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: 10331014
• 负责人: Eric Gerald Krause
• 金额: $ 86.14万
• 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/10331014
• 关键词: Angiotensin Receptor; Angiotensin Type 1a Receptor; Angiotensins; Attenuated; Blood Pressure; Brain region; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Corticosterone; Coupled; Cre lox recombination system; Development; Disease; Energy Metabolism; Etiology; Functional disorder; Gene Transfer; Genes; Genetic; Heart Rate; Human; Intervention; Laboratory mice; Link; Mediating; Modeling; Modernization; Mus; Nervous system structure; Neurons; Neurosciences; Neurosecretory Systems; Nodose Ganglion; Perception; Pharmacology; Physiology; Population; Predisposition; Pressoreceptors; Psychological Stress; Research; Stress; Stressful Event; Structure; System; Techniques; 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; perceived stress; preclinical study; receptor; relating to nervous system; resilience; therapeutically effective

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，心血管疾病是导致心血管疾病的主要原因。 压力导致心血管疾病的病理生理机制很差 缺乏缓解压力和改善心血管健康的已知和有效的治疗方法。一 这一建议的前提是，探索控制压力感知的神经回路可能会提供 深入了解CVD的潜在机制和旨在逆转CVD的干预措施。因果联系模式 神经活动的压力和发展的心血管疾病在人类是具有挑战性的。然而，临床前研究 使用实验室小鼠，实现现代神经科学和遗传技术，以激发或抑制特定的 神经回路使得神经活动和应激反应指数之间的因果联系成为可能。使用 在转基因小鼠中，我们发现表达特定编码基因的神经元的活动， 血管紧张素受体亚型与对压力的心血管、神经内分泌和行为反应相关。 具体来说，我们发现表达血管紧张素2型（AT 2 R）和Mas受体（MasR）的神经元 密集分布在控制心理压力感知的皮层和边缘脑区域， 这些神经元的兴奋会降低血压、心率、皮质酮的循环水平和焦虑， 比如行为在外周，我们发现结状神经节是密集的神经元 表达血管紧张素1a型受体（AT 1 R）。这些神经元的功能是初级压力感受器传入 这些神经元的兴奋会降低血压、心率和能量消耗。总的来说，这些 观察结果导致了一个总的假设，即特定神经元群的兴奋， 表达AT 1 R，AT 2 R或MasR改变了对压力的感知，以防止CVD。实验将 在小鼠中使用Cre-LoxP系统，使用现代神经科学技术和经典系统 生理学来证实或反驳这一假设。最初的实验利用Cre-diver小鼠， 基因转移和体内光遗传学，以确定是否兴奋或抑制神经元表达， AT 1 R、AT 2 R或MasR减弱或加剧应激反应。随后的实验使用一个模型， 应激诱导的病理生理学，以评估表达AT 1 R的神经元的结构和功能， AT 2 R或MasR因疾病而改变。最后的实验试图减轻压力引起的病理生理学 通过光遗传学、遗传学或药理学操作改变表达神经元的兴奋性， AT 1 R、AT 2 R或MasR。我们预计，拟议的研究将揭示，在详细和机械的水平， 神经回路，提供压力缓解，从而指导开发新的治疗CVD。