The sleep-wake distribution contributes to the peripheral rhythms in PERIOD-2.
The sleep-wake distribution contributes to the peripheral rhythms in PERIOD-2.
复制标题
睡眠效果分布有助于周期2中的外围节奏。
DOI：
10.7554/elife.69773
复制
发表时间：
2021-12-13
期刊：
影响因子：
7.7
通讯作者：
Franken P
中科院分区：
文献类型：
--
作者：
Hoekstra MM;Jan M;Katsioudi G;Emmenegger Y;Franken P
在小鼠中，视交叉上核（SCN）周围组织中的Period-2（Per2）表达在睡眠剥夺期间和一天中动物主要自发清醒的时间增加，表明昼夜节律睡眠-觉醒分布直接影响Per2的每日节律。我们通过记录自由行为小鼠的睡眠-觉醒状态以及 PER2 生物发光来支持这一假设，证明 PER2 生物发光在自发觉醒期间增加，在睡眠期间减少。每日反复睡眠剥夺的行为心律失常 SCN 损伤小鼠的 PER2 生物发光节律性暂时恢复证实了我们的假设。数学模型表明，PER2 动力学可以通过由两种力驱动的阻尼谐振子来描述：依赖于睡眠-觉醒的力和独立于 SCN 的昼夜节律力。我们的工作强调了这样一个概念，即在外周组织中，时钟基因电路整合了睡眠-觉醒信息，从而有助于响应稳态要求的行为适应性。昼夜节律是行为和生理的日常周期，大约每 24 小时重复一次。这些节律的主要调节器位于大脑的一小部分，称为视交叉上核。这种大脑结构调节睡眠和觉醒的时间，也被认为在分子水平上控制全身细胞的日常节律。它通过同步一组称为时钟基因的基因的活动来实现这一点。在正常情况下，时钟基因编码的蛋白质水平在一天中会按照与睡眠-觉醒模式相匹配的节律发生变化。然而，让动物和人类在自己喜欢的睡眠时间保持清醒会影响身体许多组织中时钟基因的蛋白质水平。这表明，除了视交叉上核之外，睡眠-觉醒周期也可能影响整个身体的时钟基因节律。为了检验这一理论，Hoekstra、Jan 等人。在跟踪小鼠的睡眠-觉醒状态时，测量了 PERIOD-2（一种由时钟基因 period-2 编码的蛋白质）的水平。他们通过对大脑和肾脏中的 PERIOD-2 蛋白的生物发光版本进行成像，同时记录动物的大脑活动、运动和肌肉反应来做到这一点。结果显示，PERIOD-2 在小鼠醒来时增加，在小鼠入睡时减少。此外，在睡眠-觉醒行为缺乏昼夜节律的小鼠中（其 PERIOD-2 水平随时间的变化大大减少），强制规律的睡眠-觉醒周期可以恢复正常的 PERIOD-2 节律。接下来，Hoekstra，Jan 等人。开发了一个数学模型来了解睡眠-觉醒周期和昼夜节律如何影响大脑和肾脏中的时钟基因活动。计算机模拟表明，睡眠-觉醒周期和昼夜节律因素作为驱动时钟基因动态的同等强度的力量。两者需要协调一致才能保持时钟基因的节奏。该模型还预测了睡眠剥夺对 PERIOD-2 水平的巨大而直接的影响，进一步证实了这样的观点：醒来会加速生物钟基因节律，而睡眠会减慢它们。模型还表明，有规律的时钟基因节律可以防止睡眠障碍。总之，这项工作展示了睡眠模式如何影响大脑和身体时钟基因的日常节律。研究结果支持这样的观点，即合理的睡眠-觉醒时间表可以帮助人们适应新的时区。告知其他减少轮班工作对健康影响的策略也可能有用。
In the mouse, Period-2 (Per2) expression in tissues peripheral to the suprachiasmatic nuclei (SCN) increases during sleep deprivation and at times of the day when animals are predominantly awake spontaneously, suggesting that the circadian sleep-wake distribution directly contributes to the daily rhythms in Per2. We found support for this hypothesis by recording sleep-wake state alongside PER2 bioluminescence in freely behaving mice, demonstrating that PER2 bioluminescence increases during spontaneous waking and decreases during sleep. The temporary reinstatement of PER2-bioluminescence rhythmicity in behaviorally arrhythmic SCN-lesioned mice submitted to daily recurring sleep deprivations substantiates our hypothesis. Mathematical modeling revealed that PER2 dynamics can be described by a damped harmonic oscillator driven by two forces: a sleep-wake-dependent force and an SCN-independent circadian force. Our work underscores the notion that in peripheral tissues the clock gene circuitry integrates sleep-wake information and could thereby contribute to behavioral adaptability to respond to homeostatic requirements. Circadian rhythms are daily cycles in behavior and physiology which repeat approximately every 24 hours. The master regulator of these rhythms is located in a small part of the brain called the supra-chiasmatic nucleus. This brain structure regulates the timing of sleep and wakefulness and is also thought to control the daily rhythms of cells throughout the body on a molecular level. It does this by synchronizing the activity of a set of genes called clock genes. Under normal conditions, the levels of proteins coded for by clock genes change throughout the day following a rhythm that matches sleep-wake patterns. However, keeping animals and humans awake at their preferred sleeping times affects the protein levels of clock genes in many tissues of the body. This suggests that, in addition to the supra-chiasmatic nucleus, sleep-wake cycles may also influence clock-gene rhythms throughout the body. To test this theory, Hoekstra, Jan et al. measured the levels of PERIOD-2, a protein coded for by the clock gene Period-2, while tracking sleep-wake states in mice. They did this by imaging a bioluminescent version of the PERIOD-2 protein in the brain and the kidneys, at the same time as they recorded the brain activity, movement and muscle response of animals. Results showed that PERIOD-2 increased on waking and decreased when mice fell asleep. Additionally, in mice lacking a circadian rhythm in sleep-wake behavior – whose changes in PERIOD-2 levels with respect to time were greatly reduced – imposing a regular sleep-wake cycle restored normal PERIOD-2 rhythmicity. Next, Hoekstra, Jan et al. developed a mathematical model to understand how sleep-wake cycles together with circadian rhythms affect clock-gene activity in the brain and kidneys. Computer simulations suggested that sleep-wake cycles and circadian factors act as forces of comparable strength driving clock-gene dynamics. Both need to act in concert to keep clock-genes rhythmic. The model also predicted the large and immediate effects of sleep deprivation on PERIOD-2 levels, giving further credence to the idea that waking accelerated clock-gene rhythms while sleeping slowed them down. Modelling also suggested that having regular clock-gene rhythms protects against sleep disturbances. In summary, this work shows how sleep patterns contribute to the daily rhythms in clock genes in the brain and body. The findings support the idea that well-timed sleep-wake schedules could help people to adjust to new time zones. It might also be useful to inform other strategies to reduce the health impacts of shift work.
影响因子：
11.4
作者：
Chong, S. Y. Christin;Ptacek, Louis J.;Fu, Ying-Hui
通讯作者：
Fu, Ying-Hui