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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的新出现的证据表明，创伤后应激障碍 (PTSD) 是心血管疾病 (CVD) 的有力预测因子。临床研究表明，阻断肾素-血管紧张素系统 (RAS) 对血压至关重要控制和体液稳态——减轻 PTSD 症状的严重程度。 PTSD（巴甫洛夫恐惧调节）临床前小鼠模型表明血管紧张素 1 型受体 (AT1R) 抑制会减弱条件性恐惧反应并促进条件性恐惧的消失。 AT1R 和血管紧张素 2 型受体 (AT2R) 在杏仁核中表达，杏仁核是大脑的关键区域不同的大脑 AT 受体亚型是否在压力中发挥作用。诸如创伤后应激障碍（PTSD）之类的疾病在很大程度上尚不清楚，它们对恐惧中心血管功能障碍的影响也是未知的。然而，我们的初步研究表明，大脑 AT2R 的激活和抑制具有相反的作用。利用多种方法对临床前 PTSD 小鼠模型中恐惧记忆表达的影响。结合生理、分子、分析和行为神经科学的学科方法，该提案将研究内源性脑血管紧张素 II 及其受体（AT1R 和 AT2R）和恐惧记忆和心血管事件相关的下游信号通路我们的工作假设是大脑血管紧张素 II 的表达和活性其受体（AT1R / AT2R）在巩固和回忆过程中受到差异性和动态调节恐惧记忆的变化，并且这些变化有助于兴奋性（“恐惧”）和抑制性的平衡（“恐惧”）存储和检索条件性恐惧记忆所需的信号。建议有两个方面：（1）确定均受大脑调节的信号通路和基因网络 AT1R/AT2R 激活并涉及兴奋性和抑制性信号传导的必要和充分用于恐惧学习和检索；（2）确定 AT1R 和 AT2R 的时空贡献条件性恐惧记忆和心血管表达的关键边缘和下丘脑结构我们有 2 个具体目标：具体目标 1：证明血管紧张素 II 诱导的激活。大脑 AT1R 的存在是维持和重新巩固恐惧记忆以及恐惧记忆所必需的。具体目标 2：证明大脑 AT2R 的激活刺激恐惧--减少神经元和恐惧记忆以及恐惧期间心血管的不良变化这些研究将进一步阐明肾素-血管紧张素系统的机制。作为 PTSD 病理学的重要且新颖的介质，并将提供新的目标和机会用于治疗 PTSD 和 PTSD 相关 CVD 共病的药物干预。