Neurophysiology of hunger/satiety control during hibernation

冬眠利用了一系列灵活的生理适应，使动物能够在不适宜居住的环境中茁壮成长，这种环境的特点是温度挑战和长时间的食物稀缺。十三行地松鼠是哺乳动物必须冬眠的动物。在冬眠期间，松鼠转换为脂肪代谢，在整个冬眠期间(长达8个月)不进食。这种对食物的显著禁欲被称为自发性季节性厌食症。冬眠者如何在长时间的食物缺乏的情况下表现出可以忽略不计的饥饿感，以及他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。这项提议试图了解使冬眠者在没有食物的情况下存活数月的分子、细胞和电路机制，使用光遗传学和纤维光度学等以前从未用于冬眠研究的一系列学科的工具和方法。这笔赠款将支持外展计划(Sensory Physiology Club)，这是一项课外教育活动，旨在向来自康涅狄格州、纽约州和马萨诸塞州的初中生和高中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来激发人们对生物科学的兴趣，这些活动超出了学校的课程范围。研究结果对基础生物学、医学和人类的未来具有深远的影响。诱导类冬眠状态有助于改善器官移植、从缺血、中风或脑损伤中恢复，并最终可能使长途太空旅行成为可能，例如载人火星任务。本研究的主要科学目标是扩大我们对冬眠期间季节性代谢重新编程和厌食的有限理解。这项研究将检验这一假设，即冬眠期间可逆的自我诱导性厌食症是通过外周饥饿/饱腹感激素和下丘脑摄食中心之间的解偶联实现的。这项建议的具体目的包括研究支持对代谢线索和血脑屏障通透性不敏感的神经机制，以及它们在冬眠期间抑制饥饿的作用。这一建议代表了一项跨学科的努力，它跨越了多个范围，并整合了来自广泛科学学科的各种工具和方法。从生化血液和组织分析、新陈代谢分析、转录组学到活体成像、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了活体脑成像，这是以前从未在冬眠动物中使用过的。这项研究的结果将为合理设计药理工具奠定基础，以了解哺乳动物的生命如何在长期寒冷暴露和饥饿的极端条件下持续存在。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。

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.