Neural and cellular basis of fluid homeostasis during hibernation

冬眠期间体液稳态的神经和细胞基础

• 批准号: 2015622
• 负责人: Elena Gracheva
• 金额: $ 140万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2015622&HistoricalAwards=false
• 关键词: Neural; cellular; basis; fluid; homeostasis

Mammalian hibernation is fascinating. During a short period of time, hibernating animals undergo dramatic adaptive changes, including reduction in heart and respiration rate and decrease of core body temperature from 37°C (98.6°F) to 4°C (39°F), yet they do not experience cold-induced pain, and their organs continue to function despite being cold, non-functional, and deprived of oxygen for eight months out of the year. Moreover, during hibernation, animals do not drink; therefore, hibernators must rely solely on the management and utilization of internal resources for long-term survival. This project seeks to understand the molecular mechanisms that allows hibernators to survive for months without water, using a range of cutting-edge tools and approaches not been previously used for hibernation research, such as optogenetics and fiber photometry. The outcomes of this study will have broad scientific implications, including a better understanding of general mechanisms that regulate internal water and ionic balance common to all mammals. This project also involves educational and outreach efforts in the context of an extracurricular educational program (Sensory Physiology Club) that promotes scientific knowledge in human and animal physiology among school students from middle- and high schools from Connecticut, New York, and Massachusetts. The efforts are designed to spark interest in biological science through lectures and interactive experimental activities that go beyond the science curricula of most schools.The main scientific goal of this study is to broaden our limited understanding of fluid homeostasis in mammals at the cellular, molecular, and circuit levels by studying ground squirrels during hibernation. This project tests the hypothesis that ground squirrels endure long-term water deprivation in part by modifying the hypothalamic axis, which controls thirst and mediates the release of antidiuretic hormones. Specific aims of this proposal include investigation of the neuronal mechanisms that support the release of vasopressin and oxytocin from the posterior pituitary, and suppress water-seeking behavior during hibernation. This project combines cellular, molecular, and organismal levels of research and uses tools and approaches from a spectrum of disciplines: state-specific biochemical analysis of neuropeptides and hormones, quantitative analysis of hormonal production, differential transcriptomics, electron microscopic and morphometric analyses of hormonal release, and behavioral analyses of drinking behavior. A major innovative aspect of this project is the use of optogenetics, fiber photometry, and electrophysiological tools, which have not been used previously with hibernating animals. The outcomes of this study will delineate general principles of fluid-ionic balance fine-tuning, suggest a strategy to sustain life when water is unavailable, and predict whether hibernation can be induced in other mammals.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.

哺乳动物的冬眠很有趣。在很短的时间内，冬眠动物经历了戏剧性的适应性变化，包括心脏和呼吸频率的降低，以及核心体温从37°C（98.6°F）降至4°C（39°F），但它们不会经历寒冷引起的疼痛，尽管寒冷，无功能，并且一年中有八个月缺氧，它们的器官仍然继续发挥作用。此外，在冬眠期间，动物不喝水;因此，冬眠动物必须完全依靠管理和利用内部资源才能长期生存。该项目旨在了解允许冬眠动物在没有水的情况下存活数月的分子机制，使用一系列以前未用于冬眠研究的尖端工具和方法，如光遗传学和光纤光度学。这项研究的结果将具有广泛的科学意义，包括更好地了解调节所有哺乳动物共同的内部水和离子平衡的一般机制。该项目还包括在课外教育方案（感官生理学俱乐部）的背景下开展教育和推广工作，该方案在康涅狄格州、纽约州和马萨诸塞州的初中和高中学生中推广人类和动物生理学方面的科学知识。这些努力旨在通过讲座和互动实验活动激发人们对生物科学的兴趣，这些活动超出了大多数学校的科学课程。这项研究的主要科学目标是通过研究冬眠期间的地松鼠，扩大我们对哺乳动物细胞，分子和回路水平的流体稳态的有限理解。该项目测试的假设，地松鼠忍受长期缺水的部分修改下丘脑轴，控制口渴和介导的抗利尿激素的释放。该提案的具体目标包括研究支持垂体后叶素和催产素释放的神经元机制，以及抑制冬眠期间的寻水行为。该项目结合了细胞，分子和有机体水平的研究，并使用来自一系列学科的工具和方法：神经肽和激素的状态特异性生化分析，激素生产的定量分析，差异转录组学，激素释放的电子显微镜和形态分析，以及饮酒行为的行为分析。该项目的一个主要创新方面是使用光遗传学，纤维光度学和电生理学工具，这些工具以前没有用于冬眠动物。这项研究的结果将描绘流体离子平衡微调的一般原则，提出一个战略，以维持生命时，水是不可用的，并预测是否冬眠可以诱导在其他哺乳动物。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Ground squirrels

地松鼠

• DOI: 10.1016/j.cub.2022.02.015
• 发表时间: 2022
• 期刊: Current Biology
• 影响因子: 9.2
• 作者: Pra, Rafael Dai;Bagriantsev, Sviatoslav N.;Gracheva, Elena O.
• 通讯作者: Gracheva, Elena O.

Ground squirrels initiate sexual maturation during hibernation

地松鼠在冬眠期间启动性成熟

• DOI: 10.1016/j.cub.2022.02.032
• 发表时间: 2022
• 期刊: Current Biology
• 影响因子: 9.2
• 作者: Dai Pra, Rafael;Mohr, Sarah M.;Merriman, Dana K.;Bagriantsev, Sviatoslav N.;Gracheva, Elena O.
• 通讯作者: Gracheva, Elena O.