Mechanisms of circadian disruption by the modern light environment

昼夜节律地球上的生命是在昼夜节律变化的循环中进化的。因此，几乎所有生物都进化出了周期为~24小时的内部生物钟。这些生物钟（源自拉丁语“circa diem”，意思是一天左右）使生物体能够预测并适应环境中可预测的变化。哺乳动物的主生物钟位于大脑的视交叉上核（SCN）。SCN中的节律是由一种基因反馈机制产生的，这种机制调节着我们全身的过程。光的昼夜节律效应一个时钟没有用处，除非它能被设置到正确的时间。SCN接收来自眼睛的光信息，将昼夜节律与外部光/暗（LD）周期同步——这一过程被称为夹带。这使得研究人员开始研究介导这些效应的光敏细胞（光感受器）。视网膜包含两类感光细胞——杆状细胞（调节夜间视觉）和锥状细胞（赋予我们白天的色彩视觉）。值得注意的是，缺乏视杆细胞和视锥细胞的小鼠仍然保持对光的昼夜节律反应。这导致了一种新的视网膜光感受器系统的发现，该系统由光敏视网膜神经节细胞（pRGCs）的一个子集组成，表达蓝光敏感的色素黑视素。夜间的蓝光黑视素系统的发现引起了公众对夜间蓝光对昼夜节律的影响的极大关注，包括对移动设备发出的光的特别关注。这引起了照明和电子行业越来越大的兴趣，他们热衷于开发避免这些昼夜节律影响的照明。然而，简单地减少蓝光忽略了这个系统的基本生物学原理。例如，黑视素prgc不能孤立地工作，而是接受来自杆状细胞和视锥细胞的光输入。因此，黑视素的丧失并不能消除昼夜节律干扰。事实上，越来越多的数据表明，视杆细胞和视锥细胞也起着重要作用，这表明仅仅减少蓝光可能是无效的。本项目将研究夜间光照对昼夜节律影响的调节机制。我们已经证明，在一个星期的过程中，在一个晚上暴露在昏暗的光线下，会使老鼠的昼夜节律失调——复制人类的研究。这为我们研究视网膜光感受器在昼夜节律中断中的作用提供了一个模型。通过研究此时对特定颜色和光强度的反应，我们可以确定哪些光感受器起作用。然后，我们可以根据这些光感受器开发照明条件，使我们能够最大限度地减少这些昼夜节律的影响。我们也可以用缺乏关键光感受器的小鼠模型来证实我们的发现。这些研究还将调查白天光线水平的作用，以确定白天（特别是早晨）较亮的光线是否可以减少夜晚光线的破坏性影响。基于第一组实验的结果，我们将比较非破坏性照明条件和破坏性照明条件，以研究长期暴露在夜间光线下对全身生物钟的影响。我们还将利用这些条件来研究光如何激活大脑，使我们能够了解参与这些反应的关键大脑区域。最后，我们将使用这些照明条件来研究睡眠和表现如何受到光线的影响。结果我们一生都暴露在人工照明下，却很少意识到它的生物效应。该提案将提供有关现代光环境后果和这些反应背后的生物学机制的关键信息。重要的是，这项工作还将提供新的数据来帮助设计照明，以避免这些有害影响。

CIRCADIAN RHYTHMSLife on Earth has evolved under a rhythmically changing cycle of day and night. As a result, virtually all organisms have evolved internal biological clocks with a period of ~24h. These circadian clocks (from the Latin 'circa diem', or around a day) enable organisms to anticipate and adapt to predictable changes in their environment. In mammals, the master circadian clock is located in the suprachiasmatic nuclei (SCN) in the brain. Rhythms in the SCN are generated by a genetic feedback mechanism which regulates processes throughout our bodies. CIRCADIAN EFFECTS OF LIGHTA clock is of no use unless it can be set to the correct time. The SCN receives light information from the eye, which synchronises circadian rhythms to the external light/dark (LD) cycle - a process termed entrainment. This led researchers to investigate the light sensitive cells (photoreceptors) mediating these effects. The retinal contains two classes of photoreceptor - the rods (which mediate night-time vision) and cones (which give us our day-time colour vision). Remarkably, mice lacking both rods and cones still retain circadian responses to light. This led to the discovery of a novel retinal photoreceptor system, consisting of a subset of photosensitive retinal ganglion cells (pRGCs) expressing the blue-light sensitive pigment melanopsin. BLUE LIGHT AT NIGHTThe discovery of the melanopsin system has led to a remarkable public awareness of the circadian effects of evening blue light, including a particular concern about light from mobile devices. This has resulted in an increasing interest from the lighting and electronics industry, who are keen to develop lighting to avoid these circadian effects. However, simply reducing blue light overlooks the basic biology of this system. For example, melanopsin pRGCs do not work in isolation, and receive light input from rods and cones. As such, loss of melanopsin does not abolish circadian entrainment. Indeed, increasing data indicate that rods and cones also play important roles, which suggest that reducing blue light alone may be ineffective. PROPOSED STUDIESThis project will investigate the mechanisms mediating the effects of evening light exposure on circadian rhythms. We have shown that exposure to dim light on an evening over the course of a week produces a misalignment of circadian rhythms in mice - replicating human studies. This provides a model for us to study the role of retinal photoreceptors in circadian disruption to evening light. By studying this response to specific colours and intensities of light at this time, we can define which photoreceptors contribute. We can then develop lighting conditions based upon these photoreceptors, enabling us to minimise these circadian effects. We can also confirm our findings using mouse models which lack the key photoreceptors. These studies will also investigate the role of daytime light levels to determine if brighter light during the day (and specifically the morning) can reduce the disruptive effects of evening light. Based on the findings of this first set of experiments, we will then compare our non-disruptive lighting conditions with disruptive conditions to study how circadian clocks throughout the body are affected by long-term exposure to evening light. We will also use these conditions to study how light activates the brain to enable us to understand the key brain regions involved in these responses. Finally, we will use these lighting conditions to investigate how sleep and performance are influenced by light. OUTCOMESWe are exposed to artificial lighting throughout our lives with little appreciation of its biological effects. This proposal will provide critical information about the consequences of the modern light environment and the biological mechanisms underlying these responses. Critically, this work will also provide new data to help design lighting to avoid these detrimental effects.