Mechanisms of circadian disruption by the modern light environment

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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.