Sex Differences in Central Neural Activation During Acute Hypernatremia

急性高钠血症期间中枢神经激活的性别差异

基本信息

批准号：
10749516
负责人：
Nathan Romberger
金额：
$ 4.29万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749516
关键词：
Acute Adult Age Androgen Receptor Animals Blood Blood - brain barrier anatomy Blood Pressure Brain Brain region Cardiac Output Cardiovascular system Catecholamines Cell Nucleus Data Dehydration Development Dietary Sodium Disease Estrogen Receptors Event Exercise Fluid Balance Functional Magnetic Resonance Imaging Goals Gonadal Steroid Hormones Head High Prevalence Hormonal Human Hypernatremia Hypertension Hypothalamic structure Incidence Infusion procedures Instruction Insula of Reil Intake Ischemia Isometric Exercise Lower Body Negative Pressure Measures Mediating Menstrual cycle Muscle Nerve Neurons Norepinephrine Organ Peripheral Resistance Phase Plasma Prevalence Productivity Prosencephalon Public Health Research Rest Rodent Rodent Model Saline Scientist Sex Differences Signal Transduction Sodium Sodium Chloride Subfornical Organ Thirst Training Vasopressins Woman Women&apos s Role blood oxygen level dependent blood pressure control blood pressure regulation cardioprotection female sex hormone health disparity insight male men neural neuroimaging neuroregulation organum vasculosum of the lamina terminalis response salt intake salt sensitive sex stressor technical writing young woman

项目摘要

PROJECT SUMMARY/ABSTRACT Blood pressure (BP)-related diseases continue to be a major public health challenge in both sexes. Men have a higher prevalence of hypertension compared to women until about age 60, after which prevalence is greater in women, reflecting the cardioprotective role of female sex hormones. The high incidence of hypertension in adults is associated with high dietary sodium intake. Thus, investigating sex differences in responses to sodium may be important in understanding these health disparities between men and women. Central sodium sensing is critical in mediating neurohormonal responses to the relative hypernatremia associated with high salt intake. The circumventricular organs (CVOs), including the organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), lack a complete blood brain barrier and contain osmosensitive neurons capable of sensing changes in sodium concentration in the blood. The CVOs also mediate sodium-induced changes in sympathetic nerve activity (SNA), vasopressin (AVP), thirst, and BP. Studies in humans show increased activation of the CVOs during acute hypernatremia (hypertonic saline infusion), which is similar to the underappreciated relative hypernatremia that occurs with high sodium intake. However, no human studies have investigated whether there are sex differences in central neural activation during acute hypernatremia. Therefore, the focus of this proposal is to investigate sex differences in functional connectivity of sodium sensing brain regions (SFO, OVLT) and brain regions involved in sympathetic outflow (rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM)) during acute hypernatremia (via hypertonic saline infusion) using blood oxygen level dependent (BOLD) fMRI. We will also assess whether these responses are associated with changes in AVP, norepinephrine (NE), thirst, and BP. This proposal involves 2 specific aims: aim 1 will assess sex differences in change in functional connectivity between sodium sensing brain regions (SFO, OVLT); aim 2 will assess sex differences in change in functional connectivity between sympathoregulatory brain regions (RVLM, NTS, CVLM). We hypothesize that acute hypernatremia will increase functional connectivity between sodium sensing brain regions (Aim 1) and increase connectivity with the RVLM and decrease connectivity with the NTS and CVLM (Aim 2). We hypothesize that men will have greater responses since (1) in salt sensitive rodent models, male animals display larger changes in arterial BP; (2) men have greater AVP release in response to hypertonic saline infusion; and (3) men have greater MSNA, BP, and forebrain BOLD fMRI responses to various cardiovascular stressors. This proposal has the potential to offer important insight into sex-specific mechanisms of BP regulation and fluid balance and will provide the trainee with specific instruction in BOLD fMRI and technical writing, which are critical in his development into a productive research scientist.

项目概要/摘要血压（BP）相关疾病仍然是男女面临的主要公共卫生挑战。男人有一个 60 岁左右之前，与女性相比，高血压患病率较高，此后，以下人群的患病率更高女性，反映女性性激素的心脏保护作用。成人高血压发病率高与高膳食钠摄入量有关。因此，研究对钠反应的性别差异可能会对于理解男性和女性之间的健康差异非常重要。中枢钠传感是对于调节与高盐摄入相关的相对高钠血症的神经激素反应至关重要。这室周器官 (CVO)，包括终板血管器 (OVLT) 和穹窿下器官（SFO），缺乏完整的血脑屏障，并含有能够感知变化的渗透敏感神经元血液中的钠浓度。 CVO 还介导钠诱导的交感神经变化活动 (SNA)、加压素 (AVP)、口渴和血压。人类研究表明 CVO 的激活增加在急性高钠血症（高渗盐水输注）期间，这与未被充分认识的相对相似高钠血症是由于钠摄入过多而发生的。然而，没有人类研究调查是否存在急性高钠血症期间中枢神经激活的性别差异。因此，本次提案的重点旨在研究钠传感脑区（SFO、OVLT）功能连接的性别差异，以及参与交感神经流出的大脑区域（延髓头侧腹外侧 (RVLM)、孤束核（NTS），尾侧延髓腹外侧（CVLM））在急性高钠血症期间（通过高渗盐水输注）使用血氧水平依赖性 (BOLD) fMRI。我们还将评估这些反应是否与 AVP、去甲肾上腺素 (NE)、口渴和血压的变化。该提案涉及 2 个具体目标：目标 1 将评估钠传感脑区（SFO、OVLT）之间功能连接变化的性别差异；目标2 将评估交感调节大脑区域之间功能连接变化的性别差异（RVLM、NTS、CVLM）。我们假设急性高钠血症会增加之间的功能连接钠感应大脑区域（目标 1）并增加与 RVLM 的连接并减少与 NTS 和 CVLM（目标 2）。我们假设男性会有更大的反应，因为 (1) 对盐敏感啮齿动物模型中，雄性动物的动脉血压变化较大； (2) 男性有更多的 AVP 释放作为反应输注高渗盐水； (3) 男性对 MSNA、BP 和前脑 BOLD fMRI 反应更强各种心血管应激源。该提案有可能为特定性别提供重要的见解血压调节和液体平衡机制，并将为学员提供 BOLD 的具体指导功能磁共振成像和技术写作对于他成长为一名富有成效的研究科学家至关重要。