Neurophysiology of hunger/satiety control during hibernation

冬眠期间饥饿/饱足控制的神经生理学

• 批准号: 2323133
• 负责人: Elena Gracheva
• 金额: $ 84万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2323133&HistoricalAwards=false
• 关键词: Neurophysiology; hunger; satiety; control; during

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.

冬眠采用了一系列灵活的生理适应，使动物能够在恶劣的环境中茁壮成长，其特点是长时间的热挑战和食物短缺。十三线地松鼠是一种强制性的哺乳动物冬眠者。在冬眠期间，松鼠切换到脂质代谢，在整个冬眠期间（长达8个月）不吃东西。这种明显的禁食被称为自我诱导的季节性厌食症。冬眠动物如何在长时间的食物匮乏中表现出可忽略的饥饿驱动，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。该提案旨在了解允许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学科的工具和方法，如光遗传学和纤维光度学。 这笔赠款将支持外展计划（感官生理学俱乐部），这是一项课外教育活动，旨在促进康涅狄格州、纽约和马萨诸塞州初中和高中学生对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、医学和人类的未来都有深远的影响。诱导类似冬眠的状态可以帮助改善器官移植，从缺血，中风或脑损伤中恢复，并最终实现长距离太空旅行，例如，这项研究的主要科学目标是扩大我们对季节性代谢重编程和冬眠期间厌食症的有限理解。这项研究将测试的假设，可逆的，自我诱导的厌食症在冬眠期间是通过解偶联外周饥饿/饱腹激素和下丘脑摄食中心。这项建议的具体目标包括调查的神经元机制，支持不敏感的代谢线索和血脑屏障的渗透性和它们的贡献，在冬眠期间的饥饿抑制。该提案代表了跨学科的奋进，跨越多个尺度，并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、代谢分析、转录组学到体内成像、电生理学和动物行为研究。这项建议的一个主要创新方面是使用体内脑成像，这是以前没有用于冬眠动物。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。