Communication in the Mammalian Circadian Clock: The Role of Nitric Oxide

描述（由申请人提供）：哺乳动物下丘脑视交叉上核（SCN）包含一个控制生理和行为节律的主昼夜节律钟。SCN由单细胞神经元振荡器组成，这些振荡器耦合并产生相干的昼夜节律输出。SCN内负责神经元间耦合的机制和递质尚未完全阐明。这项建议的总体目标是研究一氧化氮（NO），一种存在于SCN细胞中的气体递质，对SCN细胞间通讯的作用。具体目标C.1旨在确定NO介导的偶联在SCN内起搏器自由运行期测定中的作用。具体目标C.2将评估SCN内NO细胞间信号传导在光诱导的昼夜节律相位重置中的作用。最后，具体目标C.3将评估-在体外和体内-NO信号传导在腹外侧和背内侧SCN之间的硬化中的作用，在通过将动物暴露于光-暗周期的突然相位提前而使它们去硬化后。所提出的实验将提供深入的机制和负责SCN细胞之间的同步信号。进一步了解SCN细胞如何共同工作以构成主时钟是理解和治疗昼夜节律病理的关键。公共卫生相关性：包括人类在内的哺乳动物的生理和行为表现出强烈的24小时振荡，这些振荡是由大脑下丘脑中称为视交叉上核的区域产生和协调的。这个细胞核包含一个由数千个神经元组成的生物钟，这些神经元本身就是能够独立振荡的时钟神经元。因此，视交叉上核内神经元之间的同步对于生理和行为节律的正常定时是必不可少的，例如激素的释放和睡眠-觉醒周期。揭示这些神经元如何相互通信对于理解导致这些功能异常时间的某些疾病的神经基础以及治疗与我们现代全天候社会相关的挑战所导致的病理学至关重要，例如跨时区旅行或夜班工作时间表。

DESCRIPTION (provided by applicant): The mammalian hypothalamic suprachiasmatic nucleus (SCN) contains a master circadian clock that governs physiological and behavioral rhythms. The SCN is constituted of single-cell neuronal oscillators that are coupled and generate a coherent circadian output. The mechanisms and transmitters that are responsible for interneuronal coupling within the SCN have not been completely elucidated. The overall goal of this proposal is to study the role of nitric oxide (NO), a gaseous transmitter present in SCN cells, on SCN intercellular communication. Specific Aim C.1 seeks to establish the role of NO-mediated coupling on the determination of the free-running period of the pacemaker within the SCN. Specific Aim C.2 will assess the role of NO intercellular signaling within the SCN in light-induced phase resetting of circadian rhythms. Finally, Specific Aim C.3 will evaluate -both in vitro and in vivo - the role of NO signaling in the resynchronization between the ventrolateral and dorsomedial SCN after they have been desynchronized by exposing animals to an abrupt phase advance of the light-dark cycle. The proposed experiments will provide insights into the mechanisms and signals responsible for synchronization between SCN cells. Furthering our knowledge of how SCN cells work together to constitute a master clock is key to understand and treat circadian pathologies. PUBLIC HEALTH RELEVANCE: The physiology and behavior of mammals, including humans, show robust 24-hour oscillations that are generated and coordinated by an area within the brain's hypothalamus called the suprachiasmatic nucleus. This nucleus contains a biological clock that is made up by several thousand neurons that are themselves clock neurons capable of oscillating independently. Thus, the synchronization between neurons within the suprachiasmatic nucleus is essential for the normal timing of physiological and behavioral rhythms such as the release of hormones and the sleep-wake cycle. Revealing how these neurons communicate with each other is critical to understand the neural bases of some disorders causing abnormal timing of these functions as well as to treat pathologies that result from challenges associated with our modern around-the- clock society, such as traveling across time zones or nocturnal shift work schedules.