Interaction between circadian and sleep circuits

项目摘要 这项计划的目的是确定睡眠的时间是如何控制的。虽然生物钟 驱动睡眠的24小时节律性，睡眠的开始和持续时间也由先前的程度决定。 清醒后者代表着体内平衡控制，确保生物体获得足够的睡眠。在 一天的周期，昼夜节律和体内平衡系统是一致的，所以睡眠发生在晚上后，一天的 清醒然而，夜间睡眠不足或现代生活方式的某些方面，如轮班或时差， 导致昼夜节律和体内平衡系统失调。例如，经过一夜的睡眠剥夺， 尽管早晨是昼夜节律唤醒的时间，但体内平衡机制将驱动睡眠。即使在 在这些情况下，昼夜节律系统会影响睡眠，因此会减少夜班的睡眠量 工人可能会在白天。因此，昼夜节律和体内平衡系统之间的相互作用发生 一直以来，人们都不太了解。 使用果蝇模型，我们已经解剖了中枢大脑时钟控制节奏的电路， 自发活动我们现在发现，我们识别的特定昼夜节律输出神经元与基因座发生联系， 调节睡眠的稳态控制。我们的数据表明，睡眠稳态抑制昼夜唤醒 在一天中的错误时间允许睡眠的信号，例如在睡眠剥夺后的早晨。在 此外，我们还发现了睡眠稳态细胞中钙离子的节律，以及它们的昼夜节律调节。 睡眠输出。节律性睡眠输出可能是由于特定时钟神经元的平行效应， 在一天中的特定时间唤醒，但与睡眠中神经活动（钙）的日常调节一起 这些发现为我们提供了一个确定昼夜节律信号是如何整合的手柄， 自我平衡的线索。为了解决这些系统控制睡眠时间的机制，我们 建议：（1）确定睡眠稳态细胞如何以及何时作用于昼夜输出神经元， 抑制觉醒;（2）确定昼夜节律和睡眠信号如何整合在昼夜节律输出神经元中。 由于这些输出神经元也反馈给时钟神经元，它们在连接昼夜节律和生物钟神经元方面发挥着关键作用。 （3）确定生物钟如何与光和稳态信号相互作用，以调节生物钟。 睡眠稳态神经元的输出。 睡眠周期失调和中断会对健康造成严重影响，包括神经系统疾病 例如中风，所以我们希望这项工作具有广泛的医学相关性。

Project Summary The goal of this proposal is to determine how the timing of sleep is controlled. Although the circadian clock drives the 24 hour rhythmicity of sleep, the onset and duration of sleep is also determined by the extent of prior wakefulness. The latter represents homeostatic control, which ensures that an organism gets enough sleep. In a daily cycle, circadian and homeostatic systems are aligned, so sleep occurs at night following a day of wakefulness. However, sleep loss at night or aspects of modern lifestyles, such as shiftwork or jetlag, can cause misalignment of circadian and homeostatic systems. For instance, following a night of sleep deprivation, homeostatic mechanisms will drive sleep in the morning although it is a time of circadian arousal. Even under these conditions, the circadian system influences sleep and so will curtail the amount of sleep a night shift worker might get during the day. Thus, interactions between circadian and homeostatic systems occur constantly and are poorly understood. Using a Drosophila model, we have dissected circuits by which the central brain clock controls rhythms of locomotor activity. We now find that specific circadian output neurons we identified make contact with loci that mediate homeostatic control of sleep. Our data suggest that the sleep homeostat suppresses circadian arousal signals to allow sleep at the wrong time of day, e.g. in the morning following a night of sleep deprivation. In addition, we find a rhythm of calcium in cells of the sleep homeostat as well as circadian regulation of their sleep output. Rhythmic sleep output could be due to parallel effects of specific clock neurons, which drive arousal at specific times of day, but together with the daily modulation of neural activity (calcium) in sleep homeostatic cells, these findings provide us with a handle to determine how circadian signals are integrated with homeostatic cues. To address the mechanisms by which these systems control the timing of sleep, we propose to: (1) Determine how and when cells of the sleep homeostat act on circadian output neurons to suppress arousal; (2) Determine how circadian and sleep signals are integrated in circadian output neurons. As these output neurons also feedback to clock neurons, they play a critical role in linking the circadian and homeostatic systems; (3) Determine how the clock interacts with light and homeostatic signals to modulate the output of sleep homeostatic neurons. Misaligned and disrupted sleep cycles have severe health consequences, including neurological disorders such as stroke, so we expect this work to have broad medical relevance.