Many daily functions require us to hold the information of events that happen for a sufficient period time (e.g. remember where the car is parked for a few hours). However, our ability of holding spatial memory declines with age. Cognitive ageing imposes negative impacts on the life quality in our later life. Facing a rapidly ageing population, such impacts extend from the individual to the families and the society as a whole. If we have a better understanding on how the memory decline occurs, we are in a stronger position to provide strategies to improve our memory retention, which will lead to a cognitively healthier society. To understand how daily memory decays naturally over time, we propose to model this in rodents. This is because they provide invaluable opportunities to understand the brain mechanisms, to control the environmental factors, and to draw unconfounded causative conclusions. Indeed, using this model we know that memory formation and maintenance occurs in multi-phases. As we encounter an event in a place we 'encode' the experience. It undergoes a biological process in the brain to 'consolidate' it so we remember it later. As we 'retrieve' that information some time later, the memory undergoes another process in the brain to 'reconsolidate' and we can remember it for longer. Importantly, we have identified a time window around the spatial memory encoding, during which we can introduce a novel event to make the memory last longer. This method of using novelty as a memory-facilitating event has so far only been proven to work in young animals. The first aim will determine whether the same strategy helps middle-aged and older animals. We will also explore more effective strategies to make memories last in older animals. It will also allow us to know whether the encoding and consolidation processes are differentially affected at different stages of ageing. In real life, we do not always have the chance to target the encoding and consolidation process as the event happens. It therefore would be beneficial if we can target the reconsolidation process during the time window of memory retrieval to make the memory last. Hence, the second aim of the study is to establish whether introducing a novel event around memory retrieval can subsequently make the memory last longer. We will examine whether this is an effective approach to make memory last in older animals. While the first 2 studies provide behavioural strategies to improve the longevity of memory at different ages, at present we do not know how the memory-encoding and memory-facilitating events interact at the cellular level in the brain. Previous research has pinpointed a key brain area, called the hippocampus that is crucial for linking events and place and form an episodic or associative memory. Previous theories also hypothesize that the cellular networks activated by the memory-encoding and memory-facilitating events are overlapping in the hippocampus that interactively contribute to longer-lasting memory. To visualise the cellular activities for these two events, we will mark the active cells with two fluorescence-labelled genes that can be detected by confocal microscopes. This technique has previously been established and will be carried out with our collaborator in Japan. Together, this project will allow us to establish behavioural methods to improve memory so that they last longer in old animals and characterise the underpinning encoding or consolidation process that is affected by ageing. We will also understand the cellular mechanism for the facilitation of memory persistence to occur. The behavioural strategy that we use in this project is non-invasive and benign, and therefore can be translated to human studies in the near future through cross-discipline collaborations. Such knowledge can ultimately improve cognitive ageing in the society.

Japan

Light is a versatile tool for imaging and engineering on microscopic scales. Optical microscopes use focused light so that we can view specimens with high resolution. These microscopes are widely used in the life sciences to permit the visualisation of cellular structures and sub-cellular processes. However, the resolution of an optical microscope is often adversely affected by the very presence of the specimen it images. Variations in the optical properties of the specimen introduce optical distortions, known as aberrations, that compromise image quality. This is a particular problem when imaging deep into thick specimens such as skin or brain tissue. Ultimately, the aberrations restrict the amount of the specimen that can be observed by the microscope, the depth often being limited to a few cellular layers near the surface. This is a serious limitation if one wants to observe cells and their processes in their natural environment, rather than on a microscope slide. I am developing microscopes that will remove the problematic aberrations and enable high resolution imaging deep in specimens.Focused light also has other less well-known uses. It can be used to initiate chemical reactions that create polymer or metal building blocks for fabrication on the sub-micrometre scale. These blocks, with sizes as small as a few tens of nanometers, can be built into structures in a block-by-block fashion. Alternatively, larger blocks of material can be sculpted into shape using the high intensities of focused lasers. These optical methods of fabrication show potential for use in the manufacture of nanotechnological devices. When manufacturing such devices, the laser must be focused through parts of the pre-fabricated structure. The greater the overall size and complexity of the structures, the more the effects of aberrations degrade the precision of the fabrication system. My research centres on the use of advanced techniques to measure and correct such distortions, restoring the accuracy of these optical systems.Traditional optical systems consist mainly of static elements, e.g. lenses for focusing, mirrors for reflecting and scanning, and prisms for separating different wavelengths. However, in the systems I use the aberrations are changing constantly. Therefore they require an adaptive method of correction in which the aberrations are dynamically compensated. These adaptive optics techniques were originally developed for astronomical and military purposes, for stabilising and de-blurring telescope images of stars and satellites. Such images are affected by the aberrations introduced by turbulence in the Earth's atmosphere. The most obvious manifestation of this is the twinkling of stars seen by the naked eye. Recent technological developments, such as compact and affordable deformable mirrors for compensating the optical distortions, mean that this technology is now being developed for more down-to-Earth reasons. This has opened up the possibility of using adaptive optics in smaller scale applications.In conjunction with researchers in Japan and Australia, I will develop adaptive optical fabrication systems that will be able to produce complex micrometre-scale structures with greater accuracy than was previously possible. With biologists in the University of Oxford, I will use adaptive optics to increase the capabilities of microscopes in imaging deep into thick specimens. This will enable biologists to learn more about the processes that occur within cells and the development of organisms. The aberration correction technology will also have use in other areas such as medical imaging, optical communications and astronomy.

Nuclear physics research is undergoing a transformation. For a hundred years, atomic nuclei have been probed by collisions between stable beams and stable targets, with just a small number of radioactive isotopes being available. Now, building on steady progress over the past 20 years, it is at last becoming possible to generate intense beams of a wide range of short-lived isotopes, so-called "radioactive beams". This enables us vastly to expand the scope of experimental nuclear research. For example, it is now realistic to plan to study in the laboratory a range of nuclear reactions that take place in exploding stars. Thereby, we will be able to understand how the chemical elements that we find on Earth were formed and distributed through the Universe. At the core of our experimental research is our strong participation at leading international radioactive-beam facilities. While we are now contributing, or planning to contribute, to substantial technical developments at these facilities, the present grant request is focused on the exploitation of the capabilities that are now becoming available. Experimental progress is intimately linked with theory, where novel and practical approaches are a hallmark of the Surrey group. An outstanding feature, which is key to our group's research plans and is unique in the UK, is our powerful blend of theoretical and experimental capability. Our science goals are aligned with current STFC strategy for nuclear physics, as expressed in detail through the Nuclear Physics Advisory Panel. We wish to understand the boundaries of nuclear existence, i.e. the limiting conditions that enable neutrons and protons to bind together to form nuclei. Under such conditions, the nuclear system is in a delicate state and shows unusual phenomena. It is very sensitive to the properties of the nuclear force. For example, weakly bound neutrons can orbit their parent nucleus at remarkably large distances. This is already known, and our group made key contributions to this knowledge. What is unknown is whether, and to what extent, the neutrons and protons can show different collective behaviours. Also unknown, for most elements, is how many neutrons can bind to a given number of protons. It is features such as these that determine how stars explode. To tackle these problems, we need a more sophisticated understanding of the nuclear force, and we need experimental information about nuclei with unusual combinations of neutrons and protons to test our theoretical ideas and models. Therefore, theory and experiment go hand-in-hand as we push forward towards the nuclear limits. An overview of nuclear binding reveals that about one half of predicted nuclei have never been observed, and the vast majority of this unknown territory involves nuclei with an excess of neutrons. Much of our activity addresses this "neutron-rich" territory, exploiting the new capabilities with radioactive beams. Our principal motivation is the basic science, and we contribute strongly to the world sum of knowledge and understanding. Nevertheless, there are more-tangible benefits. For example, our radiation-detector advances can be incorporated in medical diagnosis and treatment. In addition, we provide an excellent training environment for our research students and staff, many of whom go on to work in the nuclear power industry, helping to fill the current skills gap. On a more adventurous note, our special interest in nuclear isomers (energy traps) could lead to novel energy applications. Furthermore, we have a keen interest in sharing our specialist knowledge with a wide audience, and we already have an enviable track record with the media.

It is often considered that there are two types of scientist: theoretical and experimental. Theoretical scientists invent/discover new theories to explain the natural world. Experimental scientists invent experiments to test these theories. For example, the theoretical physicist Albert Einstein invented the theory of General Relativity, and astronomers tested General Relativity by inventing the idea of observing the position of stars near the Sun during a solar eclipse. Artificial Intelligence (AI) is increasingly being used in scientific research. Almost all of this effort is in the formation of new hypotheses to explain data. This corresponds to what theoretical scientists do. Far less effort has been put into automating what experimental scientists do. This is what the proposed research focus on. We propose to develop a 'Robot Experimentalist'. This will be an AI system that when given a hypothesis to be tested, and a description of a set of laboratory equipment, will be able to plan an experiment to test the hypothesis. To make the problem tractable we will focus on experiments using the yeast S. cerevisiae. This is the organism used to make bread, beer, and wine; but its main role in biology is as a model for human cells. Surprisingly, most of what is true for S. cerevisiae is also true for H. sapiens. We will test the Robot Experimentalist using laboratory robots in the UK and Japan.