Neurophysiology of hunger/satiety control during hibernation

Yale University, New Haven CT

Investigators

Abstract

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.