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)：下丘脑的可塑性使慢性高血压成为可能 下丘脑室旁核(PVN)的神经体液输出神经元被谷氨酸和 穹隆下器(SFO)的含有Ang11的神经元输入，这是一种对 循环血管紧张素11(Ang11)。这些输入以促进荷尔蒙释放的PVN输出神经元为靶点。 通过单突触投射至胸髓的脑下垂体和交感神经活动。 慢性全身注射小剂量血管紧张素转换酶抑制剂(600)可诱导慢性高血压 Ng/kg/min)或慢性间歇性低氧暴露(CIH)。CIH引起的交感神经兴奋 而动脉压的升高不仅取决于颈动脉小体的可塑性，而且还取决于 谷氨酸NMDA受体在脑内的传递。可能导致长期接触Angll或CIH 在依赖NMDA受体的PVN脊髓投射中长期促进谷氨酸能传递 神经元，这在一定程度上是通过抑制相反的抑制性神经元来实现的。NADPH氧化酶生成 活性氧(ROS)是NMDA受体介导的突触可塑性的重要调节物， 也是Ang11细胞内信号的媒介，Ang11是一种存在于谷氨酸能SFO中的神经肽 传入下丘脑室旁核，主要通过血管紧张素转换酶1型(ATI)受体激活。项目2将测试中央 S认为，下丘脑室旁核前交感神经输出的可塑性和抑制神经元使 慢升压性高血压的发生依赖于睡眠后NMDA的机制 受体并影响血管紧张素转运蛋白和ROS。目标1将检查基本分布和功能 逆行投射至胸髓的PVN神经元的NMDA和ATI受体 运输。目标2将确定必要的NMDA的表面/突触可获得性的变化 NR1亚单位和NMDA电流是伴随的Ang11或CIH高血压，两者都是 PVN中突触后NR1的时空缺失而减弱。目标3将决定是否 Ang11和/或CIH高血压的发生与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，使用活体测量动脉压(尾部或袖带) 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 成像。项目2与其他项目相互依赖，并依赖于该项目的所有核心设施 PPG。