University of London

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.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Quantum fluctuations in one-dimensional superconductors are known to give rise to qualitative changes in behaviour of the superconductor, in a process called quantum phase slip. There are many proposals for superconducting nanowire devices making use of quantum phase slip, such as a quantum current standard, highly sensitive electric charge sensors, and phase slip flux qubits. At the moment this potential remains largely unrealised as the nature of quantum phase slip is still not fully understood. It is now known that successive phase slip events can be phase coherent, leading to a mechanism by which magnetic flux can coherently tunnel across a nanowire, and the superposition of different flux states has recently been demonstrated for the first time. In my project I aim to investigate the nature of coherent quantum phase slips, specifically by observing the interaction of nanowire devices with superconducting resonators, with a view to developing and characterising new coherent quantum phase slip flux qubits.

The vestibular system not only provides us with our sense of balance, but it helps us to understand the space around us. Starting from a set of tiny accelerometers inside the skull, the vestibular system detects our head movements and compares them to perceived movements in the world around us. By keeping track of our intended movements and the way the world seems to respond to them, the brain can assemble a mental picture of space that we use to organise our behaviour and remember how to get to the places we go. Our research seeks to understand the steps that happen between our initial detection of movement in the vestibular system, and the spatial abilities it ultimately allows. To do so, we focus on the most basic spatial construct, our sense of direction. If we rotate in place with our eyes closed, we know intuitively when we've returned to the starting point, and that same feeling allows us to walk around a city and keep track of the direction we started from. We have this sense of direction because the brain keeps a running tally of all the angular movements that the vestibular system detects, adding and subtracting from it as we change direction in a process called path integration. Keeping our sense of direction up to date seems to be the job of specialised cells in the brain called Head Direction (HD) cells. A given HD cell fires only when the head is pointed in a particular direction. When the head moves and points in a different direction, the neural signal moves to a different HD cell that corresponds with the new direction, which will remain active, even in the dark, until the next head turn. We want to understand how HD cells take movement signals from the vestibular system and turn them into directional signals, which they then pass on to parts of the brain that represent other features of space. To update the head's current direction, the size of its last rotation, its angular displacement, must be known. The vestibular system detects head acceleration, and passes along a signal that codes velocity. Do HD cells then do a velocity-to-direction conversion, or do they just respond to an already-converted displacement signal? We plan to answer this question by recording the activity of the neurons which lie between the vestibular and the HD systems, to see where their signal falls along the transition between acceleration and direction. We also want to understand how HD cells guide our navigational behaviour. Even though HD cells seem to act like a built-in compass, when we observe them as an animal is trying to solve a directional spatial problem, the behaviour and the cell activity don't always match. We want to solve this puzzle by recording HD cells while the animal solves the simplest possible spatial problem involving only their most recent rotation, and nothing else. In humans, this is done by rotating subjects in the dark, and then asking them to use a joystick to steer their rotating chair back to the starting point. We can ask a mouse to do the same thing by giving it a sweetened milk reward only at a specific, learned direction, so that when the mouse licks the reward spout, it is telling us which direction it thinks it is facing. At the same time, we can give the mice visual signals that don't match the vestibular rotation signals. When visual and vestibular signals disagree, the brain recalibrates the vestibular system to make it line up with vision again. This re-tuning means that the HD cells would receive a different input signal than usual, and the mice's judgements of rotation will reflect the changes in the HD cell firing that result. Finally, we will a use a novel technique that will allow us to visualise HD cells in the living brain. We will image the activity of HD cells while the animal walks in a virtual reality environment, and then add visual-vestibular mismatch. This will tell us if the HD neural circuit rearranges itself to accommodate the re-tuning that follows.

A birth cohort study follows the same babies throughout their lives to understand more about how a child's very early social, emotional and physical development and their family and wider environment influences their future development, health and wellbeing as well as their risk of future ill health. These special types of studies give insights into what is called the life course starting in early life - they are a unique and special way to find out how early life experiences matter for later childhood and adult life. Our study will help identify what aspects of the environment in its broadest sense protect children and maximise their life chances and the ways in which that protection operates. It will also help us understand what aspects may increase vulnerability. We wish to understand the interplay between environmental and biological influences in early life recognising that this needs understanding of parents' lives and the wider family and society too. We will invite more than 100,000 pregnant women and their partners from across the UK to join our study. We want to include women and their partners from all walks of life. We will work to maximise recruitment of people from different ethnic groups. In pregnancy both parents will be interviewed, weighed and measured and asked to take part in some simple computer based tests. Parents will be asked to bring their baby to be seen at 6 and 12 months of age for some body size measurements and eye and child development tests. There will be no blood tests for the baby. We hope to follow all the children and their families throughout childhood and adult life so that we can see how they grow and develop and how their family circumstances change. We will do that in a number of ways including by getting consent at the beginning of the study to link to future routine health and other records of the baby and the parent. Scientists and others learn a lot from these large studies about how we can help children get a good start in life and improve their life chances and future well being and happiness. The information collected will be anonymised and made available to researchers to analyse to make sure we get the most benefit from it. We will be able to compare the Life Study generation with information collected from earlier generations in similar special British cohort studies. We will make sure that families taking part are informed about the progress of the study and any early findings and will ensure that other scientists, in the UK and abroad, policymakers and all members of the public also get to hear about Life Study findings.