Regulation of Sleep by Environmental Light

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We spend around a third of our lives asleep and sleep disruption is a major contributing factor to a health problems ranging from poor vigilance and memory, reduced reaction times, reduced motivation, depression, metabolic abnormalities, obestity, reduced immunity and elevated risks of cancer and coronary heart disease. Sleep is a complex process, involving multiple areas of the brain and numerous neurotransmitters. It is regulated by the familiar process whereby there is a increased requirement for sleep with prolonged waking (the sleep homeostat) as well as a drive for wakefulness produced by the body's internal 24h clock (circadian clock). In addition, environmental light plays a critical role in regulating the timing of the sleep/wake cycle as well as acute changes in sleep and arousal states. Changes in the light environment are detected by eye via a number of different photoreceptive cells. These include the rods and cones which mediate image-forming vision. However, the last decade has witnessed the remarkable discovery of a new class of light sensitive cell in the eye. A small subset of the retinal ganglion cells that form the optic nerve that projects to the brain have been found to be directly photosensitive (pRGCs) due to the presence of the light-sensing protein melanopsin. Rather than enabling us to create precise images of the external world, these cells simply detect the brightness of environmental light (irradiance), playing a critical role in many non-image forming responses such as setting the body clock to the day-night cycle and regulating sleep. As such, the eye performs two very different sensory tasks - firstly, to generate images of the world around us and secondly, to sample the light environment to regulate a range of non-image forming responses, including sleep. Recent studies have shown that mice lacking melanopsin show reduced sleep when exposed to light during the night. However, the sleep timing with respect to the light/dark cycle is normal in these animals, and exposure to light at other times can still produce normal sleep responses. Our recent unpublished data show that whilst melanopsin contributes to sleep regulation in response to light, other photoreceptors also contribute. The light environment provides a complex stimulus, and as well as the irradiance, the wavelength and rate of change of the light are expected to determine which photoreceptors are involved. Little is known about the contribution of these photoreceptors under different lighting conditions, and as a result we have only a poor understanding of the optimum light environment for housing laboratory mice. This proposal aims to determine the contribution of rods, cones and melanopsin pRGCs to the regulation of sleep under different lighting conditions. In mice, sleep is normally measured by electroencephalography (EEG) which involves implanting electrodes to measure electrical activity of the brain. In mice, this is invasive as well as time-consuming and expensive. We have recently developed a method of measuring sleep in mice using miniature night-vision cameras placed above the animal's cage. Using computer software to track the animal's movement, and defining sleep as a period of extended immobility we are able to measure sleep with remarkable precision compared to simultaneous EEG measures. We will use this non-invasive, high-throughput approach to study responses to light in a range of mouse models in which rods, cones and melanopsin are genetically altered. We will also screen sleep responses in mutant mice produced by MRC Harwell to identify novel genes which are involved in the regulation of sleep in response to light. This work will lead to a greater understanding of the role of rods, cones and melanopsin pRGCs in the regulation of sleep and is expected to improve our understanding of how retinal disease may give rise to sleep disruption.