Hypothalamic Plasticity Enabling Slow Pressor Hypertension

下丘脑可塑性促进缓慢升压高血压

• 批准号: 7760720
• 负责人: VIRGINIA M PICKEL
• 金额: $ 33.34万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760720
• 关键词: Affect; Angiotensin II; Angiotensinogen; Angiotensins; Astrocytes; Attenuated; Bilateral; Brain; Brain Stem; Brain region; Calcium Channel; Cardiovascular system; Carotid Body; Chronic; Core Facility; Development; Dose; Electrons; Exposure to; Free Radicals; Functional disorder; Glutamates; Glutamine; Hormonal; Hypertension; Hypothalamic structure; Hypoxia; Image; Infusion procedures; Link; Location; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Microscopic; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NADP; NADPH Oxidase; NR1 gene; Neurons; Neuropeptides; Output; Patients; Physiological; Pituitary Gland; Play; Production; Property; Prosencephalon; Protein Isoforms; Reactive Oxygen Species; Research; Resolution; Role; Signal Transduction; Site; Source; Spinal; Structure; Subfornical Organ; Surface; Synapses; Synaptic plasticity; Tail; Telemetry; Testing; Thoracic spinal cord structure; Time; cerebrovascular; comparative; depression; human AKAP13 protein; in vivo; inhibitory neuron; insight; male; mouse model; paraventricular nucleus; patch clamp; postsynaptic; pressure; receptor; receptor-mediated signaling; retrograde transport; transmission process

PROJECT 2 (Pickel): Hypothalamic plasticity enabling slow pressor hypertension Neurohumoral output neurons in the hypothalamic paraventricular nucleus (PVN) are activated by glutamateand Angll-containing neuronal inputs from the subfornical organ (SFO), a brain structure responsive to circulating angiotensin 11 (Angll). These inputs target PVN output neurons that increase hormonal release from the pituitary and sympathetic activity through monosynaptic projections to the thoracic spinal cord. Slow pressor hypertension can be induced by chronic systemic infusion of low doses of Angll (600 ng/kg/min) or by chronic exposure to intermittent hypoxia (CIH). The CIH-induced sympathetic activation and elevation in arterial pressure is dependent on plasticity in the carotid body, but also on changes in glutamate NMDA receptor-dependent transmission in the brain. Chronic exposure to Angll or CIH may result in NMDA receptor-dependent long-term facilitation of glutamatergic transmission in the PVN spinal projection neurons, which is enabled in part by suppression of opposing inhibitory neurons. NADPH oxidase generated reactive oxygen species (ROS) are important modulators of NMDA receptor mediated synaptic plasticity, and are also mediators of the intracellular signaling for Angll, a neuropeptide present in the glutamatergic SFO inputs to the PVN and active mainly through the Angll type-1 (ATi) receptor. Project 2 will test the central hvpothes\s that plasticitv in pre-svmpathetic output and inhibitorv neurons of the PVN enables the development of slow pressor hvpertension through mechanisms that are dependent on postsvnaptic NMDA receptors and influenced bv both Angll and ROS. Aim 1 will examine the basal distribution and function of NMDA and ATi receptors in PVN neurons identified as projecting to the thoracic spinal cord by retrograde transport. Aim 2 will determine whether changes in the surface/synaptic availability of the essential NMDA NR1 subunit and NMDA currents are concomitants of Angll or CIH hypertension, both of which are attenuated by a spatial-temporal deletion of postsynaptic NR1 in the PVN. Aim 3 will determine whether the development of Angll and/or CIH hypertension is linked to NADPH oxidase generated ROS in the PVN. This research will be conducted in male mouse models using in vivo measurement of arterial pressure (tail-cuff or radiotelemetry), high resolution electron microscopic immunolabeling, patch-clamp recording, and ROS imaging. Project 2 is interdependent with each of the other projects and reliant on all core facilities of this PPG.

项目2（Pickel）：下丘脑可塑性使缓慢加压性高血压成为可能 下丘脑室旁核（PVN）内的神经体液输出神经元被谷氨酸激活， 来自穹窿下器官（SFO）的含AngII的神经元输入，SFO是一种对以下反应的脑结构： 循环血管紧张素II（AngII）。这些输入靶向PVN输出神经元，增加激素释放 从垂体和交感神经活动通过单突触投射到胸脊髓。 低剂量AngII（600 μ mol/L）慢性全身灌注可诱导慢性升压性高血压 ng/kg/min）或慢性暴露于间歇性缺氧（CIH）。CIH诱导的交感神经激活 动脉压的升高取决于颈动脉体的可塑性，但也取决于 谷氨酸NMDA受体依赖的传输在大脑中。长期暴露于AngII或CIH可能导致 在室旁核脊髓投射中NMDA受体依赖的突触传递的长期易化 这部分是通过抑制相反的抑制性神经元来实现的。生成的NADPH氧化酶 活性氧（ROS）是NMDA受体介导的突触可塑性的重要调节剂， 也是AngII细胞内信号传导的介质，AngII是一种神经肽，存在于神经元能SFO中， 输入到PVN，并且主要通过AngII 1型（ATi）受体激活。项目2将测试中央 提示PVN的交感前输出和交感神经元的可塑性使得 通过依赖于突触后NMDA的机制发展缓慢的加压高血压 AngII和ROS均能影响AngII受体的表达。目标1将检查基础分布和功能， 逆行注射法鉴定室旁核向胸髓投射神经元的NMDA和ATi受体 运输目的2将确定是否改变表面/突触的重要NMDA的可用性， NR 1亚单位和NMDA电流是AngII或CIH高血压的伴随物，两者都是 通过PVN中突触后NR 1的时空缺失而减弱。目标3将决定 AngII和/或CIH高血压的发展与PVN中NADPH氧化酶产生的ROS有关。这 研究将在雄性小鼠模型中进行，使用动脉压的体内测量（尾套或 无线电遥测），高分辨率电子显微镜免疫标记，膜片钳记录，和ROS 显像项目2与其他项目相互依存，并依赖于本项目的所有核心设施。 PPG。