Consequences of Artificial Light Exposure for Healthy Physiology

CIRCADIAN RHYTHMS
Life 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 LIGHT
A 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 EVENING
Research 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 STUDIES
This 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.

OUTCOMES
We 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.

This project addresses the specific mechanisms by which the modern light environment disrupts circadian rhythms. The widespread use of artificial lighting and light-emitting mobile devices means that we are increasingly exposed to dim light on an evening (DLE), when our circadian clocks are most sensitive to light. Accumulating evidence suggests that this can misalign circadian clocks found throughout our bodies, with negative consequences for long-term health. However, the extent of these effects on healthy physiology and our understanding of the mechanisms underlying them are limited. This information is critical if we are to develop and test strategies to mitigate these risks.

This proposal will characterise the long-term effects of DLE on metabolic, cardiovascular and cognitive function. Using a range of different phenotyping assays, we will determine the health consequence of long-term DLE (12 weeks). This will be complemented by small animal MRI to study changes in brain morphology and connectivity. We hypothesise that the detrimental effects of DLE occur via a mismatch between circadian rhythms and environmental time. To test this, we will study mice lacking circadian rhythms, where we expect the effects to be reduced. We will also study the effects of DLE on neuronal responses at the level of the retina and suprachiasmatic nuclei (SCN). We will use RNAseq to study the effects of DLE on gene expression at the level of the SCN, liver, heart, adrenal and hippocampus, using analysis of circadian transcriptional regulators to identify key mechanisms. Finally, we will investigate if interventions designed to reduce the circadian effects of DLE are effective in preventing these long-term health consequences.