Consequences of Artificial Light Exposure for Healthy Physiology

地球上的生命是在昼夜节律变化的周期中进化出来的。结果，几乎所有的生物体都以大约24小时的周期进化出了内部生物钟。这些生物钟(源自拉丁语的“Circa diem”，或一天左右)使有机体能够预见并适应环境中可预测的变化。在哺乳动物中，生物钟位于大脑的视交叉上核(SCN)。SCN中的节律是由遗传时钟机制产生的。这种时钟机制存在于我们全身的细胞中，调节特定组织的功能。时钟的昼夜节律效应是没有用的，除非它能设置到正确的时间。SCN从眼睛接收光信息，眼睛包含光敏感细胞(光感受器)，使昼夜节律与外部明/暗(LD)周期同步。视网膜有两类视觉感光器--视杆(调节夜间视觉)和视锥(给我们白天的色觉)。过去二十年的工作导致了一种新型的视网膜光感受器系统的发现，该系统由表达蓝光敏感蛋白黑素的光敏视网膜神经节细胞的子集组成。晚间昏暗灯光对昼夜节律影响的研究使公众意识到晚间光照对昼夜节律的影响，尤其关注家庭照明和移动设备发出的富含蓝色的光线。晚上暴露在昏暗的灯光下会导致人体昼夜节律失调。我们最近的工作表明，这种昼夜节律效应也发生在老鼠身上，并伴随着我们全身生物钟的错位，包括肝脏、心脏和大脑。这种光线暴露的长期影响尚不清楚。然而，在其他类似错位的研究条件下，体重和新陈代谢、心脏功能以及学习和记忆都会发生变化。鉴于人工光照是现代生活中不可避免的特征，这对健康具有潜在的重要影响。拟议的研究他的项目将调查晚间光线暴露的长期后果。具体地说，我们将研究在昏暗的夜间条件下饲养3个月的小鼠，以研究它们的体重、新陈代谢和心脏功能的变化。我们还将研究荷尔蒙和血液化学的变化。老鼠还将接受一系列行为测试，看看晚上昏暗的光线是否会改变学习、记忆和情绪。通过使用大脑成像，我们可以看到特定大脑区域是否发生变化，以及它们与大脑其他区域的联系是如何变化的。为了确定这些影响是否由于生物钟无法适应而发生，我们将研究缺乏生物钟的小鼠，并预测这些动物不会受到影响。我们还将研究眼睛和SCN主时钟水平上神经元活动的变化。然后，我们将研究SCN主时钟以及全身几个关键组织中的基因表达模式，以了解这些组织是如何受到影响的。通过研究基因表达的常见调节因素，这将有助于我们理解晚上昏暗的光线影响全身生物钟的机制。最后，我们将测试改变光暴露模式如何避免光的有害昼夜节律效应。我们一生都暴露在人工照明下，对其生物效应几乎一无所知。这项提议将提供关于现代光环境的长期后果和这些反应背后的生物学机制的关键信息。至关重要的是，这项工作还将提供新的数据，以帮助设计和测试避免这些有害影响的策略。

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 clock mechanism. This clock mechanism is found in cells throughout our bodies, regulating tissue-specific functions. 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 contains light sensitive cells (photoreceptors) which synchronise circadian rhythms to the external light/dark (LD) cycle. The retinatains two classes of visual photoreceptor - the rods (which mediate night-time vision) and cones (which give us our day-time colour vision). Work over the last two decades has led to the discovery of a novel retinal photoreceptor system, consisting of a subset of photosensitive retinal ganglion cells expressing the blue-light sensitive protein melanopsin. DIM LIGHT IN THE EVENINGResearch on the effects of light on circadian rhythms has led to a remarkable public awareness of the circadian effects of evening light exposure, with a particular concern about blue-enriched light from home lighting and mobile devices. Exposure to dim light in the evening results in a misalignment of human circadian rhythms. Our recent work has shown that this circadian effect also occurs in mice and is accompanied by misalignment of circadian clocks found throughout our bodies, including in the liver, heart and brain. The long-term effects of such light exposure are unknown. However, under other study conditions where similar misalignment is seen, changes in body weight and metabolism, heart function and learning and memory occur. Given that artificial light exposure is an unavoidable feature of modern life, this has potentially important implications for health. PROPOSED STUDIESThis project will investigate the long-term consequences of evening light exposure. Specifically, we will study mice housed for 3 months under dim light in the evening conditions to investigate how their body weight, metabolism and heart function change. We will also study hormones and blood chemistry for changes. Mice will also undergo a range of behavioural tests to see if dim light in the evening alters learning, memory and mood. By using brain imaging, we can see if changes in specific brain regions occur, as well as how their connections with other areas of the brain change. To determine if these effects occur due to the circadian clock being unable to adapt, we will study mice that lack circadian clocks, with the prediction that these animals will be unaffected. We will also study changes in the activity of neurons at the level of the eye and the SCN master clock. We will then study the patterns of gene expression in the SCN master clock, as well as several key tissues throughout the body to see how these are affected. By studying common regulators of gene expression, this will help us understand the mechanisms by which dim light in the evening affects clocks throughout the body. Finally, we will test how changing the pattern of light exposure may avoid the detrimental circadian effects of 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 long-term consequences of the modern light environment and the biological mechanisms underlying these responses. Critically, this work will also provide new data to help devise and test strategies to avoid these detrimental effects.