Delineating the neural basis of sequence memory in the rat

Our ability to remember the order in which things happen, or the order in which we encounter items in our daily lives is a fundamental part of our memory. For example when we travel from one place to another, one way to remember our route is to recall the series of landmarks we pass along the way. Similarly when we recount a personal experience or event, any episode will involve a sequence of events occurring in a particular order. Not only is sequential information important for recalling the past, but it is also crucial for planning and organising future behaviour. The hypothesis of this proposal is that sequence memory depends on three key brain regions, the perirhinal cortex, the medial prefrontal cortex and the hippocampus, however each region may make a different contribution to sequence memory depending on the number and position of the to-be-remembered items in the sequence. To test this hypothesis we will combine state-of-the art molecular biology technologies with specific behavioural tasks that isolate the different types of sequence information which can be used. We will also explore the hypothesis that the perirhinal cortex, medial prefrontal cortex and hippocampus must work together to form a neural circuit during the learning of a sequence of items, and that the ability to store this information depends on a specific molecule, CREB within the nucleus of cell. The results of this research willl ultimately allow a greater understanding of how we are able to learn and store memory information in the brain.

The aim of this research proposal is to examine the neural substrates of sequence memory. We have shown that memory for a sequence of two objects depends upon a neural network involving the medial prefrontal cortex (mPFC); the hippocampus (HPC) and the perirhinal cortex (PRH), however the precise role played by each of these structures is currenty unknown. Therefore our focus will be to investigate the specific contributions of different brain regions to sequence memory and assess whether the role of these structures differs depending on the type of information to be remembered. To answer these questions we will use state of the art molecular biology tools combined with behavioural techniques that isolate specific types of order information to be learned. The approach to be ued will centre on using retrogradely transported viral vectors to selectively mark those neurons which project to other regions within the neural circuit. These lentiviral vectors have been designed to express specific genes which will enable us to reversibly silence those marked neurons within each brain region of the circuit. Issues to be investigated include: 1) the importance of the PRH, mPFC and HPC in sequence memory 2) How and when do these regions interact 3. Is CREB (cyclic AMP response-element binding protein) dependent transcription necessary for the formation of sequence memories within the PRH or mPFC 4) to assess whether the functional connectivity in the network is modulated by CREB-mediated transcription

Who will benefit The research will be of benefit to a) commercial companies seeking to develop treatments that facilitate learning and memory. b) patients suffering form memory loss and their families. c) charities and organisations seeking to support patients with memory disorders and their families. d) the research staff employed on the grant will benefit from training in multidisciplinary approaches to understanding memory processes as well as training in transferable skills. e) those in the field of educational neuroscience, wishing to understand how to maximise learning potential. f) members of the general public with an interest in memory function. How will they benefit The insights gained from this research will help ultimately in understanding memory loss that occurs with ageing, dementia and trauma. Thus the research could provide therapeutic targets of benefit to commercial companies seeking to develop treatments that facilitate learning and memory. Progress in understanding memory requires a global perspective on brain function, i.e. it is not sufficient to study one brain region alone. A more global analysis will provide a more accurate picture of the neurobiology of memory, but also highlight the range of brain structures that when damaged contribute to memory loss in disease. The impact of the research on patient groups and their families will be in terms of potential new therapies and also in being able to provide a better understanding of what is happening in these distressing conditions. Further by providing insights into memory function, the research will enable charities which support patients with memory dysfunction, to realise their mission of providing education and help to patients. This project will involve the use of rodents, as they offer the opportunity to make highly selective manipulations of the brain regions are crucial to sequence memory and recognition memory as a whole. Given the proven similarities between rodent and human recognition memory the findings from this project will prove applicable to understanding human memory. Such knowledge is of wide interest to the general public and thus be relevant to display and disseminate through science museums, to audiences of school-age children and interested adults. Staff employed on the project will be trained to use the specific scientific techniques necessary for the successful completion of the project. Staff will also gain a number of transferable skills such as time/project management; communication skills training (oral & written presentations) to scientific and general audiences through public engagement opportunities; team working and networking. What will be done to ensure that they have the opportunity to benefit from this research? The research will be disseminated through peer reviewed journals within the standard timescale for this field. The research will be presented to the scientific community at national and international conferences. To realise the potential benefits of this research to private companies, Dr Warburton has connections and collaborations with pharmaceutical companies (e.g. GSK )with an interest in enhancing learning and memory and ameliorating memory impairments. Dr Warburton is a member of the British Association of Psychopharmacology, British Neuroscience Association, and the South West Memory Group, which provide networking opportunities with members of the pharmaceutical companies and with other scientists. The impact of the research will be increased through Dr Warburton's collaborative projects. These include collaborations within Bristol (Department of Anatomy, Department of Medicine, Frenchay Hospital) and with other Universities (University of Cardiff). Dr Warburton has extensive experience in presenting the research to the scientific community and wider public audiences including school children through public engagement seminars organised by Bristol Neuroscience