The neurotransmitter dopamine, in the brain region called the striatum, is vitally important for our everyday actions and motivations. Without dopamine we develop Parkinson's disease and cannot move, but with too much dopamine, we develop addictions. If we could understand more about how dopamine is controlled by the brain, we might better understand how the brain regulates these behaviours, and how we might treat them better in disease. This project builds on a newly emerging area of neuroscience research that is transforming our understanding of the way brain circuits are regulated. In particular, new research suggests that neurons in the brain can be controlled by non-neuronal cells called astrocytes. In this project, we will explore whether astrocytes might control dopamine function. This is an area of biology which has been completely overlooked until now. Astrocytes vastly outnumber neurons in the brain and have long been known to be important for generally maintaining the brain and its supply of nutrients. Our current understanding of astrocyte function in brain circuits lags significantly behind our understanding of neuronal function but is now beginning to grow rapidly thanks to the advent of new experimental tools to modulate astrocyte activity. Recent work with these new tools demonstrates that astrocytes have more roles than once believed, and that strikingly, they can play powerful roles in directly regulating neurotransmitter release. In this project, we will examine for the first time, the fundamentally important questions of whether astrocytes in the striatum can modulate dopamine release and function. Until now, no-one has established whether or not astrocytes play a role in regulating dopamine release in the striatum. We have some new data which strongly suggest that astrocytes play an important role. Our first main aims will be to establish whether astrocytes in striatum dynamically modulate dopamine release, the mechanisms through which they might do it, and whether this impacts on dopamine-dependent behaviours. We will use state-of-the art tools, called chemogenetics and optogenetics, to specifically modulate the activity of astrocytes in mouse brains to understand their impact on dopamine function. Our second main aim will be to understand better whether there are changes to the biology of astrocytes in the striatum in Parkinson's disease. Astrocytes have been implicated as playing a role in Parkinson's disease, as well as in other neurodegenerative diseases, in which they can lose their supportive roles and gain neurotoxic properties. We have some new data which suggest that there are changes to the way that astrocytes work in striatum in Parkinson's disease and that might have negative consequences for dopamine function in the striatum. In this project, we will develop a better understanding of how astrocytes change in humans as well as in animal models, and test whether and how this impacts negatively on dopamine function in Parkinson's disease. Overall we expect this new and original project to greatly increase fundamental knowledge about how astrocytes control brain function in health and disease. It should cause a big shift in thinking. We expect to find that astrocytes are key players in governing dopamine function and that there are disruptions to the way that astrocytes operate and control dopamine function in Parkinson's disease. This work could also open up potential new avenues for drug discovery, by identifying disruptions to astrocyte biology that could be targets for future treatments for Parkinson's disease and other dopamine-related disorders.

Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterised by abnormal levels of naturally occurring proteins that clump together to form dense deposits in the brain. In Alzheimer's these deposits are formed from the amyloid-beta protein, and often termed amyloid plaques. The ways in which these plaques influence the onset and progression of the disease are still not fully understood. However, detailed studies of amyloid plaques have revealed a prevalence for them to contain microscopic particles (called nanoparticles) of different metals. It is not surprising to find metals in the brain, as the human body needs an incredible range of at least 10 different metallic elements in its everyday function, with much of our iron present as tiny nanoparticles of iron oxide (a form of rust). What is far more surprising is that the iron and copper nanoparticles we have observed within amyloid plaques, are not typical of oxidized metals such as rust. Instead, using sophisticated x-ray microscopy methods, we found that these particles were in fact stabilized in what are called low-oxidation states, including pure metallic elemental forms. This discovery is akin to finding a shiny metallic iron nail after it has been left in a field for many years. Just as we would expect the nail to oxidize over time due to the chemical reactivity of the metal surface, the nanoparticles (which have a much higher surface area relative to their size) are even more likely to oxidize. This surface reactivity can also result in toxicity when such nanoparticles are exposed to living tissue. Therefore, understanding how nanoparticles in this low-oxidation state are stabilized within the protein deposits found in the brain, could provide crucial insight into the interplay between metals and proteins in the brain and how this contributes to aging and disease. It is possible that the metal oxide nanoparticles themselves could drive the abnormal protein deposition, and in the process be transformed to low-oxidation states. Looking for evidence that these metal-protein interactions occur in brain tissue, as well as investigating the mechanisms by which the transformations could proceed, is one of the key aims of this project. Equally important though is finding the source of the oxidised metal particles that are transformed by the proteins. Interactions could occur between proteins and biological sources of metal oxides already present in the brain, but it is also possible that sources from outside the body are involved. Substantial evidence now exists suggesting ultrafine metal oxide particles that are present in some airborne forms of pollution, can enter the brain. It seems they do this via routes that bypass the brain's natural defences that normally prevent foreign material entering. A further aim of this project is therefore to investigate environmental nanoparticles collected from sites of known pollution in the UK, and to assess the likelihood that such particles are transformed to low-oxidation states in the brain. The project will use new state-of-the-art methods combined with physical science approaches, to build fundamental new knowledge regarding the biochemical processes that connect metals and proteins with aging and disease in the human brain. This will be of particular importance in the development of new drugs to treat diseases such as Alzheimer's, which currently focus only on the protein deposits with modest levels of success. Combined strategies that also target metals will offer new hope for effective treatments, whilst knowledge of how iron oxides are transformed could help develop more sensitive MRI diagnosis. The latter could use the accumulation of metallic forms of iron during protein aggregation to detect key changes in the brain prior to brain atrophy. Ultimately this could have huge impact on early interventions, with treatments tailored to target specific metal forms.

Antarctic sea ice thickness is arguably the largest gap in our knowledge of the climate system. While rapid changes in ice extent are evident in satellite imagery collected over the last three decades, we have little information with which to assess the thickness of the ice. Knowledge of the thickness distribution of sea ice and its snow cover is critical in understanding a wide range of air-sea-ice interactions. It's evolution over time provides a sensitive measure of the response of the polar regions to climate change and variability, and it controls the fluxes of heat, salt, and freshwater that govern air-sea interactions and water mass transformation. Whilst we are moving closer to the 'holy grail' of measuring Arctic sea ice thickness from space, such methods are severely limited in the Antarctic due to the deep snow cover. Moreover, our understanding of the processes that control Antarctic snow and ice thickness is inadequate. This proposal has two complementary lines of investigation: (1) To determine robust statistical relationships between snow depth, ice thickness, and freeboard distribution for a range of ice classes. Understanding these relationships is critical if we are to be able to determine either snow depth or ice thickness from space - the only viable means of determining large-scale snow and sea ice thickness, trends, and variability. (2) To quantify the role that key Antarctic sea ice processes play in controlling the ice thickness evolution and its response to climate forcing. This can only be achieved through detailed simultaneous measurements of both the surface topography and ice underside. We will obtain, for the first time anywhere, coincident 3D topography maps of both the surface (from airborne Lidar) and underside (from AUV mounted multibeam sonar) for a variety of ice types and conditions. With over 1 million individual measurements per sampling station, the richness of the data set will be several orders of magnitude more than is possible with traditional methods. This will allow us to determine, for the first time, robust statistical relationships between snow depth and ice thickness spatial variability. These data will allow a definitive assessment of the feasibility and accuracy of satellite methods for estimating Antarctic sea ice thickness and snow depth for a range of ice conditions. In addition we will deploy an unprecedented number (20) of novel ice mass balance buoys (IMBs) to monitor the evolution of the snow and sea ice throughout the annual sea ice cycle. The large number of IMB deployments will allow the first regional assessment of snow accumulation rates and ice mass balance of Antarctic sea ice. To achieve these goals we have secured a 30-day dedicated cruise aboard the James Clark Ross, scheduled for November 2010, as well as use of a BAS Twin Otter for airborne Lidar missions over ice stations and the surrounding region. These platforms, provided as part of the BAS core programme, along with support and instrumentation provided by project partners at no cost, represent a unique opportunity, and a significant leverage of over £1,000,000 of in-kind contribution. This is an unprecedented opportunity for the UK to lead a coordinated campaign to produce a definitive picture of snow and sea ice thickness distribution, and to continuously monitor the processes that control these distributions throughout the annual cycle. Our programme will deliver a major step forward in our knowledge of the snow and ice thickness distribution. It will advance our understanding of Antarctic sea ice processes and improve our ability to monitor the evolution of the ice cover and air-ice-ocean interactions on a large scale. This will allow improved representation of sea ice in large-scale and global climate models, and ultimately improve our understanding of the response of the Antarctic ice cover to current and future climate change and variability.

The most common form of dementia is Alzheimer's disease, a neurodegenerative disorder that reportedly affects 30 million people worldwide, yet for which there is no cure and only limited opportunities for accurate diagnosis and treatment. The disease is characterised by pathological hallmarks in the brain including dense amyloid protein aggregates (plaques) that are deposited outside cells in the grey matter of the brain, together with significant damage internally in neurons due to 'tangles' of abnormal tau protein. These plaques and tangles are understood to contribute to the death of neurons and the progressive degeneration of the brain. Exactly how this degeneration is mediated by these protein deposits is not yet properly understood. However, oxidative stress damage to neurons, catalysed by highly reactive chemical species known as free radicals, is understood to play a significant role. In addition, substantial evidence now suggests that the dysregulation of iron resulting in a harmful excess of reactive (ferrous) iron in the brain, is a contributing factor in the disease, and may be implicated in the processes leading to oxidative stress. Interactions between aberrant protein deposits and iron, as well as other metals, are common features of neurodegenerative disorders. In Alzheimer's disease, metal-protein interactions are hypothesized to contribute to the formation of deposits containing reactive (harmful) iron observed post-mortem in diseased brain tissue. In addition, unusual calcium bio-mineralisation has been observed within areas of aberrant protein deposition suggesting that calcium could also play a significant role in the disease. Identifying these mineral products is an important first step in describing this aspect of Alzheimer's disease. However in order to make progress in diagnosing and treating the disease, it is necessary to understand how the metal-protein interactions contribute to the disease process at a level facilitating therapeutic intervention, and the extent to which resulting iron and calcium mineralization in the protein deposits can serve as an early-stage marker of the disease. We aim to explore the chemical and mineral state of iron and calcium in Alzheimer's disease brain tissue using sensitive and specific analytical methods, as well performing experiments to investigate how metal-protein interactions can lead to the initiation and evolution (both chemical and structural) of the protein deposits. Further, we will assess how the metal-protein aggregates formed in human brain tissue, as well as those created artificially, respond to treatments with the metal chelating agents that are currently being developed as potential drug therapies for Alzheimer's and other neurodegenerative conditions. To ensure the success of this project we have assembled a unique interdisciplinary research team, with a strong international track record, to build upon our successful preliminary work in this area, applying a combination of advanced synchrotron x-ray microscopy and mass spectrometry techniques to probe nanoscale variations in the bio-inorganic chemistry occurring in Alzheimer's tissue. An important aspect of the project is that in all cases we will support our evaluation using these specialist techniques, with conventional imaging and histology. From this we will build a comprehensive description of this fundamental process in Alzheimer's disease, addressing key outstanding questions about the metal-protein interactions and how they may be modified. The parallels between aberrant protein deposition and altered handling of iron and other metals in related disorders, will allow the approach developed in this project to be readily translated, enabling equivalent impact for other forms of neurodegenerative disease. With clinical advances in chelation therapy and improved scope to track brain iron status non-invasively by clinical MRI, this project is not just timely but also urgent.

Reaction-transport systems with anomalous transport are of great practical importance because they provide realistic models for complex media such as disordered solids, random porous media, living tissues, etc. The proposed research will lead to an increased understanding of the fundamental properties of complex media with anomalous transport. Applications include anomalous ion transport in dendrites, spread of epidemics and cancer cells, electrochemical processes in solid oxide fuel cells, dispersion of human or animal groups, complex chemical reactions and contaminant transport. The proposed research has a potential economic impact for chemical and nuclear industries where traditional approaches based on reaction-diffusion models are used. The aim of this project is to establish dialogues between applied mathematicians, engineers from chemical and nuclear industries, neurophysiologists, computational neuroscientists and cell biologists. In order to ensure that they can benefit and to communicate our findings to a wide audience we intend to publish papers in relevant journals. We expect that this project will allow applied mathematicians and researchers in neurobiology and cell biology to collaborate and thus to be able to make significant advances in the areas of anomalous transport within biological systems. Collaboration with neurobiologists and experts in cell biology (Project Partners) has a potential social impact in enhancing quality of life and health. Collaboration with Dr. Santamaria from Neuroscience Institute at The University of Texas at San Antonio, USA will aim at understanding how subdiffusion in spiny dendrites regulates synaptic plasticity that underlines learning and memory. We will provide a new anomalous transport theory and the Project Partner will contribute experiments in measuring subdiffusion in Purkinje and hippocampal pyramidal cells. Collaboration with our Project Partner Dr. Chauviere from Department of Pathology, University of New Mexico, USA will aim at providing a new theoretical tool that can be potentially used in designing new therapies to control cancer cell invasion. Clinical interventions aim at retarding malignant invasion by applying chemotherapeutic drugs that increase the death rate of the cells or reduce cell motility. Our mathematical models can provide important insights into the relationship between the death rate and anomalous motility. The research project will have a realistic impact by contributing scientific knowledge and new ideas in multidisciplinary area of anomalous transport-reaction systems and extending UK research expertise into this new area of mathematics. We intend to develop innovative methodologies for fractional partial differential equations and raise awareness of the importance of these equations in industries and academia. This project will foster international research collaborations with the USA and Spain.