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，几乎所有的生物体都进化出了内部生物钟，周期约为24小时。这些生物钟（来自拉丁语“circa diem”，或大约一天）使生物体能够预测和适应环境中可预测的变化。在哺乳动物中，主生物钟位于大脑的视交叉上核（SCN）中。SCN中的节律是由遗传反馈机制产生的，该机制调节我们整个身体的过程。光的昼夜效应时钟是没有用的，除非它可以设置到正确的时间。SCN接收来自眼睛的光信息，使昼夜节律与外部光/暗（LD）周期同步-这一过程称为夹带。这促使研究人员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体--视杆细胞（调节夜间视觉）和视锥细胞（给我们白天的色觉）。值得注意的是，缺乏视杆细胞和视锥细胞的小鼠仍然保持着对光的昼夜节律反应。这导致了一种新的视网膜感光系统的发现，该系统由表达蓝光敏感色素黑视素的光敏视网膜神经节细胞（pRGC）的子集组成。夜间蓝光黑视蛋白系统的发现使公众对夜间蓝光的昼夜节律效应有了显著的认识，包括对移动的设备发出的光的特别关注。这导致照明和电子行业的兴趣越来越大，他们热衷于开发照明以避免这些昼夜节律效应。然而，简单地减少蓝光忽略了这个系统的基本生物学。例如，黑视素pRGC不单独工作，并且接收来自视杆和视锥的光输入。因此，黑视素的损失不会消除昼夜节律的夹带。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的作用，这表明单独减少蓝光可能是无效的。建议的研究这个项目将调查的机制介导的影响，夜间曝光的昼夜节律。我们已经证明，在一周的时间里，在一个晚上暴露在昏暗的灯光下会导致小鼠的昼夜节律失调-复制人类研究。这为我们研究视网膜光感受器在夜间光昼夜节律紊乱中的作用提供了一个模型。通过研究此时对特定颜色和强度的光的反应，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。我们还可以使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照水平的作用，以确定白天（特别是早上）更亮的光线是否可以减少晚间光线的破坏性影响。根据第一组实验的结果，我们将比较我们的非破坏性照明条件与破坏性条件，以研究整个身体的生物钟如何受到长期暴露于夜间光线的影响。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性能如何受到光线的影响。结果我们一生都暴露在人工照明下，很少了解其生物效应。该提案将提供有关现代光环境的后果以及这些反应背后的生物机制的关键信息。重要的是，这项工作还将提供新的数据，以帮助设计照明，以避免这些不利影响。

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.