Neural and cellular basis of fluid homeostasis during hibernation

哺乳动物的冬眠很吸引人。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降低，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，它们的器官在一年中有8个月处于寒冷、无功能和缺氧的情况下仍能继续发挥作用。此外，在冬眠期间，动物不喝水；因此，冬眠者必须完全依靠内部资源的管理和利用才能长期生存。该项目试图利用一系列以前没有用于冬眠研究的尖端工具和方法，如光遗传学和纤维光度学，来了解冬眠者在没有水的情况下存活数月的分子机制。这项研究的结果将具有广泛的科学意义，包括更好地理解调节所有哺乳动物共有的体内水和离子平衡的一般机制。该项目还包括在课外教育计划(感觉生理学俱乐部)的背景下进行的教育和推广工作，该计划在康涅狄格州、纽约州和马萨诸塞州的初中生和高中生中推广人类和动物生理学的科学知识。这些努力旨在通过讲座和互动实验活动来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中的地面松鼠，在细胞、分子和电路水平上扩大我们对哺乳动物流体动态平衡的有限理解。这个项目测试了这样一种假说，即沙鼠忍受长期的缺水，部分是通过改变下丘脑轴，该轴控制口渴并调节抗利尿激素的释放。这一建议的具体目的包括研究支持垂体后叶释放加压素和催产素的神经机制，以及抑制冬眠期间的寻水行为。该项目结合了细胞、分子和生物体水平的研究，并使用了一系列学科的工具和方法：神经肽和激素的特定状态生化分析、激素产生的定量分析、差异转录学、激素释放的电子显微镜和形态计量分析，以及饮酒行为分析。该项目的一个主要创新方面是使用了光遗传学、纤维光度学和电生理工具，这些工具以前从未在冬眠动物身上使用过。这项研究的结果将描绘出流体-离子平衡微调的一般原则，建议在没有水的情况下维持生命的策略，并预测是否可以在其他哺乳动物身上诱导冬眠。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.