Putting episodic memory in context: cellular mechanisms of environmental processing

When we are asked to think of a memory we will often describe an important personal event such as a graduation, birthday or the first day of a new job. In memory research these types of memories for specific events or episodes from our lives are called episodic memories. These memories influence the kind of people we are and the way that we think about ourselves. Many of us have had the misfortune to experience how the loss of this type of memory can affect an elderly relative. In some types of dementia like Alzheimer's disease (AD) sufferers lose the ability to form new episodic memories. Patients with AD can remember detailed events from 20 years ago but have severe problems when asked to remember what happened to them earlier that day. This has a major impact on their ability to lead independent lives. In the UK approximately 465000 people have AD and this number will increase as the proportion of older people in our society increases. It is estimated that £338 billion pounds each year is spent across the world in providing care and treatment for people with dementia. Clearly this is a problem that needs addressing soon to reduce the burden on the NHS and the UK tax payer. One way to go about tackling the disease is to examine how the brain usually processes episodic memory as this will allow us to see which areas and mechanisms within the brain go wrong in the disease. Episodic memories are formed by combining the features of an event. These include where we were, what we were doing at the time and the features of the environment (e.g. was it inside or outside?). An area of the brain called the hippocampus is important for combining these pieces of information. People who have damage to their hippocampus have problems creating new episodic memories. However, we do not know how these different types of information reach the hippocampus. If we can find out the pathways in the brain that provide the hippocampus with the information that it needs to form episodic memories then we can start to examine further how these are affected in AD. At the moment we know a lot about how the brain processes spatial locations. The parts of the brain that allow us to know where we are have been described in the last 40 years in a lot of detail. However, we do not know how the other parts of episodic memory like the details of the environment in which we were are processed. The experiments in this application will address this problem by examining which parts of the brain are activated when changes to the features of an environment are experienced. We will go on to see how individual cells in these areas of the brain react to changes in the environment. Our specific aims are: 1. To determine which areas of the brain are active in response to the manipulation of contextual features and critical for the retrieval of memory for contextual information. 2. To determine which mechanisms within these brain areas are used to process contextual information. By addressing these aims we well gain a much better understanding of the mechanisms in the brain that process episodic memory. This will provide a tool for companies that produce treatments for these diseases to test their treatments effectively by examining these processes in models of the diseases. Ultimately it may help to reduce the burden on the NHS by helping to provide treatments for AD that target the early stages of the disease and so prevent significant brain damage from occurring.

Episodic memory is the memory for specific events in our past. These memories include information about where we were, what we were doing and the features of the environment that we were in (e.g. size and shape of the room we were in). The proposed experiments will examine how the non-spatial contextual features of specific events are processed by the brain. This will be done using a combination of techniques. We will manipulate contextual features of the environment (e.g. objects found in the environment, colour of the walls etc.) and use immediate early gene imaging to see which parts of the brain are active when memories for contextual features are recalled. We will go on to examine which structures are critical for processing contextual information by lesioning the parts of the brain that were active in the IEG experiments and examining the effect on memory for contextual features. This will address our first objective: 1. To determine which areas of the brain are active in response to the manipulation of contextual features and critical for the retrieval of memory for contextual information. Finally we will examine the mechanisms within the critical structures by recording from groups of individual neurons within these structures. This is a technically challenging method but in recent years has provided great steps forward by allowing researchers to correlate the activity of individual neurons and groups of neurons with ongoing behaviour at a very high temporal resolution. The techniques we use allow us to record from large numbers of cells from multiple brain areas and so we can start to analyse how networks of cells are organised to facilitate behaviour. This will address our second objective: 2. To determine which mechanisms within these brain areas are used to process contextual information. This combined approach will allow us to examine the neural basis of contextual processing at both a systems and a cellular level.

Who will benefit from this research? A number of groups will benefit from the knowledge generated from the proposed research: 1. Individuals suffering from deficits in episodic memory, their families, and support networks (including charities). 2. Commercial companies developing treatments for conditions such as Alzheimer's disease (AD), and Mild Cognitive Impairment, which affect episodic memory. 3. The National Health Service. 4. Companies developing drugs to enhance learning or memory. 5. Educators and students. 6. The individuals working on the project. How will they benefit from this research? For individuals suffering from deficits in episodic memory an understanding of how the brain processes episodic memory will lead to better understanding of how damage to specific areas of the brain contribute to cognitive deficits. Moreover, the research has the potential to benefit these groups by contributing to the development of treatments for memory disorders (see below). Episodic memory is on the of the first cognitive processes to be affected in AD and so by helping to understand its neural basis the proposed research has the potential to provide a means of assessing the impact of treatments on early symptoms of the disease This will be of great benefit to companies developing treatments for dementia and AD. Treatments aimed at early symptoms have the potential to stop the disease progression before significant brain damage occurs. This could not only transform the prognosis for patients diagnosed with AD but also dramatically reduce the burden placed on the NHS. At present around 465,000 people in the UK suffer from AD and this puts a large strain on the NHS as patients with AD are severely compromised in their ability to lead independent lives and require extensive care. This number will increase in the coming years as the UK has an ageing population and so numbers of patients with dementia and other age related neurodegenerative diseases will increase. This research consequently has potential benefits not only for the patient population but also the NHS and UK taxpayer. The timescale for this type of impact is relatively quick. A number of rodent models of AD already exist and so the findings from the proposed research could be applied to this type of model and used to test treatments for AD as soon as the research is finished and published. I have active collaborations with members of the Alzheimer's Research Trust who have expertise in using animals models of AD and so we would plan to use the findings from the current grant to further our knowledge of the early causes of the disease and potential treatments. For companies developing drugs to enhance learning and memory this research could provide information regarding potential therapeutic targets. Ultimately it may be possible to produce drugs to aid those with poor memory. Realistically the timescale for this type of project is long as we still have a lot to discover about memory processes. The proposed research will provide great insight into episodic memory but this would have to be combined with other research to see how episodic memory networks are integrated into other neural systems. For educators and students, a better understanding of mechanisms of memory will inform about effective strategies for teaching and learning. This again is a long term goal as findings will have to be incorporated into our knowledge of how neural systems support all types of learning not just information regarding episodic memory. For the individuals involved in the project, the research will provide training and expertise in in vivo systems-level research skills, which are under-represented in the UK. They will also gain valuable transferable skills in project planning and management, team work, and communication, both to scientific and lay audiences.