Neural mechanisms of memory updating

While there have been several decades of experimental research into the neurobiological mechanisms of memory, significant areas remain poorly understood. One of these is the understanding of how the cellular mechanisms in the brain enable memories to be modified. An emerging high-profile approach to the behavioural updating of memories may be useful in the future treatment of memory disorders such as posttraumatic stress and compulsive reward-seeking. However, very little is known about the underlying neurobiological mechanisms of this process.

This project will focus on the behavioural updating of a specific form of memories. These are contextual fear memories, which are robust and easily studied. Moreover, their underlying mechanisms of initial acquisition/consolidation and persistence/reconsolidation are well-described. We have recently demonstrated that established contextual fear memories can be modified and diminished, simply by briefly retrieving the memory and then a short time later subjecting it to an extinction procedure. This leads to a long-lasting revaluation of the previously fear-conditioned context as now being safe. We have data showing that this process relies upon the memory being "reactivated" at retrieval, and suggesting that it recruits a prolonged phase of neurobiological activity in order to modify the memory. The current project will test specific hypotheses based upon these initial findings:

1. The timecourse of reactivation-induced cellular processes is prolonged by subsequent extinction training.

2. This prolonged cellular activity is in the same neurons that at initially induced by memory reactivation.

3. The prolonged cellular activity means that the memory is vulnerable to disruption for a longer period.

4. The reliance of the behavioural memory updating upon memory reactivation means that it should be possible to pharmacologically stimulate memory reactivation even under behavioural conditions that do not normally support this process.

In order to test these hypotheses, we will use a multidisciplinary approach of behavioural testing, ex vivo molecular neurobiology, and in vivo molecular and behavioural pharmacological analyses. The investigators are experienced in all these approaches, though they have not previously been combined in a reconsolidation or behavioural modification setting.

The nature of the hypotheses and the approaches needed to test them require the use of experimental animals. Rats are the least sentient species that retain a level of biological similarity to humans such that our conclusions can reasonably be applied to the understanding of human learning and memory.

While the immediate aims of the project are geared towards a greater basic understanding of learning and memory processes, this research has potential clinical implications in the understanding of persistent memory-based disorders such as post-traumatic stress, specific phobias and drug addiction. Indeed, the high-profile nature of the recent papers on behavioural memory updating is due to its implications both for the basic understanding of learning and memory and its potential translational impact.

Memories can be updated long after they are initially acquired. In recent years, the process of memory reconsolidation (plasticity occurring after the reactivation of a memory through retrieval) has been proposed as a primary mechanism of memory updating. As such, disruption of reactivation-induced plasticity by pharmacological means leads to amnesia. Even more recently, a purely behavioural analog of pharmacologically-induced reconsolidation impairment has been described. This involves first reactivating the memory and then shortly after extinguishing it. We have demonstrated that this approach is effective for both appetitive pavlovian memories and hippocampal contextual fear memories.

In the contextual fear memory setting, we have recently demonstrated that the behavioural memory updating process depends upon successful memory reactivation. Moreover, we have emerging evidence that the updating process involves a prolonged phase of neurobiological activity (phosphorylation of the kinase IKKalpha). This project will test specific hypotheses using a multidisciplinary approach.

1) Time course analysis of IKKalpha phosphorylation will be conducted using western blots in order to test the hypothesis that there is an extended phase of phosphorylation induced by the addition of extinction training after memory reactivation.
2) Combined double immunofluorescence and dual in situ hybridisation/immunohistochemistry will be used to test the hypothesis that the extended IKKalpha phosphorylation is in a single population of neurons.
3) In vivo molecular inhibition of pIKKalpha will be used to test the hypothesis that the extended phase of cellular activity renders the memory vulnerable to disruption for a longer time window.
4) In vivo behavioural pharmacology will be used to test the hypothesis that contextual fear memories can be stimulated to undergo reactivation and hence behavioural memory updating, even under conditions that do not usually trigger the process.

We are committed to the dissemination of our research to a wide audience. Our work has been reported previously in popular magazines and we have contacts within the excellent Birmingham University Public Relations Office. We will work with them to communicate our results via diverse media such as newspaper, magazines, and TV and radio. Both the PI and researchers in the lab are involved in the activities of Understanding Animal Research, promoting the value of animal-based research (within the context of the importance of our own research) to school-age children. Moreover, the University of Birmingham is making increasing efforts to engage the public during the Dana Foundation-associated Brain Awareness Week, through which our findings will also be publicised.

The results of this research will have potential implications for the application of reconsolidation-based treatment strategies for Posttraumatic stress disorder and other memory-related psychiatric conditions. Such strategies rely upon the successful destabilisation of the maladaptive memories. Through the research in this project, the mechanisms of memory destabilisation will be delineated. This may lead to a greater understanding of how successfully to destabilise maladaptive memories. The focus also upon purely behavioural methods of memory modification has parallels to behavioural therapeutic approaches to the treatment of the same disorders.

Within the University of Birmingham, we are involved in discussion groups and collaborations, both within the School of Psychology and also in the Medical School. The School of Psychology has a strong Clinical Psychology group with expertise in Cognitive Behavioural Therapy, to which the behavioural element of this work may become relevant. Our links to the Clinical and Experimental Medicine group in the medical school enables our work to be disseminated effectively towards translationally-relevant clinical settings. The close relationship between the Medical School and the local NHS Trust, as well as the Royal Centre for Defence Medicine, is a particular advantage in ensuring that the results of our work are made known to relevant clinical researchers and practitioners.

Finally, it should be noted that the application of reconsolidation-based treatments, while promising, is in its early stages, with ongoing preliminary trials using beta blockers in relation to PTSD. The nature of this research means that its potential impact is unlikely to be realised in the near future.