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

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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.