Identify the cellular and receptor mechanisms in ageing-dependent memory decline

With increasingly ageing population, cognitive aging and related disorders exert substantial impact on the society. Basic research in understanding how cognitive function changes across lifespan and its underlying brain mechanisms is vital for providing knowledge on improving the wellbeing.

Some of the key symptoms in cognitive ageing are confusion among environments and problems with remembering locations of objects. Simulating these symptoms in rodent models, we have developed behavioural paradigms that capture the phenomenon of memory generalisation across contexts (Fujinaka et al, 2016). Mice, like humans, can normally discriminate between environments that are dangerous (a conditioned context) or safe (a neutral context). However, depending on the behavioural history, confusion between contexts can occur rapidly. This model will be extended to understand the impact of ageing on memory precision. Second, to capture the effect of memory decline over ageing, we have designed a rodent appetitive spatial task. Simulating our daily experience of finding objects in an environment, this task reflects age-dependent memory decline. Behavioural procedures that can facilitate memory persistence have also been identified (Wang et al, 2010, and unpublished data).

Combining these two behavioural models with brain imaging and pharmacology, this project will investigate how ageing-dependent memory decline is manifested at cellular and receptor levels, and, through this knowledge, inspect the role of NMDA receptors in memory improvement.

Aim 1: Identify behaviour factors in this training history that contribute toward the decline of memory precision over aging. This will involve training of rodent behaviour neuroscience, Home Office license (modules 1-4), experimental design, data analysis, and statistics.

Aim 2: Visualise cell assembles in the hippocampus and neocortex that represent the memory events by using fluorescent brain imaging. Training will involve fluorescent in situ hybridisation, immunohistochemistry, confocal microscopy, image acquisition and analysis.

Aim 3: Correlate the memory-activated cell assembles with ageing-related pathological markers. We will combine the behavioural paradigms with genetic mouse models that share the molecular signatures of dementia (Spires-Jones and Hyman, 2014) to characterise the behavioural phenotype of cognitive dysfunction In relation to the severity of the pathological phenotype. Training will include animal breeding, histology, and imaging.

Aim 4: Characterise the key molecular domain in NMDA receptors that is critical for memory formation and through this identify drug targets for enhancing memory persistence. Collaborating with Dr Komiyama (CCBS, University of Edinburgh), we will examine the role of C-terminals of subunits of NMDA receptors in learning and the effect of NMDA receptor agonists or co-agonists on memory. Training will include drug administration, potentially stereotaxic surgery, and overseas collaboration with National Taiwan University through funded BBSRC-IPA.