How does light control the activity and electrical properties of neurons integrating arousal behaviour, circadian rhythms, and sleep?

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Life on our planet is exposed to the regular changes of night and day. As a consequence animals have evolved a 24 hour timing mechanism, the so-called 'circadian clock', which tunes our behaviour and physiology to the day-night cycle (e.g. sleep-wake cycles, metabolism). An animal's clock still ticks when it lives in continuous darkness (i.e. a cave). Circadian clocks work similar to a normal clock, e.g. they run at a steady pace (with a 24hr period) and can be reset if they go wrong. In nature this resetting is caused by the environment, i.e. the regular changes of light and dark. As a consequence, circadian rhythms are synchronized with the environment. Famous examples for both the independence of circadian clocks and their ability to communicate with the environment are jetlag (caused by travel across time zones) or shift work. If you are jetlagged, your circadian clock is still ticking according to the time where you boarded your plane and is telling you to be awake in the middle of the night. Gradually though, your internal clock will adjust (synchronize) to the new time zone and you will feel comfortable again. Circadian clocks consist of clock genes that switch on and then switch themselves off every 24hrs in the clock neurons of the brain. Classical genetic experiments mostly performed using the fruit fly Drosophila identified nearly all the clock genes and the clock mechanism that was later found to be similar in humans. However, it is still not known how all the parts are integrated to form a working clock sensitive to light and able to orchestrate the physiology and behaviour of the whole animal: this is the overall aim of the current proposal.The fly clock consists of 150 neurons that communicate with each other via electrical and chemical signals that are thought to synchronise rhythms between these neurons generating the overall circadian behaviour. The number and frequency of these impulses (called electrical activity) controls the flow of information in the clock circuit, much like a computer. We wish to study the proteins involved in relaying these signals (called channels, co-transporters and receptors) between the clock neurons, which in turn control circadian behaviour and sleep. We know that the clock is exquisitely sensitive to light so we are interested in the proteins that transmit information about the light conditions to and around the clock. We previously isolated a light sensitive clock protein called Cryptochrome (Cry) in flies, which later was shown to have important circadian functions from plants to humans. Again we have used the power of fly genetics and discovered another key light sensor called Qsm, a channel called Shaw, a receptor called GABAA and co-transporter called NKCC that all influence the clock. In this proposal we want to work out how they fit together to control circadian behaviour, arousal and sleep. This will be achieved by answering the following experimental questions:1) What is the mechanism by which light activates Qsm and causes molecular and behavioural synchronization of the clock? We will go on to see if the human version of Qsm can also function in the clock.2) How do Qsm, Shaw and NKCC interact with each other in the clock?3) How does Shaw generate electrical signals in the clock neurons and how are these affected by light and Qsm? This will involve placing small electrodes on the clock neurons in the fly's brain and recording their electrical signals under different light conditions.4) How do Qsm, NKCC and GABAA receptors act together in the clock to control arousal and sleep? This research will help us to better understand the effect of light on circadian clocks and sleep identifying new potential targets for treatment of sleep disorders and jetlag. Research into circadian clocks and sleep is important as they profoundly affect our health, productivity and quality of life.