Neurophysiology of hunger/satiety control during hibernation

冬眠采用了一系列灵活的生理适应，使动物能够在不适宜生存的环境中茁壮成长，这些环境的特点是长时间的热挑战和食物短缺。十三棱地松鼠是哺乳动物中必不可少的冬眠动物。冬眠期间，松鼠以脂质代谢为主，在整个冬眠期间（长达8个月）不进食。这种显著的禁食被称为自我诱发的季节性厌食症。冬眠动物如何在长时间的食物剥夺下表现出微不足道的饥饿感，以及它们的新陈代谢如何应对这一过程，仍然是能量稳态调节中最大的谜团之一。该提案旨在了解冬眠动物在没有食物的情况下存活数月的分子，细胞和电路机制，使用以前未用于冬眠研究的一系列学科的工具和方法，如光遗传学和纤维光度法。这笔资金将用于支持外展项目（感官生理学俱乐部），这是一项课外教育活动，旨在向康涅狄格州、纽约州和马萨诸塞州的中学生推广动物神经生理学的科学知识。这些努力旨在通过讲座和互动实验活动激发人们对生物科学的兴趣，这些活动超出了学校课程的范围。研究结果对基础生物学、医学和人类的未来有着深远的影响。诱导类似冬眠的状态有助于促进器官移植，从缺血、中风或脑损伤中恢复，并可能最终实现长途太空旅行，例如载人火星任务。本研究的主要科学目标是拓宽我们对冬眠期间季节性代谢重编程和厌食症的有限理解。本研究将验证冬眠期间可逆的、自我诱导的厌食症是通过外周饥饿/饱腹激素与下丘脑进食中心之间的解耦而实现的。本提案的具体目的包括研究支持代谢线索不敏感和血脑屏障通透性的神经元机制及其在冬眠期间对饥饿抑制的贡献。该提案代表了跨学科的努力，跨越多个尺度，整合了来自广泛科学学科的各种工具和方法。从血液和组织生化分析、代谢谱、转录组学到体内成像、电生理学和动物行为研究。这一提议的一个主要创新方面是使用体内脑成像，这在冬眠动物中从未被使用过。这项研究的结果将为合理设计药理学工具奠定基础，以了解哺乳动物如何在长期寒冷暴露和饥饿的极端条件下生存。该奖项反映了美国国家科学基金会的法定使命，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。

Hibernation employs a collection of flexible physiological adaptations that allow animals to thrive in inhospitable environments, characterized by thermal challenges and scarcity of food for extended periods of time. The thirteen-lined ground squirrel is an obligatory mammalian hibernator. During hibernation, squirrels switch to lipid metabolism and do not eat during the entire hibernation (up to 8 months). This remarkable abstinence from food is referred to as self-induced seasonal anorexia. How hibernators exhibit negligible hunger drive despite a prolonged period of food deprivation and how their metabolism copes with this process remains one of the biggest mysteries in energy homeostasis regulation. This proposal seeks to understand the molecular, cellular and circuitry mechanisms that allow hibernators to survive for months without food, using tools and approaches from a spectrum of disciplines that have not been previously used for hibernation research, such as optogenetics and fiber photometry. This grant will support outreach program (Sensory Physiology Club), an extracurricular educational activity aimed to promote scientific knowledge in animal neurophysiology 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, which go beyond the school curricula. The outcomes of study have far-reaching implications for fundamental biology, medicine, and the future of humanity. Induction of a hibernation-like state could help improve organ transplantation, recovery from ischemia, stroke, or brain injury, and may ultimately enable long-distance space travel, e.g., for manned missions to Mars.The main scientific goal of this study is to broaden our limited understanding of seasonal metabolic reprogramming and anorexia during hibernation. This study will test the hypothesis that the reversible, self-induced anorexia during hibernation is achieved through uncoupling between peripheral hunger/satiety hormones and the hypothalamic feeding center. Specific aims of this proposal include investigation of the neuronal mechanisms that support insensitivity to metabolic cues and permeability of blood brain barrier and their contribution to hunger suppression during hibernation. This proposal represents an interdisciplinary endeavor that spans multiple scales and integrates various tools and approaches from a wide spectrum of scientific disciplines. Ranging from biochemical blood and tissues analysis, metabolic profiling, transcriptomics to in vivo imaging, electrophysiology, and animal behavior studies. A major innovative aspect of this proposal is the use of in vivo brain imaging, which has not been previously used in hibernating animals. The outcome gained from this study will lay the foundation for rational design of pharmacological tools to understand how life in mammals can persist under extreme conditions of long-term cold exposure and starvation.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.