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

昼夜节律系统控制着24小时的行为和生理节奏，比如我们什么时候吃、什么时候睡、什么时候代谢糖和脂肪。从苍蝇到人类，打乱昼夜节律会加剧代谢风险。因此，研究代谢过程的时间对于制定调节能量平衡和代谢风险的方法至关重要。大脑中调节昼夜饮食节奏的神经通路，或者我们什么时候吃东西，尚不清楚。为了发现这条神经通路，该项目研究了在营养高脂肪饮食挑战期间饮食节奏的性别差异。雌性老鼠体内的雌性激素，而不是雄性老鼠体内的雌性激素，在营养挑战期间调节着饮食行为的昼夜节律。这项研究通过操纵大脑中的雌激素信号来揭示控制老鼠饮食节奏的神经回路。高中生、本科生和研究生通过付费奖学金参与研究。该项目还为非STEM和STEM学生开发了新的基于课程的本科研究课程（CUREs），以研究人类昼夜节律的性别差异，这是对小鼠研究的补充。哺乳动物的昼夜节律系统是按等级组织的。视交叉上核（SCN）是主要的生物钟，协调大脑和外周的生物钟，调节行为和生理节律。这种昼夜节律系统的等级组织早在几十年前就在哺乳动物中被发现，但对于SCN下游调节行为和生理昼夜节律的回路仍然知之甚少。本项目研究调节代谢昼夜节律的scn外神经回路，以扩大对昼夜节律控制能量平衡的理解。该项目的研究目标是验证雌激素调节控制代谢昼夜节律的神经回路，从而导致能量平衡中的性别差异的总体假设。第一个目的是通过敲除小鼠和ERα特异性激动剂确定雌激素受体α (ERα)信号是否调节代谢昼夜节律的性别差异。第二个目标是通过Cre-lox和aav介导的基因敲低靶向特定神经元中的雌激素信号来确定大脑的哪些区域控制饮食节律。该方法整合了分子、组织和行为水平上能量平衡的昼夜节律调节研究，以了解昼夜节律网络如何调节代谢。该项目的教育目标是发展可持续的教育项目，为昼夜节律中的性别差异的科学探究和分析提供指导，包括来自不同培训、种族和经济背景的学生。这些教育项目通过CUREs为学员提供独立的研究经验，并为本科生群体提供研究经验。该项目由综合有机体系统部的神经系统集群和刺激竞争研究的既定计划（EPSCoR）共同资助。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。

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.