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 尽管治疗取得了进展，但约20%的高血压患者患有不受控制的高血压， 与脑心血管控制中心功能障碍有关的疾病。因此，有一个关键的 我们需要了解参与心血管调节的神经通路，以及它们的功能障碍是如何发生的。 会导致高血压这对于由慢性社会性疾病引起的高血压尤其重要。 压力是当今世界的一个主要问题，它涉及神经内分泌和自主神经的激活 机制等我们以前的研究使用新的遗传小鼠模型，病毒介导的基因转移， 光遗传学揭示了细胞核内含有血管紧张素2型受体（AT 2 R）的神经通路 孤束核（NTS）是抗高血压的重要靶点。含AT 2 R的NTS神经元的激活 [称为NTSAT 2 R神经元]引起血压显著升高;相反，AT 2 R本身 起负调节作用，因为它们的激活降低了正常和 高血压病基于我们的研究结果，我们提出了NTSAT 2 R神经元是一个神经元的假说。 神经通路的重要组成部分，介导由慢性社会压力引起的高血压。 具体来说，我们预测，在慢性社会压力下，他们的活动是由兴奋性（兴奋性）输入驱动的。 从下丘脑室旁核（PVN），他们反过来提高血压通过两个 机制：GABA能NTSAT 2 R神经元的激活，其是含有AT 2 R的最大群体。 NTS中的细胞，兴奋性压力反射抑制;谷氨酸能NTSAT 2 R神经元的激活，其投射到更高的 PVN等顺序脑区增加交感神经流出和神经内分泌。我们进一步 预测选择性激活NTS神经元上的AT 2 R（s）将抵消社会应激诱导的高血压 通过恢复压力反射功能和使交感神经流出和神经内分泌正常化。我们的整体 假设将在三个目标中进行测试，这些目标利用小鼠中的新型高血压模型（慢性社会失败 应激[CSDS]）沿着遗传（例如，光遗传学和化学遗传学）和药理学方法。目的 1：解剖影响和调节NTSAT 2 R神经元的特定神经回路，将测试特定的神经元回路。 假设PVN输入NTSAT 2 R神经元是必要的，足以促进CSDS高血压。 目的2：研究GABA能与谷氨酸能NTSAT 2 R神经元在脑缺血中的不同机制作用。 高血压期间血压的调节，将检验GABA能NTSAT 2 R 神经元抑制压力感受性反射，而神经元PVN投射NTSAT 2 R神经元刺激加压素 神经元和交感神经流出。目的3：靶向NTSAT 2 R神经元以减轻CSDS高血压， 测试NTSAT 2 R神经元是CSDS高血压发展所必需的特定假设， 这些神经元或AT 2 R可能是缓解它的靶点。总的来说，这些研究将提供机制 这可能指导新疗法开发以治疗由社会压力引起的高血压。