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

职业：破译协调代谢昼夜节律性别差异的神经网络

• 批准号: 2045267
• 负责人: Julie Pendergast
• 金额: $ 87.5万
• 依托单位: University of Kentucky Research Foundation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2045267&HistoricalAwards=false
• 关键词: CAREER; Deciphering; neural; network; orchestrating

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.

昼夜节律系统控制着24小时的行为和生理节律，例如我们吃饭、睡觉以及代谢糖和脂肪的时间。从苍蝇到人类，扰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开发调节能量平衡和代谢风险的方法至关重要。大脑中调节昼夜进食节律或我们何时进食的神经通路尚不清楚。为了发现这种神经通路，该项目研究了在营养高脂肪饮食挑战中饮食节奏的性别差异。雌激素在雌性而非雄性小鼠中调节营养挑战期间的进食行为昼夜节律。这项研究操纵大脑中的雌激素信号，以揭示控制小鼠进食节奏的神经回路。高中生、本科生和研究生通过有偿奖学金参与研究。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，这补充了小鼠的研究。哺乳动物的昼夜节律系统是按等级组织的。视交叉上核（SCN）是主要的昼夜节律钟，协调大脑和外周的时钟，以调节行为和生理节律。这种昼夜节律系统的层次结构早在几十年前就在哺乳动物中发现了，但人们对SCN下游调节行为和生理昼夜节律的回路知之甚少。该项目研究调节代谢昼夜节律的额外SCN神经回路，以扩大对能量平衡的昼夜控制的理解。本项目的研究目标是测试总体假设，即雌激素调节控制代谢昼夜节律的神经回路，导致能量平衡的性别差异。第一个目标是使用基因敲除小鼠和雌激素受体α（ERα）特异性激动剂确定ERα信号传导是否调节代谢昼夜节律的性别差异。第二个目标是确定大脑的哪些区域通过用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传导来控制进食节律。该方法整合了跨分子，组织和行为水平的能量平衡的昼夜节律调节的研究，以了解昼夜节律网络如何调节代谢。该项目的教育目标是开发可持续的教育项目，提供科学探究和昼夜节律性别差异分析方面的指导，并包括来自不同培训，种族和经济背景的学生。这些教育项目为学员提供独立的研究经验，并通过CURE为本科生群体提供研究经验。该项目由综合有机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NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。