Retrieval-mediated learning: Analysis of a model system

Aristotle argued that when events are presented in close succession, the ideas or memories corresponding to those events become linked - a view that was echoed and embellished in the principles developed by the British associationists of the eighteenth century. This simple form of associative learning provides organisms with a powerful means of representing the causal texture of their environments: The fact that one event succeeds another in the world can be represented by an association in the brain between the memories corresponding to those events. However, associations can also form between the retrieved memory of one event, that is not physically present, and another event that is in the world. The existence of retrieval-mediated learning means that the content of associations can be arbitrarily related to real-world relationships, and this form of learning is not well understood. Yet, understanding retrieval-mediated learning is important because it could provide a substrate for the symptoms of some pathological conditions. For example, retrieval-mediated learning could provide a basis for the 'loosening of associations', and their oft-bizarre nature, in people with Schizophrenia and in those with various forms of Dementia (e.g., Alzheimer's Disease); and for related memory difficulties that become a nuisance during healthy aging. While our understanding of the role of the brain in association formation involving the succession of events in the world is well developed, the neural structures that underlie retrieval-mediated learning are largely unknown. In this project we will test the theory that the hippocampus and a related cortical structure, the enthorhinal cortex, play a central role in retrieval-mediated learning. This theory is primarily based on the results of pilot studies using a novel combination of behavioral assays for retrieval-mediated learning and selective manipulations of the brain; but the theory is also broadly consistent with the observation that the hippocampus and enthorhinal cortex are atypical in people with Schizophrenia and Dementia. Our pilot research has revealed that the hippocampus is involved in some forms of retrieval-mediated learning, but that it is not involved in learning about real-world relationships between stimuli. However, a great deal of further research is needed to understand how retrieval-mediated learning takes place, the neural mechanisms that support it, and the brain systems involved. The results of this project will have both theoretical significance and the potential to contribute to our understanding of mnemonic abnormalities in human disease states and in healthy aging.

Our understanding of conventional associative learning, involving real-world relationships, is well developed at a variety of levels of analysis. However, associations can also form between the memories of two stimuli even when they share no corresponding real-world relationship. For example, a rat will form an association between food and illness when the memory of food has been retrieved (by presentation of a stimulus previously paired with food) and this retrieved memory is coincident with illness. This type of retrieval-mediated learning vastly increases the range of conditions under which associations can form, and means that their content can be arbitrarily related to real-world contingencies. Indeed, retrieval-mediated associations could provide a substrate for the symptoms of some pathological conditions. For example, retrieval-mediated learning could provide a substrate for the 'loosening of associations' and their oft-bizarre content in people with Schizophrenia and various forms of Dementia (e.g., Alzheimer's Disease); and for related mnemonic difficulties that become prevalent during healthy aging. The neural basis of retrieval-mediated associations is unknown. However, psychobiological models have identified the hippocampus and enthorhinal cortex as candidate structures that might support some forms of memory retrieval; and these structures are atypical in both people with Schizophrenia and Dementia. Our pilot research indicates that the rat hippocampus plays an important role in retrieval-mediated learning and provides support for a specific neural network model: blocking either synaptic transmission or synaptic plasticity in the hippocampus abolishes retrieval-generated learning involving successfully stored configural memories. The overarching objective of this project is to understand how retrieval-mediated learning takes place, the brain systems involved, and the neural mechanisms that support it.

The School of Psychology at Cardiff University has an excellent reputation for research. In the most recent RAE the profile was: 4*=25%, 3*=45%; with the RAE panel highlighting animal learning and neuroscience as being a particular strength. The facilities for conducting animal research within the Behavioural Neuroscience Laboratory (BNL) are commensurate with this profile. The research would help to support an internationally recognized laboratory in the field, and serve as an enabling condition to continue to train the calibre of postgraduates (and RAs) who go onto take up academic positions of various types. The research will benefit the academic life of the School of Psychology, the members of the BNL, and those undergraduates and postgraduates who receive training therein. The training received by people who are directly (and indirectly) involved in the research (e.g., research design and reporting, neuroscience methods, statistical analysis) will benefit the broader scientific community within and outside academia. The applicants publish in leading specialist and more general international journals. We think that the research supported by this project would be of interest to general and well as specialist journals; and we will present it at a broad range of conferences (e.g., Associative Learning Symposium, Experimental Psychology Society, Society for Neuroscience). The research will thereby benefit the immediate research community and broader scientific community both in academia and industry. The development of sophisticated behavioural assays for cognitive processes in animals is a central aspect of behavioural neuroscience; and understanding the neural bases of these processes is fundamental to translational neuroscience. The PI and Co-PI have links with industrial collaborators (e.g., Eli Lilley, MSD) that gives them the potential to exploit their research and research expertise. The research will benefit these collaborators through their future use of both the knowledge gained and assays developed. Moreover, Cardiff University provides structural support for commercialising both the outcomes of research and expertise, and for knowledge transfer partnerships (Cardiff: Public relations http://www.cf.ac.uk/prcom/whatwedo/index.html http://www.cf.ac.uk/racdv/index.html. The School of Psychology regularly organizes workshops and visits by children (aged 9-18) from schools and colleges, participates in science open days, and is involved in other outreach activities. The PI plays a central role in these activities, and encourages postgraduates within the School to do the same, in his role as Director of Postgraduate Research. In the longer term, the research has the potential to contribute to our understanding of the mnemonic substrates that underlie the symptoms of a number of debilitating human diseases (e.g., Schizophrenia and Alzheimer's Disease), and some of the commonly experienced memory difficulties associated with healthy aging.