Angiotensin-sensitive neurons in the nucleus of the solitary tract mediate social stress induced hypertension

孤束核中血管紧张素敏感神经元介导社会压力诱发的高血压

• 批准号: 10668569
• 负责人: COLIN SUMNERS
• 金额: $ 61.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668569
• 关键词: Acute; Angiotensins; Antihypertensive Agents; Area; Baroreflex; Blood Pressure; Brain; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cells; Central Nervous System; Characteristics; Chronic; Data; Development; Diagnosis; Disease; Functional disorder; Gene Transfer; Genetic; Glutamates; Homeostasis; Hypertension; Hypothalamic structure; Individual; Life Expectancy; Liquid substance; Mediating; Modeling; Mus; Neural Pathways; Neurons; Neurosecretory Systems; Nucleus solitarius; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Publishing; Regulation; Resistant Hypertension; Role; Social status; Societies; Stress; Stroke; Testing; Therapeutic; Type 2 Angiotensin II Receptor; Vasopressins; Viral; biological adaptation to stress; blood pressure elevation; blood pressure reduction; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; hypertensive; insight; mouse model; neural circuit; neural patterning; novel; novel strategies; novel therapeutics; optogenetics; paraventricular nucleus; pharmacologic; prevent; social adversity; social defeat; social stress; vasoconstriction

Project Summary Despite therapeutic advances, ~20% of patients with hypertension have uncontrolled high blood pressure, a condition that is associated with dysfunction in brain cardiovascular control centers. Therefore, there is a critical need to understand the neural pathways involved in cardiovascular regulation and how their dysfunction contributes to high blood pressure. This is particularly important for hypertension that is induced by chronic social stress, a major problem in today’s world, which involves activation of neuroendocrine and autonomic mechanisms. Our previous studies using novel genetic mouse models, viral-mediated gene transfer and optogenetics have revealed angiotensin type-2 receptor (AT2R)-containing neural pathways within the nucleus of the solitary tract (NTS) as important anti-hypertensive targets. Activation of AT2R-containing NTS neurons [referred to as NTSAT2R neurons] elicits profound increases in blood pressure; in contrast the AT2R(s) themselves serve a negative regulatory function, as their activation decreases blood pressure under both normal and hypertensive conditions. Based on our findings, we have developed the hypothesis that NTSAT2R neurons are a critical component of the neural pathways that mediate hypertension induced by chronic social stress. Specifically, we predict that during chronic social stress their activity is driven by excitatory (glutamatergic) inputs from the paraventricular nucleus of the hypothalamus (PVN), and that they in turn raise blood pressure via two mechanisms: Activation of GABAergic NTSAT2R neurons, which are the largest population of AT2R containing cells in the NTS, elicits baroreflex inhibition; Activation of Glutamatergic NTSAT2R neurons, which project to higher order brain regions such as the PVN, increases sympathetic outflow and neuroendocrine secretion. We further predict that selective activation of AT2R(s) present on NTS neurons will offset social stress-induced hypertension by restoring baroreflex function and normalizing sympathetic outflow and neuroendocrine secretions. Our overall hypothesis will be tested in three Aims that utilize a novel model of hypertension in mice (Chronic Social Defeat Stress [CSDS]) along with genetic (e.g., optogenetic and chemogenetic) and pharmacological approaches. Aim 1: Dissecting a specific neural circuit that impinges on and regulates NTSAT2R neurons, will test the specific hypothesis that PVN inputs to NTSAT2R neurons are necessary and sufficient to promote CSDS hypertension. Aim 2: Investigating distinct mechanistic roles for GABAergic vs. glutamatergic NTSAT2R neurons in regulation of blood pressure during hypertension, will test the specific hypothesis that GABAergic NTSAT2R neurons inhibit the baroreflex, while glutamatergic PVN-projecting NTSAT2R neurons stimulate vasopressin neurons and sympathetic outflow. Aim 3: Targeting NTSAT2R neurons to alleviate CSDS hypertension, will test the specific hypotheses that NTSAT2R neurons are necessary for the development of CSDS hypertension, and that these neurons or AT2R may be targeted to alleviate it. Collectively, these studies will provide mechanistic insight that may direct development of novel therapeutics to treat hypertension induced by social stress.

项目摘要 尽管有治疗性进步，但约有20％的高血压患者无法控制高血压，A 与心脏血管控制中心功能障碍有关的状况。因此，有一个关键 需要了解心血管调节中涉及的神经途径以及其功能障碍 导致高血压。这对于由慢性社会引起的高血压特别重要 压力是当今世界上的主要问题，涉及神经内分泌和自主神经的激活 机制。我们先前使用新型遗传小鼠模型，病毒介导的基因转移和 光遗传学揭示了细胞核内的血管紧张素2受体（AT2R）的神经途径 固体道（NTS）作为重要的抗高血压靶标。激活含AT2R的NTS神经元 [称为NTSAT2R神经元]引起血压的巨大升高；相反，AT2R本身 在正常和 高血压条件。根据我们的发现，我们提出了一个假设，即NTSAT2R神经元是一个 介导由慢性社会压力引起的高血压的神经病道的关键组成部分。 具体而言，我们预测在慢性社会压力期间，它们的活动是由兴奋性（谷氨酸能）输入驱动的 从下丘脑（PVN）的室室核，并通过两个 机制：GABA能NTSAT2R神经元的激活，该神经元是含有AT2R的最大群体 NTS中的细胞会引起压力反射抑制作用；谷氨酸能NTSAT2R神经元的激活，该神经元较高 诸如PVN之类的大脑区域增加了交感神经出口和神经内分泌分泌。我们进一步 预测NTS神经元上存在的AT2R的选择性激活将抵消社会压力引起的高血压 通过恢复压力反射功能并使交感神经出口和神经内分泌分泌正常化。我们的整体 假设将以三个利用小鼠的高血压模型（慢性社会失败）进行测试 压力[CSD]）以及遗传（例如，光遗传学和化学遗传学）和药物方法。目的 1：剖析撞击和调节NTSAT2R神经元的特定神经元电路，将测试特定 假设PVN输入NTSAT2R神经元是必要的，足以促进CSD高血压。 AIM 2：研究GABA能与谷氨酸能NTSAT2R神经元的不同机械作用 高血压期间血压调节，将检验以下特定假设：GABA能NTSAT2R 神经元抑制降压力，而谷氨酸能PVN-PVN射击NTSAT2R神经元刺激加压素 神经元和同情出口。目标3：靶向NTSAT2R神经元以减轻CSD高血压，将 测试特定的假设，即NTSAT2R神经元对于开发CSD高血压是必需的， 这些神经元或AT2R可能是针对减轻它的。总的来说，这些研究将提供机理 可能会导致新疗法发展以治疗社会压力引起的高血压的见解。