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多尺度时间分辨分析揭示了没有典型生物钟的小鼠中剩余的行为节律。

Multiscale Time-resolved Analysis Reveals Remaining Behavioral Rhythms in Mice Without Canonical Circadian Clocks.

机构信息

Department of Physics, Lancaster University, Lancaster, UK.

Department of Bioengineering, Imperial College London and The Institute of Cancer Research, London, UK.

出版信息

J Biol Rhythms. 2022 Jun;37(3):310-328. doi: 10.1177/07487304221087065. Epub 2022 May 16.

Abstract

Circadian rhythms are internal processes repeating approximately every 24 hours in living organisms. The dominant circadian pacemaker is synchronized to the environmental light-dark cycle. Other circadian pacemakers, which can have noncanonical circadian mechanisms, are revealed by arousing stimuli, such as scheduled feeding, palatable meals and running wheel access, or methamphetamine administration. Organisms also have ultradian rhythms, which have periods shorter than circadian rhythms. However, the biological mechanism, origin, and functional significance of ultradian rhythms are not well-elucidated. The dominant circadian rhythm often masks ultradian rhythms; therefore, we disabled the canonical circadian clock of mice by knocking out genes, where and are essential components of the mammalian light-sensitive circadian mechanism. Furthermore, we recorded wheel-running activity every minute under constant darkness for 272 days. We then investigated rhythmic components in the absence of external influences, applying unique multiscale time-resolved methods to analyze the oscillatory dynamics with time-varying frequencies. We found four rhythmic components with periods of ∼17 h, ∼8 h, ∼4 h, and ∼20 min. When the ∼17-h rhythm was prominent, the ∼8-h rhythm was of low amplitude. This phenomenon occurred periodically approximately every 2-3 weeks. We found that the ∼4-h and ∼20-min rhythms were harmonics of the ∼8-h rhythm. Coupling analysis of the ridge-extracted instantaneous frequencies revealed strong and stable phase coupling from the slower oscillations (∼17, ∼8, and ∼4 h) to the faster oscillations (∼20 min), and weak and less stable phase coupling in the reverse direction and between the slower oscillations. Together, this study elucidated the relationship between the oscillators in the absence of the canonical circadian clock, which is critical for understanding their functional significance. These studies are essential as disruption of circadian rhythms contributes to diseases, such as cancer and obesity, as well as mood disorders.

摘要

昼夜节律是生物体内大约每 24 小时重复的内部过程。主要的昼夜节律起搏器与环境的明暗周期同步。其他昼夜节律起搏器可以具有非典型的昼夜节律机制,这些起搏器可以通过唤醒刺激来揭示,例如定时喂养、美味的食物和跑步轮的使用,或使用安非他命。生物体也有超昼夜节律,其周期短于昼夜节律。然而,超昼夜节律的生物机制、起源和功能意义还没有很好地阐明。主要的昼夜节律往往掩盖了超昼夜节律;因此,我们通过敲除 和 基因来破坏小鼠的典型生物钟, 和 是哺乳动物光敏感昼夜节律机制的重要组成部分。此外,我们在持续黑暗下每 1 分钟记录一次跑步轮活动,持续 272 天。然后,我们在没有外部影响的情况下研究了节律成分,应用独特的多尺度时间分辨方法来分析具有时变频率的振荡动力学。我们发现了四个节律成分,周期分别为约 17 小时、约 8 小时、约 4 小时和约 20 分钟。当约 17 小时的节律占主导地位时,约 8 小时的节律幅度较低。这种现象大约每 2-3 周周期性地发生。我们发现,约 4 小时和 20 分钟的节律是约 8 小时节律的谐波。从较慢的振荡(约 17、约 8 和约 4 小时)到较快的振荡(约 20 分钟)的提取瞬时频率的脊线耦合分析揭示了强而稳定的相位耦合,反之亦然,以及较慢的振荡之间的弱而不太稳定的相位耦合。总的来说,这项研究阐明了在没有典型生物钟的情况下振荡器之间的关系,这对于理解它们的功能意义至关重要。这些研究是必要的,因为昼夜节律的破坏会导致癌症、肥胖症以及情绪障碍等疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b8b/9160956/f37897f17b47/10.1177_07487304221087065-fig1.jpg

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