Putting episodic memory in context: cellular mechanisms of environmental processing

Lead Research Organisation: University of St Andrews
Department Name: Psychology

Abstract

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 episodi 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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description The research from this grant has opened up a new research area that is currently being further explored by my lab, collaborators and other researchers in the field. There are two principle research findings:
1. Memories for everyday events involve the integration of multiple features; what happened, where we were and on which occasion the event took place. Research from this grant showed that one part of the brain, lateral entorhinal cortex (LEC) is specifically activated when rats remember integrated features of an event.
2. LEC was shown to be necessary for any and all combinations of features needed to remember an event. This suggests LEC has a general and specific role in associative memory.
These two findings have been published (see publications) and highly cited.
The findings from these studies have formed the basis of a significant new collaboration with Professor Matt Nolan's lab. We have already secured funding for pilot work to characterise specific molecular and genetic tools to examine the LEC network in more detail. This work was very productive and will form the basis of a further grant application to BBSRC in the near future. These future experiments will allow us to examine in detail the systems neuroscience underlying memory for integrated aspects of our experience.
Finally, further work has applied these findings in collaboration with Dr Jenni Harvey and Dr Gayle Doherty examining how performance on these tasks can be enhanced by fragments of the leptin hormone. This provides a potential therapeutic target for disorders of memory such as Alzheimer's disease.
Exploitation Route As detailed above the research has had large impact on the academic community as expected and we are capitalising on this with further experiments and new collaborations. We are also exploiting this work with reference the leptin work detailed in the previous section. Leptin is not a viable drug target as the molecule is too big. We are currently examining how small fragments of the molecule (6 amino acid chains) affect memory performance. We are currently discussing how these findings might be applied through contacts in the pharmaceuticals industry both in the UK and the US.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description The grant has examined the network involved in allowing us to process the information needed to form episodic memories. Episodic memories are memories for specific events from our past. Disorders of episodic memory such as Alzheimer's disease have a profound social and economic cost. Our present research has demonstrated that the lateral entorhinal cortex (LEC) is critically involved in this type of memory. On-going research is examining the cellular mechanisms that help support this type of memory. The impact of the current work is being realised through collaborations with fellow academics and institutions such as the Dundee Drug Discovery Unit through which we are aiming to develop drugs that can be used to enhance functioning in LEC or potentially compensate for loss of LEC function. This is at a relatively early stage and the drug targets are still being refined but we expect to be able to use the research from the current grant to refine the protocols needed to test any therapeutic strategies.
First Year Of Impact 2013
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Carnegie Studentship
Amount £59,088 (GBP)
Organisation Carnegie Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2014 
End 09/2017
 
Description Carnegie collaborative grant
Amount £44,363 (GBP)
Funding ID 50243 
Organisation Carnegie Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2015 
End 09/2016
 
Description Collaboration with Dr Rosamund Langston and Dr Jenni Harvey 
Organisation University of Dundee
Department Division of Neuroscience
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have collaborated with Dr Rosamund Langston at the University of Dundee to develop new tests of episodic memory in rats and mice. I have also collaborated with Dr Jenni Harvey to examine the potential use of leptin as a therapeutic target for Alzheimer's disease. I provided expertise in behavioural testing of rodents, immediate early gene imaging and surgcial manipulation of the brain.
Collaborator Contribution Dr Langston provided expertise in behavioural testing of rodents. Dr Harvey provided expertise in synaptic plasticity.
Impact Numerous conference presentations. 2 published papers : Wilson, D. I. G., Langston, R. F. , Schlesiger, M. I. , Wagner, M. , Watanabe, S. & Ainge, J. A. (2013). Lateral entorhinal cortex is critical for novel object-context recognition. Hippocampus, 23, 352-366. Ainge JA, Langston RF. (2012). Ontogeny of neural circuits underlying spatial memory in the rat. Frontiers in Neural Circuits. 6: 1-9.
 
Description Collaboration with Professor Matt Nolan 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have contributed expertise in the behavioural testing of rodents specifically in the use of tests that are dependent on the medial temporal lobe netowrk of the brain.
Collaborator Contribution Professor Nolan has provided molecular and genetic tools that he developed in his lab.
Impact We have secured a collaborative grant from the Carnegie Trust.
Start Year 2015
 
Description Alzheimer's Research Uk meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact I gave a talk at the meeting of Alzheimer's Research Uk which has resulted in a number of collaborative projects getting underway.
Year(s) Of Engagement Activity 2010
 
Description Bright club presentation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Bright club is a stand-up comedy night where scientists communicate their research in short comedy sets. The events are usually attended by approximately 50 people including members of the public, students and staff of the university. These are also recorded and released as youtube clips allowing a greater interaction with the public.

We have had a number of enquiries from members of the audience about the research and hope to organise a lab visit.
Year(s) Of Engagement Activity 2013,2014,2015
 
Description First chances 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact First chances is a programme run by the University of St Andrews that focuses on pupils from local schools that have low progression rates to university. This allows us to interact with students who might not normally consider university as an option. I have presented work from the grant at the workshop and the feedback from pupils was very positive. This is one of a number of factors which has helped the university in its aim to widen particiaption to higher education.
Year(s) Of Engagement Activity 2009,2010,2013,2014
 
Description Teachers together 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Approximately 50 teachers from across Scotland come to the University to be introduced to the cutting edge research in different disciplines. I have presented the work carried out in the grant and this has resulted in lively discussions on the nature of memory and how this is taught in the psychology undergrdaute degree. The teachers feedback was very positive.
Year(s) Of Engagement Activity 2009,2010,2012,2013,2015