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

描述(申请人提供)：哺乳动物的下丘脑视交叉上核(SCN)包含一个主生物钟，它控制生理和行为节律。SCN由单细胞神经元振荡器组成，这些振荡器相互耦合，产生连贯的昼夜节律输出。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)在SCN细胞间通讯中的作用。具体目标C.1旨在确定非介导性耦合在确定起搏器在SCN内的自由运行周期方面的作用。具体目的C.2将评估SCN内的NO细胞间信号在光诱导的昼夜节律的相位重置中的作用。最后，特殊目标C.3将在体外和体内评估NO信号在腹外侧和背内侧SCN之间的再同步中的作用，这些SCN通过将动物暴露在明暗周期的突然阶段推进而使它们失去同步性。拟议的实验将提供对SCN细胞之间同步的机制和信号的洞察。进一步了解SCN细胞如何共同构成主时钟是理解和治疗昼夜节律病理的关键。与公共健康相关：包括人类在内的哺乳动物的生理和行为显示出强大的24小时振荡，这种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。这个核团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性对于生理和行为节律的正常计时是必不可少的，例如激素的释放和睡眠-觉醒周期。揭示这些神经元是如何相互通信的，对于了解一些导致这些功能异常计时的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来说是至关重要的，例如跨越时区或夜间轮班工作时间。

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.