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

摘要 新出现的证据表明，PTSD是心血管疾病（CVD）的一个强有力的预测因子。最近 临床研究表明，阻断对血压至关重要的肾素-血管紧张素系统（RAS）， 控制和体液平衡-减少创伤后应激障碍症状的严重性。我们还在一个 PTSD（巴甫洛夫恐惧条件反射）的临床前小鼠模型，血管紧张素1型受体（AT 1 R） 抑制减弱条件性恐惧反应并促进条件性恐惧的消除。两 AT 1 R和血管紧张素2型受体（AT 2 R）在杏仁核中表达，杏仁核是大脑中的一个关键区域， 恐惧学习和灭绝。不同的大脑AT受体亚型是否在应激中起作用 创伤后应激障碍等疾病在很大程度上是未知的，因为它们对恐惧心血管功能障碍的影响。 然而，我们的初步研究表明，大脑AT 2 R的激活和抑制具有相反的作用。 对PTSD临床前小鼠模型中恐惧记忆表达的影响。利用多- 学科方法，结合生理，分子，分析和行为神经科学， 这项建议将研究内源性脑血管紧张素II，其受体（AT 1 R和 AT 2 R）和下游信号通路在恐惧记忆和心血管事件中的作用 条件性恐惧我们的工作假设是，大脑血管紧张素II和血管紧张素II的表达和活性， 其受体（AT 1 R/AT 2 R）在巩固和回忆过程中受到不同的动态调节 这些变化有助于兴奋性（“恐惧”）和抑制性记忆的平衡。 （“恐惧关闭”）的信号所需的存储和检索条件的恐惧记忆。这个的目标 建议有两个方面：（1）确定信号通路和基因网络，都是由大脑调节 AT 1 R/AT 2 R激活并参与兴奋性和抑制性信号传导是必要和充分的 （2）确定AT 1 R和AT 2 R在恐惧学习和提取中的时空贡献。 关键的边缘系统和下丘脑结构对条件性恐惧记忆和心血管 改变。我们有两个具体目标。具体目的1：证明血管紧张素II诱导的激活 大脑AT 1 R的水平是必要的，并且是维持和重新巩固恐惧记忆所必需的， 条件性心血管反应具体目标2：证明大脑AT 2 R的激活 刺激恐惧神经元，减少恐惧记忆和恐惧期间心血管的不良变化。 条件反射这些研究将进一步阐明肾素-血管紧张素系统 作为PTSD病理学的一个重要的和新的介质，并将提供新的靶点和机会 用于PTSD和PTSD相关CVD合并症的药物干预。

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.