Brain Angiotensin II as a Mediator of Fear Memory and Cardiovascular Dysfunction

脑血管紧张素 II 作为恐惧记忆和心血管功能障碍的调节剂

• 批准号: 9924153
• 负责人: Paul J Marvar
• 金额: $ 4.59万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924153
• 关键词: Affect; Amygdaloid structure; Angiotensin II; Angiotensin II Receptor; Anxiety; Attenuated; Autonomic Dysfunction; Autoradiography; Award; Bacterial Artificial Chromosomes; Behavior; Behavioral; Blood Pressure; Brain; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular alteration; Cardiovascular system; Cell Nucleus; Clinical; Clinical Research; Comorbidity; Corticotropin-Releasing Hormone; Cre-LoxP; Data; Diagnosis; Disease; Electrolytes; Emotional; Emotional Stress; Equilibrium; Event; Exposure to; Extinction (Psychology); Freezing; Fright; Functional disorder; Gene Expression; Goals; Heart Rate; Homeostasis; Hypertension; Hypothalamic structure; Image; Immunofluorescence Immunologic; Impairment; Individual; Intervention; Investigation; Laboratories; Learning; Link; Liquid substance; LoxP-flanked allele; Maintenance; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Memory; Modeling; Molecular; Monitor; Mus; Myocardial; Neurons; Neuropeptides; Neuropsychology; Neurosciences; Pathologic; Pathology; Peptides; Pharmacology; Phase; Physiological; Play; Post-Traumatic Stress Disorders; Predisposition; Process; Publishing; Receptor Activation; Receptor Cross-Talk; Receptor Inhibition; Receptor Signaling; Receptor, Angiotensin, Type 1; Recovery; Renin-Angiotensin System; Reporter; Retrieval; Risk; Role; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stress; Stroke; Structure; Symptoms; Synapses; System; Tachycardia; Technology; Testing; Transgenic Organisms; Trauma; Type 2 Angiotensin II Receptor; anxiety-related disorders; blood pressure regulation; conditioned fear; fear memory; inhibitory neuron; interdisciplinary approach; learning extinction; memory consolidation; mouse model; novel; pre-clinical; preclinical study; psychological trauma; receptor; response; spatiotemporal; stress disorder; stress related disorder; therapeutic target

ABSTRACT Emerging evidence suggests that PTSD is a strong predictor of cardiovascular disease (CVD). Recent clinical studies suggest that blockade of the renin-angiotensin system (RAS)—crucial to blood pressure control and fluid homeostasis—reduces the severity of PTSD symptoms. We have also demonstrated in a preclinical mouse model of PTSD (Pavlovian fear conditioning) that angiotensin type 1 receptor (AT1R) inhibition attenuates conditioned fear responses and facilitates the extinction of conditioned fear. Both AT1Rs and angiotensin type 2 receptors (AT2Rs) are expressed in the amygdala, a brain region critical for fear learning and extinction. Whether different brains AT receptor subtypes play a role in stress disorders such as PTSD is largely unknown, as is their impact on cardiovascular dysfunction in fear. Our preliminary studies suggest, however, that activation and inhibition of brain AT2Rs have opposing effects on the expression of fear memory in a preclinical mouse model of PTSD. Utilizing a multi- disciplinary approach that combines physiological, molecular, analytical and behavioral neuroscience, this proposal will investigate the role of endogenous brain angiotensin II, its receptors (AT1R and AT2R) and downstream signaling pathways in fear memory and cardiovascular events associated with conditioned fear. Our working hypothesis is that the expression and activity of brain angiotensin II and its receptors (AT1R / AT2R) are differentially and dynamically regulated during the consolidation and recall of fear memory, and that these changes contribute to the balance of excitatory (“fear-on”) and inhibitory (“fear-off”) signals required for the storage and retrieval of conditioned fear memories. The goals of this proposal are two-fold: (1) Identify signaling pathways and gene networks that are both regulated by brain AT1R/AT2R activation and implicated in the excitatory and inhibitory signaling necessary and sufficient for fear learning and retrieval; (2) Determine the spatio-temporal contributions of AT1Rs and AT2Rs in key limbic and hypothalamic structures on the expression of conditioned fear memories and cardiovascular alterations. We have 2 specific aims. Specific Aim 1: To demonstrate that angiotensin II-induced activation of brain AT1Rs is necessary and required for the maintenance and reconsolidation of fear memory and the conditioned cardiovascular responses. Specific Aim 2: To demonstrate that activation of brain AT2Rs both stimulates fear- off neurons and reduces fear memory and adverse cardiovascular changes during fear conditioning. These studies will further elucidate the mechanism(s) by which the renin- angiotensin system acts as an important and novel mediator of PTSD pathology, and will provide new targets and opportunities for pharmacological interventions in PTSD and PTSD-related CVD co-morbidity.

抽象的 新兴证据表明，PTSD是心血管疾病（CVD）的有力预测指标。最近的 临床研究表明，对血压至关重要的肾素 - 血管紧张素系统（RAS）的封锁 控制和液体稳态 - 降低了PTSD症状的严重程度。我们也在 PTSD的临床前小鼠模型（Pavlovian恐惧调节），血管紧张素1型受体（AT1R） 抑制作用减轻了有条件的恐惧反应，并促进了条件恐惧的扩展。两个都 AT1RS和血管紧张素2型受体（AT2R）在杏仁核中表达，杏仁核是大脑区域的关键 恐惧学习和扩展。受体亚型的不同大脑是否在压力中​​起作用 PTSD等疾病在很大程度上是未知的，它们对恐惧中心血管功能障碍的影响也是如此。 但是，我们的初步研究表明，大脑AT2R的激活和抑制具有相反 PTSD的临床前小鼠模型中恐惧记忆表达的影响。利用多 结合物理，分子，分析和行为神经科学的纪律方法， 该提案将调查内源性脑血管紧张素II，其接收器的作用（AT1R和 AT2R）和恐惧记忆和心血管事件中的下游信号通路 有条件的恐惧。我们的工作假设是，脑血管紧张素II和 它的受体（AT1R / AT2R）在整合过程中受到差异性和动态调节 恐惧记忆，这些变化有助于兴奋平衡（“恐惧”）和抑制性 （“恐惧”）存储和检索条件恐惧记忆所需的信号。目标的目标 提案是两个倍：（1）识别均由大脑调节的信号通路和基因网络 AT1R/AT2R激活，与练习和抑制信号有关，必要和足够 因为恐惧学习和检索； （2）确定AT1RS和AT2RS的时空贡献 关于条件恐惧记忆和心血管表达的关键边缘和下丘脑结构 改变。我们有2个具体目标。特定目标1：证明血管紧张素II诱导的激活 大脑AT1RS的维护和重新整合是必要的，并且需要 条件心血管反应。特定目的2：证明大脑AT2RS的激活 刺激恐惧 - 神经元，减少恐惧记忆和恐惧期间不良心血管变化 调理。这些研究将进一步阐明肾素血管紧张素系统的机制 充当PTSD病理学的重要且新颖的调解人，将提供新的目标和机遇 用于PTSD和PTSD相关CVD合并症的药物干预措施。