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Neuroendocrine mechanisms regulating drinking behavior in females

调节女性饮酒行为的神经内分泌机制

基本信息

批准号：
2019346
负责人：
Jessica Santollo
金额：
$ 97.53万
依托单位：
University of Kentucky Research Foundation
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2019346&HistoricalAwards=false
关键词：
Neuroendocrine mechanisms regulating drinking behavior

项目摘要

Maintaining adequate body fluid levels is essential for life. Mammals, including humans, experience continual water and electrolyte loss through urine, defecation, and the evaporation of fluids during sweating and breathing. To replace these lost fluids, water and electrolyte consumption is necessary. Failure to replace lost fluids results in fatigue, headache, cognitive impairments, and ultimately will result in death. Therefore, understanding how the body controls fluid intake is critical for understanding how animals survive. Importantly, there is overwhelming evidence that the ovarian hormone estradiol regulates fluid balance, and specifically fluid intake, in females. However, how estradiol controls drinking behavior is not well understood. This project addresses this fundamental question and thereby will contribute critically to understanding of how estradiol controls fluid intake in females. This question is important also because elucidating how estradiol controls drinking is key to understanding how whole-body fluid balance is maintained in females. The demand for fluid changes dramatically across the female reproductive lifespan, both during pregnancy and lactation, and is coupled with marked fluctuations in estradiol secretion during these times. Therefore, research investigating how estradiol regulates intake is also necessary for understanding cardiovascular physiology in females. An additional part of this project is the dissemination of this work, and more generally information about research in neuroendocrinology and hydration, to the public. Toward this goal, the investigators of this project contribute to events at the University of Kentucky, such as Expanding Your Horizons and BioBonanza. Finally, inclusion of university students in this project provides training in scientific research and outreach.The goal of this project is to understand how estradiol inhibits fluid intake in female laboratory rats. Toward this goal, the investigators test the overarching hypothesis that estradiol signaling in the brain decreases angiotensin II-stimulated water and saline intake through distinct actions of various estrogen receptor (ER) subtypes. The project examines this question at multiple levels of analysis, from gene expression to behavior, to determine the roles of estrogen receptor alpha, estrogen receptor beta, and G protein estrogen receptor 1 in the regulation of fluid intake by estradiol. Aim 1 use AAV-mediated shRNA knockdown of ER subtypes and parenchymal injections of ER agonists to determine which areas of the brain and ER subtypes are necessary and sufficient for estradiol’s inhibitory effect on water and saline intake. Aim 2 quantifies gene and protein expression to determine if ER subtypes differentially influence angiotensin type 1 receptor intracellular signaling in areas of the brain that control fluid intake. Aim 3 uses immunohistochemistry to determine if estradiol modulates excitatory and/or inhibitory cells in fluid-relevant brain areas to inhibit fluid intake. In addition to identifying how estradiol controls fluid intake in females, this work will advance more generally understanding of how ovarian hormones signal in the brain and influence behavior. This project is jointly funded by the Modulation Program in the Division of Integrative Organismal Biology and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

保持足够的体液水平对生命至关重要。包括人类在内的哺乳动物在出汗和呼吸过程中通过尿液、排便和液体蒸发经历持续的水和电解质损失。为了补充这些流失的液体，需要消耗水和电解质。不能补充流失的液体会导致疲劳、头痛、认知障碍，最终导致死亡。因此，了解身体如何控制液体摄入对于了解动物如何生存至关重要。重要的是，有压倒性的证据表明，卵巢激素雌二醇调节液体平衡，特别是液体摄入量，在女性。然而，雌二醇如何控制饮酒行为还不清楚。这个项目解决了这个基本问题，从而将有助于理解雌二醇如何控制女性的液体摄入量。这个问题也很重要，因为阐明雌二醇如何控制饮酒是理解女性如何维持全身液体平衡的关键。在整个女性生殖寿命期间，无论是在怀孕期间还是在哺乳期间，对液体的需求都会发生巨大变化，并且在这些时间内，雌二醇的分泌也会出现明显的波动。因此，研究雌二醇如何调节摄入量对于了解女性心血管生理也是必要的。该项目的另一部分是向公众传播这项工作，以及有关神经内分泌学和水合作用研究的更广泛的信息。为了实现这一目标，该项目的研究人员为肯塔基州大学的活动做出了贡献，如“拓展你的视野”和“生物财富”。最后，将大学生纳入该项目提供了科学研究和推广方面的培训。该项目的目标是了解雌二醇如何抑制雌性实验室大鼠的液体摄入。为了实现这一目标，研究人员测试了总体假设，即大脑中的雌二醇信号通过各种雌激素受体（ER）亚型的不同作用减少血管紧张素II刺激的水和盐水摄入。该项目从基因表达到行为的多个层面分析了这个问题，以确定雌激素受体α，雌激素受体β和G蛋白雌激素受体1在雌二醇调节液体摄入中的作用。目的1利用腺相关病毒介导的雌激素受体亚型的shRNA敲低和脑实质注射雌激素受体激动剂来确定哪些脑区和雌激素受体亚型是雌二醇抑制水和盐水摄入的必要和充分的。目的2量化基因和蛋白质表达，以确定ER亚型是否差异影响血管紧张素1型受体在控制液体摄入的大脑区域的细胞内信号传导。目的3使用免疫组织化学来确定雌二醇是否调节与液体相关的脑区的兴奋性和/或抑制性细胞以抑制液体摄入。除了确定雌二醇如何控制女性的液体摄入量外，这项工作还将促进对卵巢激素如何在大脑中发出信号并影响行为的更普遍的理解。该项目由综合有机生物学部的调制计划和刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。