的神经元（MASR） 密集的皮质和边缘大脑区域控制着心理压力的感知，并 这些神经元的激发降低了血压，心率，皮质酮的循环水平和焦虑 喜欢行为。在外围，我们发现淋巴神经节密度被神经元构成 表达血管紧张素1A型受体（AT1R）。这些神经元充当主要的压力感受器传入 这些神经元的激发降低了血压，心率和能量消耗。总的来说，这些 观察结果导致了总体假设，即特定神经元种群的激发 表达AT1R，AT2R或MASR改变了应力的感知以防止CVD。实验会 使用现代神经科学技术和经典系统的干部在小鼠中使用CRE-LoxP系统 生理学确认或反驳这一假设。最初的实验利用病毒介导的Cre-Diver小鼠 基因转移和体内光遗传学，以确定表达神经元的激发或抑制 AT1R，AT2R或MASR减弱或加剧压力。随后的实验使用 压力诱导的病理生理学，以评估表达AT1R的神经元的结构和功能如何 AT2R或MASR被疾病改变。最终的实验试图减轻压力诱导的病理生理学 使用光遗传学，遗传或药理操纵，改变了表达神经元的兴奋性 AT1R，AT2R或MASR。我们预计拟议的研究将在详细的机械水平上揭示 提供缓解压力的神经回路，从而指导开发CVD的新型治疗剂。