CAREER: Deciphering the neural network orchestrating sex differences in metabolic circadian rhythms

University Of Kentucky Research Foundation, Lexington KY

Investigators

Abstract

The circadian system controls 24-hour rhythms of behavior and physiology, such as when we eat, sleep, and metabolize sugars and fats. From flies to man, disrupting circadian rhythms exacerbates metabolic risk. Thus, studying the timing of metabolic processes is critical for developing approaches to regulate energy balance and metabolic risk. The neural pathway in the brain that regulates the circadian eating rhythm, or when we eat, is not known. To discover this neural pathway, the project studies sex differences in eating rhythms during a nutritional high-fat diet challenge. Estrogen in female, but not in male, mice regulates eating behavior circadian rhythms during a nutritional challenge. This study manipulates estrogen signaling in the brain to reveal the neural circuitry controlling the eating rhythm in mice. High school, undergraduate, and graduate students participate in the research through paid fellowships. The project also develops new course-based undergraduate research courses (CUREs) for non-STEM and STEM students to study sex differences in human circadian rhythms, which complements the studies in mice. The mammalian circadian system is organized hierarchically. The suprachiasmatic nucleus (SCN) is the main circadian clock that coordinates the timing of clocks in the brain and periphery to regulate behavioral and physiological rhythms. This hierarchical organization of the circadian system was discovered decades ago in mammals and yet still little is known about the circuits downstream from the SCN that regulate circadian rhythms of behavior and physiology. This project studies the extra-SCN neural circuitry that regulates metabolic circadian rhythms to expand understanding of circadian control of energy balance. The research goal of this project is to test the overarching hypothesis that estrogen regulates the neural circuitry controlling metabolic circadian rhythms resulting in sex differences in energy balance. The first objective determines whether estrogen receptor α (ERα) signaling regulates sex differences in metabolic circadian rhythms using knockout mice and ERα-specific agonists. The second objective determines which areas of the brain control eating rhythms by targeting estrogen signaling in specific neurons with Cre-lox and AAV-mediated gene knockdown. The approach integrates the study of circadian regulation of energy balance across molecular, tissue, and behavioral levels to understand how the circadian network regulates metabolism. The educational goal of this project develops sustainable educational projects that provide instruction in scientific inquiry and analysis of sex differences in circadian rhythms, and includes students from diverse training, ethnic, and economic backgrounds. The educational projects provide independent research experiences for trainees as well as research experiences for groups of undergraduates through CUREs. This project is jointly funded by the Neural Systems Cluster in the Division of Integrative Organismal Systems and the Established Program to Stimulate Competitive Research (EPSCoR). 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.