期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：13498-13503
DOI：10.1073/pnas.1610342113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state can influence the phase of the circadian clock. Here we demonstrate that the level of wakefulness is critical for arousal to reset circadian clock phase. We then show that treatments that produce arousal and reset the circadian clock activate the basal forebrain. Finally, we demonstrate that cholinergic input from the basal forebrain is both necessary and sufficient for eliciting this arousal-induced resetting of the circadian clock. These results establish a functional link between the major forebrain arousal center and the circadian system. Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system.
