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）：下丘脑可塑性可实现缓慢的压力高压 下丘脑室室中核（PVN）中的神经肿瘤输出神经元被谷氨酸激活 来自副构造器官（SFO）的含Angll神经元输入，一种大脑结构对 循环血管紧张素11（Angll）。这些输入目标PVN输出神经元增加了激素释放 从垂体和交感神经活动到单突触投影到胸椎。 缓慢的压力高血压可以通过慢性全身输注低剂量的Angll诱导（600 Ng/kg/min）或长期暴露于间歇性缺氧（CIH）。 CIH引起的交感神经激活 动脉压的升高取决于颈动脉体的可塑性，但也取决于变化 大脑中谷氨酸NMDA受体依赖性传播。长期暴露于Angll或CIH可能导致 在NMDA受体依赖性长期促进PVN脊柱投影中的谷氨酸能传播 神经元，部分是由于抑制相反的抑制神经元而启用的。 NADPH氧化酶产生 活性氧（ROS）是NMDA受体介导的突触可塑性的重要调节剂，并且 也是Angll的细胞内信号传导的介体，Angll是谷氨酸能SFO中存在的神经肽 对PVN的输入和主要通过Angll Type-1（ATI）受体进行活跃。项目2将测试中央 hvpothes \ s塑料中的塑性剂在pPathetic输出和PVN的抑制剂神经元中可以实现 通过依赖于后vnaptic NMDA的机制开发缓慢的压力HVPertension 受体并影响了BV均为Angll和ROS。 AIM 1将检查的基础分布和功能 NMDA和ATI受体中的PVN神经元中的NMDA和ATI受体通过逆行投射到胸椎投射到胸椎 运输。 AIM 2将确定基本NMDA的表面/突触可用性的变化 NR1亚基和NMDA电流是Angll或CIH高血压的伴随物，这两个都是 PVN中突触后NR1的时空缺失减弱。 AIM 3将确定是否 Angll和/或CIH高血压的发展与PVN中产生的NADPH氧化酶有关。这 将使用动脉压的体内测量（尾扣或 radiotelemetry），高分辨率电子显微镜免疫标记，斑块钳记录和ROS 成像。项目2与其他每个项目相互依存，并依赖于所有核心设施 ppg。