CAREER: Bidirectional Control of Sleep and Wakefulness by the Hypothalamic Arcuate Nucleus

尽管睡眠在动物王国中是普遍存在的，并且占据了动物一生中相当大的一部分，但大脑对睡眠和清醒的调节却知之甚少。此外，全国调查显示，公众对睡眠知之甚少，许多美国人，尤其是学生，睡眠严重不足。因此，这个项目整合了一系列的研究和教育目标，以影响我们对控制哺乳动物睡眠的大脑机制的理解。PI将使用强大的基因技术操纵啮齿动物大脑中的两种神经元（称为AgRP神经元和POMC神经元），以确定它们在调节睡眠/觉醒行为中的作用。这些神经元群以感知身体的营养和热量需求而闻名，因此我们的研究将研究食物摄入如何影响睡眠和清醒状态。因此，这项工作将增加我们对大脑如何协调复杂行为状态的理解，在这个例子中是饥饿和睡眠。教育目标将扩大这个项目的影响，包括本科生参与这项研究的各个方面，并在威廉姆斯学院实施一门关于睡眠科学的新课程。本课程将制作有关睡眠的教育材料，免费提供和分发。该奖项的研究和教育部分将共同提高美国在科学和技术方面的竞争力，特别是在神经科学领域。该项目的目标是确定调节能量稳态的神经元如何也调节睡眠。先前的研究表明，睡眠/清醒状态受到食物需求和可获得性的显著影响，但调节食物摄入的神经元在睡眠/清醒行为中的作用尚不清楚。下丘脑弓状核包含两个调节食物摄入行为的神经元群：表达厌氧性阿古提相关蛋白（AgRP）的神经元和表达厌氧性促阿皮质素（POMC）的神经元。我们实验室的初步证据表明，AgRP神经元可以独立地促进清醒和食物摄入，POMC神经元除了抑制食欲外还可以维持睡眠状态。先前的数据还表明，AgRP和POMC神经元可能通过分别投射到下丘脑外侧表达下丘脑分泌素的神经元和表达黑色素集中激素的神经元来影响睡眠/觉醒状态。该项目将使用尖端的光遗传学和化学遗传学方法，结合脑电图（EEG）和行为分析，以增加我们对睡眠/清醒行为中这些系统的理解，从而了解大脑如何协调复杂的行为状态。本科生将参与这项工作的各个方面，通过为下一代科学家和教育工作者提供实践培训，这将进一步影响神经科学领域。

Despite the fact that sleep is universal across the animal kingdom and occupies a substantial portion of an animal's lifetime, the regulation of sleep and wakefulness by the brain is poorly understood. Additionally, national surveys show that sleep is poorly understood among the general public and that many Americans, particularly students, are extremely sleep deprived. Therefore, this project integrates a series of research and educational goals to impact our understanding of the brain mechanisms that control mammalian sleep. The PI will manipulate two populations of neurons (called AgRP neurons and POMC neurons) in rodent brains using powerful genetic technologies to determine their roles in regulating sleep/wake behavior. These groups of neurons are well-known for sensing the nutritional and caloric needs of the body, and so our research will study how food intake affects states of sleep and wakefulness. This work will thus increase our understanding of how the brain coordinates complex behavioral states, in this case hunger and sleep. The educational goals will broaden the impact of this project by including undergraduates in all aspects of this research and by implementing a new course at Williams College on the science of sleep. This course will produce educational materials on sleep that will be freely available and distributed. Together, the research and educational components of this award will increase the United States' competitiveness in science and technology, particularly in the field of neuroscience. The goal of this project is to determine how neurons that regulate energy homeostasis also regulate sleep. Previous studies indicate that sleep/wake states are significantly affected by food need and availability, but the role of neurons that regulate food intake in sleep/wake behavior is unknown. The hypothalamic arcuate nucleus contains two populations of neurons that regulate food intake behavior: orexigenic agouti-related protein (AgRP)-expressing neurons and anorexigenic pro-opiomelanocortin (POMC)-expressing neurons. Preliminary evidence from our laboratory suggests that AgRP neurons can independently promote wakefulness and food intake and that POMC neurons maintain sleep states in addition to suppressing appetite. Previous data also suggest that AgRP and POMC neurons might influence sleep/wake states by projecting to hypocretin-expressing neurons and melanin-concentrating hormone-expressing neurons, respectively, in the lateral hypothalamus. This project will use cutting-edge optogenetic and chemogenetic methods in combination with electroencephalography (EEG) and behavioral analyses to increase our understanding of these systems in sleep/wake behavior and thus how the brain coordinates complex behavioral states. Undergraduate students will be involved in all aspects of this work, which will further impact the field of neuroscience through the hands-on training it will provide for the next generation of scientists and educators.