Our population is ageing rapidly and ageing-related cognitive deficits cause substantial impact on the society. Fundamental research in understanding how cognitive function changes across the lifespan, as well as the brain mechanisms that underlying it, is vital for providing knowledge to improve wellbeing.
Simulating human cognitive functions in rodent models, we recently developed behavioural tasks that capture the phenomena of memory decline in early aging (Gros and Wang, 2018 Neurobiology of Aging) and memory confusion across environment (Fujinaka et al, 2016 Molecular Brain). We recently show that there is a selective decline in long-term memory persistence in middle-aged animals that is reflecting an age-dependent decline in the encoding aspect of cognitive processes (Gros and Wang, 2018). However, it is yet to delineate whether the poorer encoding in ageing reflects a change in attention capability that affects the subsequent encoding in the hippocampus or reflects reduced cellular and synaptic capacity in the hippocampus, or both.
We propose to use four approaches to address this question. First, in addition to using our established task to address the memory function, we will work with Professor Verity J. Brown in University of St Andrews to incorporate attentional behaviour tasks. This will allow us to detect changes in attention and in decision making that are coincident with age-dependent memory decline. This part of project will involve training on rodent behavioural neuroscience, experimental design, data analysis, and statistics.
Second, our colleagues recently developed a genetic animal model that allows fluorescent-labelling of neural plasticity proteins in the brain (Fernández, et al, 2017 Cell Report). The Arc proteins have been widely implicated in spatial exploration and memory functions. Through collaborating with Prof Grant and Dr Komiyama in our Centre, we will use this animal model to generate high-resolution (at the synaptic level) brain imaging. We will correlate the age-related cellular and synaptic changes in the brain with the memory performance. We will identify whether the brain regions for attention or for spatial encoding are preferentially affected in ageing. Training will include tissue perfusion and preparation, cryosection, spinning-disc microscopy, imaging analysis with informaticians.
Third, we will target the key brain region identified above and verify if increasing neurotransmissions or neural plasticity in this region will improve the memory persistence in ageing. This will allow us to provide causal evidence on remediating the cognitive decline. Training will include animal brain stereotaxic surgery, micro-infusion, histology, and microscopy.
Finally, we will use computational modelling, by working with Dr Gedi Luksys, to address different mental processes involved in the tasks that animals perform, such as slow learning of the spatial task and one shot learning of associations that is tested after a delay (e.g. short-term and long-term memory). For that purpose we will extend the classical reinforcement-learning paradigm to not only address learning of reward predictions (which can be fast) but also learning of states themselves (which is slower). Then we will estimate model parameters for different animals and try to find out how aging affects specific mental processes involved in the task (as e.g. has been done for studying the effects of stress, Luksys and Sandi, 2011 Current Opinion of Neurobiology).