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升压高血压 下丘脑室旁核 (PVN) 中的神经体液输出神经元由谷氨酸和 来自穹窿下器官 (SFO) 的含有 Angll 的神经元输入，这是一种对 循环血管紧张素 11 (Angll)。这些输入针对 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。 慢性全身输注低剂量AngII（600 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，也取决于颈动脉体的变化 谷氨酸 NMDA 受体依赖性大脑传输。长期接触 Angll 或 CIH 可能会导致 NMDA 受体依赖性长期促进 PVN 脊髓投射中的谷氨酸能传递 神经元，这部分是通过抑制相反的抑制性神经元来实现的。 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， 也是 AngII 细胞内信号传导的介质，AngII 是存在于谷氨酸能 SFO 中的一种神经肽 输入至 PVN，主要通过 Angll 1 型 (ATi) 受体激活。项目2将测试中央 假设 PVN 的前感神经输出和抑制神经元中的可塑性能够实现 通过依赖于突触后 NMDA 的机制发展缓慢升压高血压 受体并受到 AngII 和 ROS 的影响。目标 1 将检查基础分布和功能 PVN 神经元中的 NMDA 和 ATi 受体被确定为逆行投射到胸脊髓 运输。目标 2 将确定必需 NMDA 的表面/突触可用性是否发生变化 NR1 亚基和 NMDA 电流是 AngII 或 CIH 高血压的伴随物，两者都是 PVN 中突触后 NR1 的时空缺失会减弱。目标 3 将确定是否 AngII 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，使用体内动脉压测量（尾套或 放射遥测）、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 与其他每个项目相互依赖，并依赖该项目的所有核心设施 PPG。