BBSRC EASTBIO DTP - Zoom in memory representation in the brain: from networks and cells to synapses

The decline of cognitive health with age has become an important global issue. Some of the key symptoms in cognitive ageing are confusion among environments and problems with remembering. While the majority of memory research focuses on studying how a single memory is formed, it becomes increasingly important to understand how multiple memories are stored. In particular, we need to know how we distinguish between environments based on the learning experience and elucidate the underlying biological principles of memory representation. This project will visualise how two contextual memories are embodied at the network, cellular, and synaptic levels, using interdisciplinary imaging methods. To model the confusion of environments, we use contextual conditioning in rodents and examine the impact of training protocols and behavioural histories on contextual generalisation [1]. For example, mice, like humans, can normally tell whether an environment is dangerous (i.e. a conditioned context) or safe (i.e. a neutral context). However, if they are familiarised with the neutral context before conditioning and recall this information soon after, they start to treat both contexts similarly, which occurs as rapid as 1 day after conditioning. This project will ask how two generalised memories are represented in the whole brain as well as at the cellular and synaptic levels in the hippocampus, a key region for contextual learning.

Study 1 Validate the key behavioural factors that lead to rapid memory generalisation. Current studies suggest that there are three behavioural factors, reflecting three mental processes, contributing toward the 1-day contextual generalisation: forming representations of two contexts of interest, consolidating the conditioned context, and retrieving of the neutral context during the consolidation time window. We will further investigate which one, or which pair, of these factors is required for the generalisation to occur. Our recent unpublished data show that pre-exposure to the neutral context at certain frequency is sufficient to lead to the generalisation. This will be replicated and the other processes will be verified in this project. Second supervisor: Prof Brown.

Study 2 Visualise the brain network by using in vivo ‘online’ brain imaging. We will use functional magnetic resonance imaging (fMRI) in awake mice to visualise which brain areas consume more oxygen during memory recall [2]. One salient feature of the context to which mice are very sensitive is the olfactory cue and it serves as a powerful memory trigger. We will use this feature to reactivate both memories in the fMRI scanner. The feasibility of odour-triggered brain activities has been established in our lab. By contrasting brain areas involved in retrieving the conditioned and the neutral memories, we will test the hypothesis that generalised memories are represented by overlapping brain regions. Co-supervisor: Prof Holmes.

Study 3 Visualise the cellular assemblies by using in vitro brain imaging. Immediate early genes (IEGs) are informative biomarkers to show memory-related brain regions. We will use fluorescent mRNA in-situ hybridisation to identify those cells activated by the conditioned and neutral contexts. We will particularly focus on sub-regions of the hippocampus (CA1, CA3 and dentate gyrus) which are implicated in pattern separation or completion. This will allow us to test the hypothesis that generalised memories engage a significant amount of overlapping between cell assemblies. Collaborator: Dr McHugh.

Study 4 Visualise the synaptic representation by using genetic markers. Synapses display a dynamic change with behavioural experiences and have been proposed to be an important unit for memory representation. Traditional mRNA or protein staining of IEGs cannot detect synaptic changes. We will use mice carrying genetically modified synaptic proteins that are tagged with fluorescent proteins [3] to examine the synaptic changes in the conditioned and the neutral memories. Co-supervisor: Prof Grant.
Together, this project will provide knowledge advancement on how multiple memories are processed in the brain and further inform new ways of monitoring brain ageing and tracking effective interventions in the future. (Research training provided: rodent behaviour models, fMRI image analysis, fluorescent in situ hybridisation, confocal microscopy, Home office licence training.)